Skip to main content
Download PDF
Download ePub

Pomegranate (Punica granatum L.) peel extract ameliorates metabolic syndrome risk factors in patients with non-alcoholic fatty liver disease: a randomized double-blind clinical trial

Nutrition Journal volume 22, Article number: 40 (2023) Cite this article

Abstract

Introduction

Non-alcoholic fatty liver disease (NAFLD) is a metabolic syndrome (MS)-related liver disorder that has an increasing prevalence. Thus, the aim of our study is to evaluate the effects of pomegranate peel extract (PP) supplementation on hepatic status and metabolic syndrome risk factors.

Methods

In phase one, the hydro-alcoholic extraction of the peel of 750 kg of pomegranate (Punica granatum L.) was performed by the soaking method. Then, in phase two, NAFLD patients received 1500 mg of placebo (n = 37) or pomegranate peel capsules (n = 39) with a 500-kcal deficit diet for 8 weeks. Gastrointestinal intolerance, dietary intake, lipid and glycemic profiles, systolic and diastolic blood pressure, body composition, insulin resistance indexes, and elastography-evaluated NAFLD changes were followed.

Results

The mean age of participants was 43.1 ± 8.6 years (51.3% female). Following the intervention, the mean body weight (mean changes: -5.10 ± 2.30 kg), waist circumference (-7.57 ± 2.97 cm), body mass index (-1.82 ± 0.85 kg/m2), body fat index (-1.49 ± 0.86), and trunk fat (− 3.93 ± 3.07%), systolic (-0.63 ± 0.29 cmHg) and diastolic (-0.39 ± 0.19 cmHg) blood pressure, total cholesterol (-10.51 ± 0.77 mg/dl), triglyceride (-16.02 ± 1.7 mg/dl), low-density lipoprotein cholesterol (-9.33 ± 6.66 mg/dl; all P < 0.001), fat free mass (− 0.92 ± 0.90 kg; P < 0.003), and fasting blood sugar (-5.28 ± 1.36 mg/dl; P = 0.02) decreased significantly in PP in contrast to the placebo group in the raw model and when adjusted for confounders. Also, high-density lipoprotein cholesterol (5.10 ± 0.36 mg/dl), liver steatosis and stiffness (− 0.30 ± 0.17 and − 0.72 ± 0.35 kPa, respectively, all P < 0.001) improved in the PP group. However, fasting insulin (P = 0.81) and homeostatic model assessment for insulin resistance (HOMA-IR) (P = 0.93) were not significantly different when comparing two groups during the study in the raw and even adjusted models.

Conclusion

In conclusion, 1500 mg pomegranate peel extract along with a weight-loss diet improved metabolic syndrome risk factors and reduced hepatic steatosis in patients with NAFLD after 8 weeks.

Peer Review reports

Introduction

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disease ranging from isolated steatosis to steatohepatitis (NASH), which can eventually progress to NASH-fibrosis, cirrhosis and hepatocellular carcinoma [1]. It is also known as a multi-system disease affecting various extra-hepatic organs, subsequently leading to high morbidity and mortality, with global prevalence estimated between 25 and 38% [1, 2]. The detailed pathophysiology of NAFLD is complicated and involves heterogeneous exogenous and endogenous factors, which involved lifestyle, nutritional factors, lipogenesis, cell death, chronic low-grade inflammatory response and an altered gut microbiome [3, 4]. NAFLD is an obesity-related metabolic liver disorder considered a hepatic element of metabolic syndrome (MS) and has been associated with obesity, insulin resistance, type 2 diabetes, dyslipidemia, hypertension, and cardiovascular disease [5]. Currently, there are no approved drugs to specifically target or treat NAFLD. Weight loss, achieved through change in dietary and physical activity behaviors is the recommended treatment for NAFLD, which can reduce liver fat, inflammation and fibrosis [6, 7]. The Mediterranean diet has been effective in reducing metabolic syndrome and CVD risk factors, as well as NAFLD improvement by reduction of the severity of hepatic steatosis [8,9,10]. A plant-based diet, with significant fiber, anti-oxidants, vegetable proteins, polyunsaturated, and monounsaturated fat have been emphasized [11].

Several studies in recent years have revealed that dietary components or medicinal plants (with pharmacological capabilities) could be thought of as a substitute for traditional NAFLD management methods [12,13,14,15,16].

Pomegranate fruit (Punica granatum L.) has a high level of various phytochemicals such as polyphenols, fatty acids, amino acids, tocopherols, sterols, terpenoids, and alkaloids, due to their therapeutic effects such as anti-inflammatory, antioxidant, and antineoplastic, reducing blood glucose, fat-lowering, anti-hypertension and antimicrobial effects in animal and clinical trials on NAFLD or other diseases [17,18,19,20,21,22,23]. The peel of the pomegranate fruit contains the highest amount of phytochemicals in it. About 48 phenolic compounds (flavonoids, hydrolyzed tannins such as ellagitannins and galagyl esters, anthocyanins, gallotannins, hydroxycinnamic acid and hydroxybenzoic acid) have been identified in the skin and other parts of pomegranate [17].

A lot of evidence shows that hydrolysable polyphenols in pomegranate red peel, especially ellagitannins, are the most active antioxidants among the tannins in it, and others such as punicalagin, panicalin and gallic acid have antioxidant and pleiotropic biological activities and especially act synergistically as a strong antioxidant network that causes various beneficial effects [24, 25] (Fig. 1). Also, recent studies show that pomegranate peel, in addition to its antioxidant properties, can be a promising candidate for the treatment of non-alcoholic fatty liver by maintaining the balance of the microbiome of the digestive system and influencing the expression of key genes in the pathways of inflammation and liver lipogenesis and inhibiting the signaling pathways in liver fibrogenesis [26, 27]. Thus, the aim of our study is to evaluate the effects of pomegranate peel extract (PP) supplementation on hepatic status and metabolic syndrome risk factors including lipid profile, blood pressure, insulin and fasting blood glucose, and body composition data such as weight, waist circumferences, body fat percent, trunk fat and lean body mass in patients with non-alcoholic fatty liver disease.

Fig. 1
figure 1

Some of active phenolic contents of Pomegranate Peel

Full size image

Materials and methods

Study design

The present study constitutes a randomized, double-blind, controlled clinical trial aimed to examine the impact of pomegranate peel extract, administered as a dietary supplement over an eight-week duration, on various parameters including inflammatory and oxidative stress markers, nutritional status, and liver fibrosis and steatosis in individuals diagnosed with non-alcoholic fatty liver disease (NAFLD). The study was conducted in Mashhad, Iran, spanning from December 2021 to November 2022, and adhered to the ethical guidelines set forth in the Helsinki Declaration. Approval for the study was obtained from the ethics committee of Mashhad University of Medical Sciences (ethics code: IR.MUMS.MEDICAL.REC.1400.195 and IRCT20210726051988N1).

The study had two phases; first, the extraction of pomegranate peel (PP) hydro-alcoholic extract; second, the randomized clinical trial. The study participants were selected from patients with NAFLD who sought medical attention at the Nutrition Clinic and fulfilled specific inclusion criteria. These criteria encompassed individuals between the ages of 18 and 60 years, diagnosed with liver fibrosis and steatosis through elastography or liver fibro scan, possessing the ability to read and write, and providing informed consent by completing the requisite form. Conversely, individuals were excluded from participation if they were pregnant or lactating, exhibited morbid obesity (with a body mass index exceeding 40), had a history of alcohol consumption surpassing 20 g per day for women or 30 g per day for men, suffered from any immune disorder, including autoimmune disorders, cancer, or human immunodeficiency virus (HIV) infection, experienced liver or kidney failure, presented with other liver diseases such as hepatitis or alcoholic liver disease, utilized hepatotoxic drugs such as sodium valproate, possessed a history of food allergies to pomegranate or herbal supplements, or had undergone bariatric surgery for weight loss.

Throughout the study, participants who voluntarily withdrew from the research, became pregnant, developed hypersensitivity to either the pomegranate peel extract or the placebo, or exhibited less than 70% compliance with their assigned treatment regimen were excluded from further analysis.

At the study’s initiation, all participants provided written informed consent. Demographic and socio-economic information, including education level, family size, housing status, occupation, medical history, and medication and supplement usage, was collected through a questionnaire. The sample size calculation for each group was based on Soleimani et al.‘s research on non-alcoholic fatty liver disease (NAFLD) [28], utilizing a formula for comparing proportions of a qualitative attribute in independent statistical populations. This calculation determined that 39 NAFLD patients were needed per group, considering a significance level (α) of 0.05, study power of 80%, and accounting for a 20% dropout rate [29].

To minimize heterogeneity among the study groups, a blocked randomization design was implemented to allocate participants randomly. The blinding principles were strictly adhered to, ensuring that both the drug and placebo were indistinguishable in terms of color, size, smell, and packaging. This maintained blinding throughout the study and statistical analysis, with only the pharmacist possessing knowledge of the allocation. To conceal the random allocation, coded boxes were utilized. This ensured that neither the participants nor the researchers were aware of the group assignments until the conclusion of the study.

Demographic and socio-economic information about the individuals was obtained using a specific questionnaire at beginning the study. The questionnaire included questions about education level, family size, housing status, occupation, medical history, and use of medications and supplements.

Fatty liver evaluation

In this study, liver tissue imaging was conducted utilizing the SuperSonic Aixplorer device (SuperSonic Imagine S.A., Aix-en-Provence, France) and the two-dimensional elastography technique. To assess the severity of steatosis, numerical values for the hepatorenal sonographic index were derived from the research conducted by Webb et al. Specifically, the values of 49.1, 86.1, and 23.2 were assigned to mild (grade 1), moderate (grade 2), and severe (grade 3) steatosis, respectively [30].

Biochemical evaluations

At the beginning and end of the study, 5 cc blood samples were collected from all participants who had fasted for 10–12 h. Serum samples were obtained by centrifuging the blood samples at 3000 rpm for 15 min and immediately stored at -20 °C until testing. Using the Alpha Classic AT Plus analyzer, serum levels of fasting blood glucose, triglycerides, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were evaluated by the colorimetric method. The serum insulin level was measured by the quantitative luminescence method using a diagnostic kit from “Snibe Company” (Shenzhen, China) and the Maglumi 800 analyzer in specialized laboratory. The triglyceride-to-glucose ratio was obtained by logarithmically multiplying the product of triglycerides and half of the fasting plasma glucose, and values greater than or equal to 4.49 were considered indicative of insulin resistance [31]. Additionally, the serum total cholesterol to high-density lipoprotein cholesterol ratio was calculated at the beginning and end of the study.

Food intake assessment

In this study, dietary intake was assessed using a three-day food record, including two weekdays and one weekend day. To accurately assess the participants’ dietary patterns, they were asked to complete a three-day food record at the beginning of the study and at the end of each month. The energy and nutrient intake of each participant were then calculated using Nutritionist IV software (N-Squared Computing, Salem, OR, USA).

Anthropometric assessment

In present study, the participants’ height and weight were measured following standardized procedures [32]. Height measurements were obtained using a wall-mounted stadiometer (Seca 206, Germany) with a precision of 0.1 cm, while weight measurements were recorded using a digital floor scale (Seca 813, Germany) with a precision of 0.1 kg. These measurements were taken without shoes and with minimal clothing to ensure accuracy. To assess body composition, the Tanita BC-418 body composition analyzer (Tanita Corporation, Tokyo, Japan) was employed. Additionally, waist circumference was measured with a flexible, non-stretchable tape measure. The measurement was taken at the midpoint between the lower border of the rib cage and the iliac crest while the participants stood with their feet close together and no pressure applied to the body surface. The waist circumference measurement was recorded with an approximate precision of 1.0 cm [32].

Blood pressure assessment

The blood pressure of the participants was measured at each visit by a non-dominant person using a calibrated and standardized mercury sphygmomanometer (ALPK2) with a standard cuff size of 12 × 25 cm. Blood pressure was also measured using a digital medical device as a secondary measurement method.

Physical activity assessment

Data on the participants’ physical activity levels were collected using the International Physical Activity Questionnaire-Short form (IPAQ) [33]. The Persian version of this questionnaire has been validated and shown to be reliable [34, 35]. The questionnaire is designed for individuals between the ages of 18 and 65 and encompasses inquiries regarding the duration and intensity of physical activities undertaken over the past seven days. The IPAQ assesses the number of hours engaged in physical activity at different intensities, including walking, moderate-intensity activities, and vigorous-intensity activities. The energy expenditure from physical activities over the course of a week is quantified using Metabolic Equivalent Task (MET) minutes per week. The total MET-minute/week value is obtained by summing the walking, moderate, and vigorous MET-minute/week values. Participants’ physical activity levels were classified as low, moderate, or high based on their total MET-minutes per week. Less than 600 MET-minutes per week were classified as low activity, 600 to 3000 MET-minutes per week as moderate activity, and more than 3000 MET-minutes per week as high activity.

Gastrointestinal evaluation

Potential gastrointestinal symptoms, were evaluated using the Gastrointestinal Symptom Severity Rating (GSSR) questionnaire [36] at beginning, in the middle and at the end of the study. This questionnaire consists of 15 questions that are scored on a Likert scale ranging from no discomfort (zero) to severe discomfort (seven). It assesses five different dimensions, including abdominal pain (heartburn, hunger pains, nausea), reflux (stomach burning and food regurgitation), diarrhea (loose stools, urgent need to defecate), constipation (difficulty passing stools, painful defecation, sensation of incomplete evacuation), and dyspepsia (abdominal bloating, belching, stomach rumbling, increased abdominal gas) [36].

Intervention

The study had 2 phases

Pomegranate peel hydro-alcoholic extraction

According to our knowledge, this was the first study in evaluating the effects of PP in NAFLD patients. Thus, we calculate the optimal dose from a related animal study which reported promising results for the RCT. Then, the PP extraction and capsule preparation were done. The details are explained in the following.

Clinical intervention

In this phase the RCT was performed. After intervention and data collection, the statistical analysis and conclusion were done.

The details of each phases are explained in the following.

PHASE 1: Pomegranate peel hydro-alcoholic extraction

Dose selection

In this study, the dosage of the pomegranate peel supplement was determined based on the research conducted by Wei X. et al. [37] and further confirmed by Wei X.L which demonstrated the effectiveness of the supplement at a dosage of 150 mg/kg in improving liver condition in rats. Under the supervision of the study pharmacologist, the optimal dose conversion from animal to human was calculated using the following formula. The resulting dose was determined to be 1500 mg (Fig. 2). The formula utilized for dose conversion takes into account the body ratio between humans and the studied animal to ensure a safe human dosage that does not induce any complications [38] (Fig. 2). Moreover, previous studies have reported no adverse effects associated with this dosage.

Fig. 2
figure 2

The dose conversion of animal study for RCT: The human equivalent dose was 24.3 mg/kg which for a 60-kg person was about 1500 mg/day

Full size image

Pomegranate peel extraction

The pomegranate peel supplement used in this study was prepared in the Department of Pharmaceutical Sciences in Iranian Medicine, School of Persian and Complementary Medicine, Mashhad University of Medical Sciences, Mashhad, Iran via soaking method [39, 40]. A total of 750 kg of pomegranates of a single variety were procured from the local market in Mashhad. Careful selection was made to choose pomegranates without any chemical, physical, or microbial damage. The pomegranates were then peeled in a pharmacology laboratory and subsequently dried in the shade at a controlled room temperature using an air-conditioned oven. To obtain the extract, a 50% hydro-ethanolic solution was prepared from the dried pomegranate peel powder. The powder was mixed with ethanol (50% v/v), and the resulting suspension was placed on a shaker at 37 °C for 72 to 96 h to extract the active ingredients from the pomegranate peel powder [39]. After 96 h, the liquid was concentrated using a rotary-evaporator device and then dried using a freeze-dryer. The resulting dry powder of the extract was weighed, and the yield of the extract was measured. Standardization of the extract involved measuring the total phenol content using the Folin Miran method, and the extract components were determined using the HPLC method.

PP and placebo capsules

For the study’s required daily dose of 1500 mg pomegranate peel (PP) capsules, four capsules of 500 mg each were utilized. Each capsule contained 375 mg of dried extract and an additional 125 mg of microcrystalline cellulose (Avicel®). Therefore, the mixture consisted of 66.6% PP extract and 33.3% Avicel. The pomegranate peel capsules for the intervention group were prepared using a capsule-filling machine. In contrast, the placebo group received capsules filled with 500 mg of placebo, which was prepared using Avicel, food coloring, and a unique essence. The placebo capsules closely resembled the pomegranate peel extract capsules in terms of color, smell, and texture. To maintain blinding, one of the pharmacologic laboratory experts filled the capsules into specific medicine containers under clean conditions. Both groups were labeled as “group A” and “group B,“ and each contained 120 placebo or intervention capsules. The identity of the jars containing the PP capsules was not revealed until the end of the study to ensure blinding.

PHASE 2: clinical intervention

Upon meeting the eligibility criteria and providing written consent, all participants in this study were divided into control and intervention groups in equal proportions, considering sex and age strata. The intervention group was assigned to receive a daily regimen of four pomegranate peel capsules. Each capsule contained 375 mg of dried peel extract, resulting in a total daily dosage of 1500 mg. The capsules were taken alongside breakfast and dinner for a duration of 8 weeks. Conversely, the control group followed a similar regimen, taking four capsules that contained an inactive ingredient as placebo. Both groups received a 500-kcal deficit diet (53% of carbohydrates, 17% of protein and 30% of fat) along with mediterranean diet advices.

Data collection

Data were collected at three key time points: baseline, on the 28th day of the intervention, and on the 56th day during the follow-up visit. At baseline, participants completed a questionnaire to gather demographic characteristics. Anthropometric assessments, including height, weight, body mass index (BMI), body composition, blood pressure, and gastrointestinal complications, were measured at baseline, in the middle, and at the end of the intervention.

To assess hepatic status, transient elastography was performed at beginning and the end of the study. Participants also completed a 3-day food record and the International Physical Activity Questionnaire (IPAQ) at baseline and at the end of the intervention to evaluate dietary intake and physical activity levels, respectively. Moreover, biochemical variables, including complete blood count with differential (CBC-diff), lipid profiles including low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-c), triglyceride (TG), and total cholesterol (TC), fasting blood sugar (FBS) and serum insulin, were assessed at baseline and at the end of the study.

Statistical analysis

The data collected in this study were analyzed using version 16 of the SPSS statistical software. Intention-to-treat analysis was employed to accurately estimate the intervention effect, with missing data imputed using the last observed value. The distribution of qualitative variables both among and within groups was assessed using the chi-square test. For comparisons between groups of quantitative variables with a normal distribution, the independent samples t-test was used, while the paired t-test was utilized for comparisons within groups over time. In cases where the distribution of variables was non-normal, the Mann-Whitney U test and Wilcoxon signed-rank test were employed for between-group and within-group comparisons, respectively. To minimize potential confounding effects of variables such as baseline values, changes in energy intake, physical activity, and body weight on secondary outcomes, analysis of covariance (ANCOVA) was performed. Qualitative variables were presented as percentages, quantitative variables with a skewness of less than one were reported as mean ± standard deviation, and variables with a skewness equal to or greater than one were presented as median (interquartile range). P values of less than 5% (p < 0.05) was considered statistically significant.

Results

The study was conducted between December 2021 and the spring, summer, and fall of 2022, and it involved adult patients diagnosed with non-alcoholic fatty liver disease who met the predetermined inclusion criteria. Prior to their participation, written informed consent was obtained from all individuals. A total of 78 participants were enrolled and randomly allocated to either the pomegranate peel group or the placebo group, utilizing a stratified block design to ensure equal distribution. Specifically, 39 participants were assigned to the pomegranate peel group, while the remaining 39 were assigned to the placebo group. The participants were then observed and followed up for a duration of 8 weeks. During the study period, the majority of patients adhered to their assigned treatment, with only two individuals from the placebo group discontinuing their participation. The flow diagram of participant selection process and study procedure is illustrated in Fig. 3.

Gastrointestinal symptom severity rating (GSSR) did not change significantly within (P = 0.29 and 0.54, respectively) and also between (P = 0.64) pomegranate peel and placebo group when measured in different time sequences. The quality assessment of the extract reported the mean polyphenol content (ellagic acid)/gram of 15%.

Fig. 3
figure 3

The flow diagram of participant selection process and study procedure

Full size image

Baseline characteristics

The results of demographic data of the study participants by study groups are presented in Table 1. The results of the study indicate that the randomization process was effectively implemented, ensuring a balanced distribution of participants across the study groups. The mean age of the participants was 43.1 ± 8.6 years, with no statistically significant difference between the pomegranate peel group (mean age 42.8 ± 7.2 years) and the placebo group (mean age 43.3 ± 10.13 years) (p = 0.8). Out of the enrolled participants, 37 (48.7%) were male and 39 (51.3%) were female, and there was no significant difference in sex distribution between the groups (p = 0.65). Regarding body weight status, among the participants in the pomegranate peel group, 6.2% were classified as normal weight, 35.9% as overweight, and 61.5% as obese. In the placebo group, the corresponding percentages were 7.2%, 37.8%, and 54.9% for underweight, overweight, and obese categories, respectively. However, there was no significant difference in body weight status between the two groups (p = 0.15). Furthermore, no significant differences were observed between the pomegranate peel group and the placebo group in terms of other demographic variables, as indicated in the Table 1.

Table 1 Baseline characteristics of study participants
Full size table

Dietary intake evaluations

Table 2 in the study presents the results of dietary intake evaluations for both the pomegranate peel and placebo groups at the beginning and end of the study. The table indicates the mean food intake in each group and examines the differences between them. At baseline, there was no significant difference observed between the two groups (P > 0.05). During the study, following the prescribed dietary regime and supplement intake, both the pomegranate peel and placebo groups showed significant reductions in mean energy, carbohydrate, and saturated fat intakes (p < 0.05). However, when comparing the mean changes in nutrient intakes between the two groups, no statistically significant differences were found. To provide a more comprehensive analysis, the mean changes in nutrient intake were reported as both raw values and energy-adjusted values. Moreover no significant changes was observed between groups in mean dietary vitamin E intake (-1.95 ± 8.90 in the placebo and − 2.52 ± 6.70 mg in the PP groups) as a representative of antioxidant intake from diet, during the study (P = 0.79).

Table 2 Dietary intake changes of placebo and PP groups during the study
Full size table

Body composition evaluations

The results of the body composition assessments during the study for each study group are presented in Table 3. In this table, the raw mean and adjusted model based on baseline values, weight, energy, and physical activity for each variable are reported. As presented in table, there was no significant difference observed between the two groups at baseline (P > 0.05). Following the intervention, the mean body weight, waist circumference, body mass index, body fat index, and trunk fat decreased in both the pomegranate peel and placebo groups. Although these changes did not differ significantly between the two groups statistically, at beginning the study. However, comparing different time sequences, weight (-0.62 ± 1.08 and − 5.10 ± 2.30 kg in the placebo and PP groups, respectively), waist circumferences (WC) (-1.05 ± 1.68 and − 7.57 ± 2.97 cm in the placebo and PP groups, respectively), fat free mass (+ 0.01 ± 0.01 and − 0.92 ± 0.90 kg in the placebo and PP groups, respectively), fat mass index (-0.21 ± 0.15 and − 1.49 ± 0.86 in the placebo and PP groups, respectively), total body water (+ 0.51 ± 0.16 and + 2.35 ± 1.83% in the placebo and PP groups, respectively), trunk fat (− 0.64 ± 0.25 and − 3.93 ± 3.07% in the placebo and PP groups, respectively) decreased significantly more in the pomegranate peel group than in the placebo group (All P < 0.001 except for fat free mass (P < 0.003)). Moreover, after adjusting for potential confounders, physical activity, and energy intake, the mean changes remained significantly greater in the pomegranate peel group than in the placebo group.

Table 3 Anthropometric changes of placebo and PP groups during the study
Full size table

Lipid and glycemic profile evaluations

The results of serum metabolic indices assessment during the study for each study group are presented in Table 4. In this table, the raw mean and adjusted model based on baseline values, weight, energy, and physical activity for each variable are reported. As presented in table there was no significant difference observed between the two groups at baseline (P > 0.05).

In this study, following the diet plan and supplemental interventions, fasting blood glucose levels (FBS) (0.32 ± 0.07 and − 5.28 ± 1.36 mg/dl in the placebo and PP groups, respectively), triglyceride to glucose ratio (-0.008 ± 0.11 and − 0.16 ± 0.11 in the placebo and PP groups, respectively), total cholesterol (TC) (3.21 ± 0.95 and − 10.51 ± 0.77 mg/dl in the placebo and PP groups, respectively), triglyceride (TG) (0.27 ± 0.96 and − 16.02 ± 1.7 mg/dl in the placebo and PP groups, respectively), low-density lipoprotein-cholesterol (LDL-C) (1.40 ± 2.90 and − 9.33 ± 6.66 mg/dl in the placebo and PP groups, respectively), and cholesterol to lipoprotein ratio (0.009 ± 0.21 and − 0.74 ± 0.73 in the placebo and PP groups, respectively) were significantly decreased in pomegranate peel group (All P < 0.001 except from FBS (P = 0.02)). Additionally, serum HDL-C levels (0.70 ± 0.18 and 5.10 ± 0.36 mg/dl in the placebo and PP groups, respectively; P < 0.001) were significantly increased in individuals who received the pomegranate peel. Moreover, after adjusting for potential confounders, physical activity, and energy intake, the mean changes remained significantly greater in the pomegranate peel group than in the placebo group. Changes in fasting insulin (2.78 ± 1.57 and 1.73 ± 2.27 µIU/ml in the placebo and PP groups, respectively; P = 0.81) and homeostatic model assessment for insulin resistance (HOMA-IR) (0.39 ± 0.68 and 0.83 ± 1.20 in the placebo and PP groups, respectively; P = 0.93) were not significantly different when comparing two groups during the study in raw and even adjusted model.

Table 4 Lipid and glycemic profile changes of placebo and PP groups during the study
Full size table

Blood pressure evaluations

The results of Systolic and diastolic blood pressure values during the study for each study group are presented in Table 5. In this table, the raw mean and adjusted model based on baseline values, weight, energy, and physical activity for each variable are reported. There were a significant difference between the two groups at baseline in systolic blood pressure (SBP) (P = 0.01) but not in diastolic blood pressure (DBP) (P = 0.05). Although the mean systolic and diastolic blood pressures decreased in both the pomegranate peel and control groups, the reductions were not statistically significant (P = 0.65 and 0.23, respectively). Nevertheless, the slope of the changes in the pomegranate peel group was significantly steeper than that of the control group in the measured time sequences in systolic (-0.16 ± 0.19 and − 0.63 ± 0.29 cmHg in the placebo and PP groups, respectively; P < 0.001) and diastolic pressure (-0.09 ± 0.16 and − 0.39 ± 0.19 cmHg in the placebo and PP groups, respectively; P < 0.001).

Table 5 Blood pressure changes of placebo and PP during the intervention
Full size table

Fatty liver status evaluations

Table 6 presents the liver elastography results for the pomegranate peel and placebo groups at baseline and the end of the study in raw and adjusted model. There were no significant differences between the groups at baseline in liver stiffness and hepatorenal ultrasound index (p = 0.06 and 0.07, respectively). At the end of the study, both groups showed a significant reduction in liver elastography reports in within group analysis. However, when comparing between two groups, the pomegranate peel group exhibited a significantly greater decrease in liver stiffness (0.14 ± 0.02 kPa in the placebo in contrast to -0.72 ± 0.35 kPa in the PP group; P < 0.001) and hepatorenal ultrasound index (0.07 ± 0.05 in the placebo in contrast to − 0.30 ± 0.17 in the PP group; P < 0.001) in raw and even after adjusting for baseline values and potential confounders. The improvements in the pomegranate peel group was statistically significant (P = 0.002). However, the changes in the degree of liver steatosis in the control group were not statistically significant (P = 0.66). The results of the between-group analysis showed that the reduction in the degree of liver steatosis in the pomegranate peel group was statistically significant compared to the control group, even after adjusting for potential confounding factors (P < 0.001).

Table 6 Liver elastography results of placebo and PP during the intervention
Full size table

Discussion

Our results suggested that an 8-week pomegranate peel supplementation along with a 500-calorie deficit diet, resulted in improvement of liver steatosis grade, as well as metabolic syndrome risk factors including weight, body fat index, metabolic biochemistry indices, and blood pressure of NAFLD patients in contrast to placebo. In the following, we will discuss about effects of pomegranate peel (PP) on risk factors of metabolic syndrome (MS) including anti-obesity, anti-glycemic, anti-hypertension, lipid lowering, and fatty liver improvement effects. Figure 4 summarized the effects of PP on MS risk factors.

Anti-obesity and anti-fat effects of pomegranate peel

The study findings suggest that pomegranate peel supplementation significantly reduces weight, body mass index, waist circumference, fat mass index, and trunk fat in patients with non-alcoholic fatty liver disease after adjusting for potential confounders and baseline values. Furthermore, in adjusted model, the pomegranate peel group showed a statistically significant decrease in fat free mass, with a mean change of -0.99 ± 2.0 kg. In comparison, the control group showed a tiny increase of 0.08 ± 2.0 kg. The decrease in the FFM in the pomegranate peel (PP) group may be due to the lack of control over all factors and confounding variables affecting FFM such as diet, physical activity, age and sex, race, and hormonal status of the individual.

The study conducted by Grabez et al. [18] was consistent with our findings regarding decreased waist circumference in the group receiving pomegranate peel. However, they did not find significant differences in weight, body mass index, body fat percentage, or fat free mass index. Similarly, Khadem-Haghighian et al. [41] did not observe a significant difference in mean BMI changes before and after intervention in osteoarthritis patients receiving pomegranate peel.

A review of changes in anthropometric indices between studies revealed conflicting results in animal studies [42,43,44]. A study conducted on rats with a high-fat diet in 2019 found that the group receiving cake containing 15% pomegranate peel powder had less weight gain than other groups [42], consistent with our findings. However, evidence suggests that the appetite-reducing effects of pomegranate peel are greater under high-fat diet conditions. Another study by Soliman and colleagues in 2022 on overweight rats reported a significant decrease in leptin levels with pomegranate peel powder supplementation[43]. However, Rahnama et al. reported in their study on obese desert rats, who had two months of aerobic exercise and pomegranate peel consumption, that pomegranate peel extract with exercise led to a 50% decrease in body weight [44]. They did not observe a significant effect on rats’ weight or insulin levels.

In our study, we observed no significant impact of the pomegranate peel extract supplement on the dietary intake of the participants. These findings align with previous investigations, such as the study by Khadem-Haghighian et al.[45], which examined the effects of pomegranate peel extract on overweight women with knee osteoarthritis. Similarly, Grabez et al. [18], explored the effects of pomegranate peel in diabetic patients and did not report any substantial alterations in energy intake before and after the intervention. Correspondingly, a study involving overweight women with dyslipidemia [41] and another study on hemodialysis patients by Jafari et al. [46] also did not find any notable changes in macronutrient and micronutrient intake following pomegranate peel supplementation. Therefore, collectively, the published clinical trials on pomegranate peel support our findings.

Although the reduction in calorie intake in the pomegranate peel group may not have reached statistical significance compared to the control group, it is noteworthy from a nutritional standpoint as it contributed to greater weight loss. Animal studies have indicated that pomegranate peel can positively affect appetite through its influence on leptin [43, 44]. Hence, the underreporting of meal intake by individuals who did not achieve weight loss could potentially account for the lack of difference in dietary intake between the two study groups. Our study advised all patients to have an active lifestyle. However, there was no changes in physical activity levels before and after the intervention in either group. The difference in our findings compared to other studies may be due to the fact that in our study, a calorie-restricted diet and recommendations for a Mediterranean diet were provided to both groups for ethical reasons. However, weight, fat mass, and FFM did not show significant changes in the control group. The mechanism of pomegranate peel’s effect on weight and appetite changes may occur through inhibition of the pancreatic lipase enzyme, suppression of energy intake, and a significant reduction in leptin levels [43, 44]. The appetite-reducing effects of pomegranate peel can explain the lack of significant weight loss in the control group despite receiving a similar low-calorie diet during the study and a weaker diet acceptance than the intervention group.

Anti-glycemic effects of pomegranate peel

The results of our study indicate that daily supplementation of 1500 milligrams of pomegranate peel for 8 weeks significantly reduces fasting blood glucose levels, even after adjusting for potential confounding factors. However, our intervention did not result in a significant change in fasting serum insulin levels. Additionally, our results showed that pomegranate peel supplementation improves the triglyceride-glucose index, which measures insulin resistance but does not significantly affect the homeostatic model assessment of insulin resistance (HOMA-IR). In a similar study by Grabez et al.[18], pomegranate peel supplements were administered to patients with type 2 diabetes for 8 weeks. However, no significant changes were observed in fasting blood glucose levels and insulin sensitivity, including the HOMA-IR and QUICKI indices. However, a significant difference in the level of hemoglobin A1C was reported. Furthermore, consistent with our study, there was no significant difference in serum insulin levels between the pomegranate peel and placebo groups. The different results in fasting blood glucose levels compared to our study may be due to the fact that participants in the Grabez study [18] had diabetes and were receiving routine and long-term metformin therapy, as well as the lack of dietary recommendations in that study.

Animal studies on pomegranate peel have shown contradictory results [47,48,49,50]. While pomegranate peel extract has been shown to significantly reduce serum glucose levels in diabetic rats with or without induced diabetes [47,48,49], another animal study on rats with induced diabetes did not report any significant effects of pomegranate peel supplementation on weight or blood glucose levels [50]. In most studies, the intervention dose was lower than in our study, and diabetic samples were used, which may explain the contradictory results. Animal studies have shown that pomegranate peel’s polyphenols can improve carbohydrate metabolism and insulin sensitivity by inhibiting alpha-glucosidase and alpha-amylase enzymes, reducing blood glucose levels [51, 52].

Lipid lowering effects of pomegranate peel

One of the significant findings of our study was a meaningful reduction in the levels of total cholesterol, triglycerides, low-density lipoprotein (LDL), and a significant increase in the levels of high-density lipoprotein (HDL) in the pomegranate peel group compared to the placebo group. Our results are consistent with the study by Khadem-Haghighian et al.[41], who investigated the effects of a pomegranate peel extract supplement (1000 mg/day) for 8 weeks on lipid profiles in obese women with dyslipidemia in 2016. They reported a significant improvement in total cholesterol, triglycerides, and LDL cholesterol levels. However, the trend toward reduction in the lipid profile in our study was greater, which may be due to the difference in intervention dosage between the two studies.

In another study conducted by Grabez et al. [18] in 2019, pomegranate peel supplement was administered to patients with type 2 diabetes for 8 weeks. Similar to our study, they reported a significant reduction in serum triglyceride levels, the ratio of LDL to HDL cholesterol, and a significant increase in high-density lipoprotein cholesterol levels. However, there was no significant difference in total cholesterol and LDL levels. Another study in 2021 administered a pomegranate peel supplement (1000 mg/day) for 8 weeks to women with osteoarthritis, which resulted in a significant reduction in total cholesterol and triglyceride levels[45], which is consistent with our results. However, there was no significant difference in serum levels of high-density and low-density lipoproteins. They attributed the lack of significance in the pomegranate peel group’s lipid profile changes to the high standard deviation of the serum lipoprotein levels, which could potentially be resolved by increasing the sample size.

Moreover, animal studies have reported pomegranate peel’s cholesterol and triglyceride-lowering effects [53, 54], which aligns with our findings. The conflicting results regarding the effect of pomegranate peel on lipid profiles may be due to the small sample size, different treatment durations, supplement dosages, and types of pomegranates used in supplement production.

Furthermore, in our study, the ratio of cholesterol to high-density lipoprotein cholesterol significantly decreased by 72.0 ± 0.5% in the pomegranate peel group compared to the placebo group. A ratio below 5 is acceptable, but values less than 3.5 are considered excellent [55]. Therefore, our study demonstrated that a pomegranate peel supplement of 1500 mg/day for 8 weeks have beneficial effects on the serum lipid profile in patients with fatty liver, as the cholesterol to high-density lipoprotein cholesterol ratio decreased from 24.1 ± 29.4 to 0.76 ± 55.3, which is close to the acceptable range. These results are valuable in evaluating PP effects on cardiovascular disease risk of NAFLD patients which are due to pomegranate peel’s anti-inflammatory, antioxidant, lipid-lowering, and blood pressure-lowering effects and also its constituent compounds, such as ellagic acid.

The lipid-lowering effects of pomegranate peel are related to its polyphenolic compounds, such as ellagic acid, gallic acid, punicalagin, and ellagic acid tannins [56,57,58,59]. Studies have shown that these polyphenols inhibit the activity of pancreatic lipase, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, and acyl-CoA: cholesterol acyl transferase (ACAT), resulting in a decrease in serum cholesterol and triglyceride levels [56, 57]. Also, catechins present in pomegranate peel reduce intestinal fat absorption and inhibit critical enzymes in lipid biosynthesis [58]. Another polyphenolic compound found in pomegranate peel is ellagic acid, which has lipid-lowering effects by activating peroxisome proliferator-activated receptor gamma (PPAR) receptor and increasing cholesterol metabolism in L02 cells, a human hepatocyte cell model. This can improve the underlying causes of cardiovascular diseases [59].

Anti-hypertension effects of pomegranate peel

In our study, systolic and diastolic blood pressure were evaluated at baseline, midpoint, and endpoint of the intervention. The pomegranate peel group showed a significant decrease in systolic and diastolic blood pressure even after adjusting for potential confounding factors.

Khadem-Haghighian et al. [41] investigated the effect of a supplement containing 1000 mg of pomegranate peel extract for 8 weeks in 38 obese women with dyslipidemia. After the intervention, a significant decrease was observed in the systolic blood pressure of the patients, which is consistent with our results. However, the mean diastolic blood pressure did not change significantly despite the decreasing trend. This difference in results may be due to the sample size in the two studies. As a decreasing trend in diastolic blood pressure was observed in their study, statistical significance may be achieved with an increase in sample size. Grabez et al. (2019) [18] reported a significant decrease in systolic and diastolic blood pressure after receiving 1000 mg of dried pomegranate peel extract for 8 weeks in 38 diabetic patients, which is consistent with our results. Studies on pomegranate juice, which contains some similar polyphenols to pomegranate peel, have also confirmed the antihypertensive effects of pomegranate on systolic and diastolic blood pressure [19, 24, 25]. The probable mechanism is related to the polyphenols present in pomegranate peel and fruit, which lead to a reduction in the level of angiotensin-converting enzyme and improvement of vasodilation through the effect on nitric oxide [60,61,62].

Fig. 4
figure 4

Effects of pomegranate peel on metabolic syndrome risk factors. In this figure, the anti-oxidant, anti-inflammatory, and prebiotic effects of pomegranate peel are illustrated. PP as a prebiotic leads to the production of short-chain fatty acids (SCFA), the reduction of lipopolysaccharides (LPS), and the regulation of GLP-1 secretion. On the other hand, PP resulted in reduced inflammatory pathways and regulated lipolysis and insulin sensitivity. Together, they cause lower cholesterol and blood sugar levels, as well as lower fibrosis in the liver. Also, PP as an antioxidant leads to lower lipotoxicity and regulated lipid-related hormones such as leptin and adiponectin which all result in lower lipid globules in the liver and reduced appetite as well as weight gain

Full size image

Anti-steatosis and anti-fibrosis effects of pomegranate peel

Our study demonstrated a significant reduction in liver stiffness and the hepatorenal ultrasound index among patients receiving pomegranate peel supplements. In contrast, the placebo group exhibited a slight increase in these indices, which reached statistical significance. This discrepancy may be attributed to non-adherence to the recommended diet and physical activity in some individuals within the placebo group. Notably, no clinical trial investigating the effects of pomegranate peel on patients with non-alcoholic fatty liver disease has been published thus far. Therefore, our study relied on existing animal and human studies in this field.

The findings of our study align with previous research examining the impact of pomegranate peel extract on liver fibrosis and fatty liver disease in animal models. For instance, Vi et al. administered pomegranate peel extract to rats with carbon tetrachloride-induced liver fibrosis for a duration of four weeks in 2015. They observed a reduction in aspartate and alanine transaminases, as well as total bilirubin levels. Additionally, they reported improvements in liver fibrosis by reducing markers such as hydroxyproline, procollagen type III, hyaluronic acid, laminin, and TGF-β1 [19]. Another study investigating liver fibrosis examined rats with obstructed bile ducts who were treated with 50 mg/kg body weight of pomegranate peel extract for a duration of 13 weeks. The results revealed notable improvements in various liver-related parameters, including reductions in aspartate and alanine transaminases, lactate dehydrogenase levels, and liver myeloperoxidase activity. Furthermore, there was an enhancement in liver antioxidant capacity and a decrease in malondialdehyde levels compared to the control group. These findings suggest that pomegranate peel extract may have a beneficial effect on liver fibrosis and associated liver markers in this animal model [63].

Also, our findings align with the research conducted by Liu et al., who demonstrated a reduction in liver fat content and inflammation following a 13-week administration of pomegranate peel extract in mice [64]. Similarly, Abou-Zeid et al. observed a decrease in cholesterol and triglyceride levels in rat liver tissue after a 30-day intervention [65]. Several other animal studies investigating the effects of pomegranate peel on fatty liver disease have reported similar outcomes to our study [66,67,68]. These consistent findings across multiple animal studies further support the potential beneficial effects of pomegranate peel in ameliorating fatty liver disease.

Pomegranate peel has been attributed with various mechanisms underlying its anti-steatotic effects. These mechanisms encompass the enhancement of adiponectin signaling, modulation of genes involved in fatty acid oxidation pathways, regulation of lipid metabolism in adipose tissue, and mitigation of insulin resistance [64, 69, 70]. Together, these mechanisms contribute to the reduction of hepatic fat content. Additionally, the significance of the gut microbiome in liver health has led to the emergence of the gut-liver axis hypothesis in the pathogenesis of NAFLD [71]. Dysbiosis of the gut microbial flora disrupts crucial processes including the production of short-chain fatty acids, choline metabolism, gut mucosal integrity, and endotoxemia. These imbalances influence the expression of lipogenic genes, blood ethanol levels, and bile acid composition, thereby playing a pivotal role in the progression of hepatic steatosis [72,73,74,75,76,77,78]. Pomegranate peel, on the other hand, exerts inhibitory effects on the TLR4/NF-kβ pathway and enhances its antimicrobial properties through various mechanisms [79,80,81]. These include promoting the growth of beneficial bifidobacteria, balancing the ratio of Firmicutes to Bacteroidetes, stimulating mucin secretion, up-regulating proteins involved in maintaining tight junctions, preserving the integrity of the gastrointestinal mucosal barrier, preventing bacterial adhesion to the gut epithelium, reducing circulating levels of bacterial lipopolysaccharides, and down-regulating the expression of the TLR4 gene [27, 82,83,84]. These actions collectively contribute to the attenuation of inflammatory pathways implicated in the initiation and progression of hepatic steatosis [80, 85].

Our study had limitations. Lack of complete adherence to the diet in some participants is one of the limitations of this research. However, it should be noted that this is not a weakness but rather one of the limitations of lifestyle modification studies, because according to the results of published studies, only 30% of patients participating in lifestyle modification programs for the treatment of NAFLD were able to achieve the desired weight loss at the end of the year. Also, according to our knowledge, when we had first started the study, there were no RCT on fatty liver disease. Thus, we had to calculate the pomegranate peel intervention dose from related animal study in fatty liver which was consider as both strength and limitation. The animal to human dose conversion formula suggested to use the median weight of 60 kg for participants for safety considerations. However; the mean weight of our population was unknown at the beginning of study. So, we used 1500 mg of pomegranate peel which considered as safe. However, our study had strengths. This was the first study evaluating the peel of pomegranate as a therapeutic supplement which in regular life is considered as a wastage. Thus, if proved, the supplement of PP will be inexpensive, affordable and environmental friendly. Our results along with the mentioned probable underlying mechanisms suggest a valuable insights in effects of pomegranate peel on fatty liver improvement and also metabolic syndrome risk factors. In addition we suggest to determine the precise molecular pathways, and the best effective dose of supplementation further studies are suggested.

Conclusion

In conclusion, an 8-week supplementation of pomegranate peel along with a 500 Kcal-deficit diet in NAFLD patients led to improved metabolic syndrome risk factors including lipid profile, fasting blood sugar, systolic and diastolic blood pressure, weight, fat mass and waist circumferences as well as fatty liver status in contrast to placebo.

Data Availability

Data will be available on request.

Abbreviations

ACAT:

Acyl-CoA Cholesterol acyl transferase

ALP:

Alkaline Phosphatase

ALT:

Alanine Aminotransferase

AST:

Aspartate Aminotransferase

BMI:

Body Mass Index

CBC-Diff:

Complete Blood Count with Differential Count

CRP:

C-reactive Protein

CT:

Computerized Tomographic

FBS:

Fasting Blood Sugar

FFM:

Fat Free Mass

GSH-Px:

Glutathione Peroxidase

GSSR:

Gastrointestinal Symptom Severity Rating

Hba1c:

Haemoglobin A1C

HDL:

High Density Lipoprotein

HMG-CoA:

3-Hydroxy-3-Methylglutaryl-Coenzyme A

HOMA-IR:

Homeostatic Model Assessment for Insulin Resistance

IL:

Interleukin

IPAQ:

International Physical Activity Questionnaire

LDL:

Low Density Lipoprotein

MDA:

Malondialdehyde

MET:

Metabolic Equivalent Task

MRI:

Magnetic Resonance Imaging

MS:

Metabolic Syndrome

NAFLD:

Non-Alcoholic Fatty Liver Disease

NASH:

Non-Alcoholic Steatohepatitis

NF-Κβ:

Nuclear Factor Kappa β

PNPLA3:

Patatin-Like Phospholipase Domain Containing 3

PP:

Pomegranate Peel

PPAR:

Peroxisome Proliferator-Activated Receptor Gamma

RCT:

Randomized Clinical Trial

SOD:

Super Oxide Dismutase

TC:

Total Cholesterol

TG:

Triglyceride

TNF-ɑ:

Tumor necrosis factor ɑ

References

  1. Sheka AC, Adeyi O, Thompson J, Hameed B, Crawford PA, Ikramuddin S. Nonalcoholic steatohepatitis: a review. JAMA. 2020;323(12):1175–83.

    CAS  PubMed  Google Scholar 

  2. Perumpail BJ, Khan MA, Yoo ER, Cholankeril G, Kim D, Ahmed A. Clinical epidemiology and disease burden of nonalcoholic fatty liver disease. World J Gastroenterol. 2017;23(47):8263.

    PubMed  PubMed Central  Google Scholar 

  3. Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24(7):908–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Furman D, Campisi J, Verdin E, Carrera-Bastos P, Targ S, Franceschi C, et al. Chronic inflammation in the etiology of disease across the life span. Nat Med. 2019;25(12):1822–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Estes C, Anstee QM, Arias-Loste MT, Bantel H, Bellentani S, Caballeria J, et al. Modeling nafld disease burden in china, france, germany, italy, japan, spain, united kingdom, and united states for the period 2016–2030. J Hepatol. 2018;69(4):896–904.

    PubMed  Google Scholar 

  6. Hallsworth K, Adams LA. Lifestyle modification in NAFLD/NASH: facts and figures. JHEP Rep. 2019;1(6):468–79.

    PubMed  PubMed Central  Google Scholar 

  7. Romero-Gómez M, Zelber-Sagi S, Trenell M. Treatment of NAFLD with diet, physical activity and exercise. J Hepatol. 2017;67(4):829–46.

    PubMed  Google Scholar 

  8. Papadaki A, Nolen-Doerr E, Mantzoros CS. The effect of the Mediterranean diet on metabolic health: a systematic review and meta-analysis of controlled trials in adults. Nutrients. 2020;12(11):3342.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Sangouni AA, Zadeh SH, Mozaffari-Khosravi H, Hosseinzadeh M. Effect of Mediterranean diet on liver enzymes: a systematic review and meta-analysis of randomised controlled trials. Br J Nutr. 2022:1–9.

  10. Becerra-Tomás N, Blanco Mejía S, Viguiliouk E, Khan T, Kendall CW, Kahleova H, et al. Mediterranean diet, cardiovascular disease and mortality in diabetes: a systematic review and meta-analysis of prospective cohort studies and randomized clinical trials. Crit Rev Food Sci Nutr. 2020;60(7):1207–27.

    PubMed  Google Scholar 

  11. Campanella A, Iacovazzi PA, Misciagna G, Bonfiglio C, Mirizzi A, Franco I, et al. The effect of three Mediterranean diets on remnant cholesterol and non-alcoholic fatty liver disease: a secondary analysis. Nutrients. 2020;12(6):1674.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Faghihzadeh F, Adibi P, Rafiei R, Hekmatdoost A. Resveratrol supplementation improves inflammatory biomarkers in patients with nonalcoholic fatty liver disease. Nutr Res. 2014;34(10):837–43.

    CAS  PubMed  Google Scholar 

  13. Navekar R, Rafraf M, Ghaffari A, Asghari-Jafarabadi M, Khoshbaten M. Turmeric supplementation improves serum glucose indices and leptin levels in patients with nonalcoholic fatty liver diseases. J Am Coll Nutr. 2017;36(4):261–7.

    CAS  PubMed  Google Scholar 

  14. Rahmani S, Asgary S, Askari G, Keshvari M, Hatamipour M, Feizi A, et al. Treatment of non-alcoholic fatty liver disease with curcumin: a randomized placebo‐controlled trial. Phytother Res. 2016;30(9):1540–8.

    CAS  PubMed  Google Scholar 

  15. Sakata R, Nakamura T, Torimura T, Ueno T, Sata M. Green tea with high-density catechins improves liver function and fat infiltration in non-alcoholic fatty liver disease (NAFLD) patients: a double-blind placebo-controlled study. Int J Mol Med. 2013;32(5):989–94.

    CAS  PubMed  Google Scholar 

  16. Yari Z, Rahimlou M, Eslamparast T, Ebrahimi-Daryani N, Poustchi H, Hekmatdoost A. Flaxseed supplementation in non-alcoholic fatty liver disease: a pilot randomized, open labeled, controlled study. Int J Food Sci Nutr. 2016;67(4):461–9.

    CAS  PubMed  Google Scholar 

  17. Akhtar S, Ismail T, Fraternale D, Sestili P. Pomegranate peel and peel extracts: chemistry and food features. Food Chem. 2015;174:417–25.

    CAS  PubMed  Google Scholar 

  18. Grabez M, Skrbic R, Stojiljkovic M, Rudic Grujic V, Paunovic M, Arsic A, et al. Beneficial effects of pomegranate peel extract on plasma lipid profile, fatty acids levels and blood pressure in patients with diabetes mellitus type-2: a randomized, double-blind, placebo-controlled study. J Funct Foods. 2019;64:103692.

    Google Scholar 

  19. Wei X-l, Fang R-t, Yang Y-h, Bi X-y, Ren G-x, Al L, et al. Protective effects of extracts from pomegranate peels and seeds on liver fibrosis induced by carbon tetrachloride in rats. BMC Complement Altern Med. 2015;15(1):389.

    PubMed  PubMed Central  Google Scholar 

  20. Fogacci F, Di Micoli A, Grandi E, Fiorini G, Borghi C, Cicero AFG. Black garlic and pomegranate standardized extracts for blood pressure improvement: a non-randomized Diet-Controlled study. Appl Sci. 2022;12(19):9673.

    CAS  Google Scholar 

  21. Pfohl M, DaSilva NA, Marques E, Agudelo J, Liu C, Goedken M, et al. Hepatoprotective and anti-inflammatory effects of a standardized pomegranate (Punica granatum) fruit extract in high fat diet-induced obese C57BL/6 mice. Int J Food Sci Nutr. 2021;72(4):499–510.

    CAS  PubMed  Google Scholar 

  22. Jafarirad S, Goodarzi R, Mohammadtaghvaei N, Dastoorpoor M, Alavinejad P. Effectiveness of the pomegranate extract in improving hepatokines and serum biomarkers of non-alcoholic fatty liver disease: a randomized double blind clinical trial. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2023;17(1):102693.

    CAS  Google Scholar 

  23. Goodarzi R, Jafarirad S, Mohammadtaghvaei N, Dastoorpoor M, Alavinejad P. The effect of pomegranate extract on anthropometric indices, serum lipids, glycemic indicators, and blood pressure in patients with nonalcoholic fatty liver disease: a randomized double-blind clinical trial. Phytother Res. 2021;35(10):5871–82.

    CAS  PubMed  Google Scholar 

  24. Ekambaram SP, Perumal SS, Balakrishnan A. Scope of hydrolysable tannins as possible antimicrobial agent. Phytother Res. 2016;30(7):1035–45.

    CAS  PubMed  Google Scholar 

  25. Heber D. Pomegranate ellagitannins. 2012.

  26. Song H, Shen X, Deng R, Chu Q, Zheng X. Pomegranate peel anthocyanins prevent diet-induced obesity and insulin resistance in association with modulation of the gut microbiota in mice. Eur J Nutr. 2022;61(4):1837–47.

    CAS  PubMed  Google Scholar 

  27. Zhao R, Long X, Yang J, Du L, Zhang X, Li J, et al. Pomegranate peel polyphenols reduce chronic low-grade inflammatory responses by modulating gut microbiota and decreasing colonic tissue damage in rats fed a high-fat diet. Food Funct. 2019;10(12):8273–85.

    CAS  PubMed  Google Scholar 

  28. Soleimani D, Rezaie M, Rajabzadeh F, Gholizadeh Navashenaq J, Abbaspour M, Miryan M, et al. Protective effects of propolis on hepatic steatosis and fibrosis among patients with nonalcoholic fatty liver disease (NAFLD) evaluated by real-time two-dimensional shear wave elastography: a randomized clinical trial. Phytother Res. 2021;35(3):1669–79.

    CAS  PubMed  Google Scholar 

  29. Barghchi H, Milkarizi N, Dehnavi Z, Askari V-R, RajabZadeh F, Norouzian Ostad A, et al. Effects of Pomegranate Peel supplementation on Depression, anxiety and stress symptoms of patients with non-alcoholic fatty liver: a Randomized Clinical Trial. J Nutr Fasting Health. 2023;11(2):–.

  30. Webb M, Yeshua H, Zelber-Sagi S, Santo E, Brazowski E, Halpern Z, et al. Diagnostic value of a computerized hepatorenal index for sonographic quantification of liver steatosis. AJR Am J Roentgenol. 2009;192(4):909–14.

    PubMed  Google Scholar 

  31. Tao L-C, Xu J-n, Wang T-t, Hua F, Li J-J. Triglyceride-glucose index as a marker in cardiovascular diseases: landscape and limitations. Cardiovasc Diabetol. 2022;21(1):68.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Raymond JL, Morrow K. Krause and Mahan’s Food and the Nutrition Care Process. Elsevier; 2020.

  33. Craig C, Marshall A, Sjostrom M, Bauman A, Lee P, Macfarlane D, et al. International physical activity questionnaire-short form. J Am Coll Health. 2017;65(7):492–501.

    Google Scholar 

  34. Amini H, Isanejad A, Chamani N, Movahedi-Fard F, Salimi F, Moezi M, et al. Physical activity during COVID-19 pandemic in the iranian population: a brief report. Heliyon. 2020;6(11):e05411.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Hazavehei SMM, Asadi Z, Hassanzadeh A, Shekarchizadeh P. Comparing the effect of two methods of presenting physical education Π course on the attitudes and practices of female students towards regular physical activity in Isfahan University of Medical Sciences. Iran J Med Educ. 2008;8(1):121–31.

    Google Scholar 

  36. Mazaheri M, SadatKhoshouei M. Comparison between psychometric characteristics of Persian Version of the gastrointestinal symptoms Rating Scale in Functional Gastrointestinal Disorders and normal groups. GOVARESH. 2012;17(1):7.

    Google Scholar 

  37. Wei X, Li S, Li T, Liu L, Liu Y, Wang H, et al. Pomegranate peel extract ameliorates liver fibrosis induced by carbon tetrachloride in rats through suppressing p38MAPK/Nrf2 pathway. J Funct Foods. 2020;65:103712.

    CAS  Google Scholar 

  38. Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J basic Clin Pharm. 2016;7(2):27.

    PubMed  PubMed Central  Google Scholar 

  39. Harscoat-Schiavo C, Khoualdia B, Savoire R, Hobloss S, Buré C, Ben-Ali S et al. Extraction of phenolics from pomegranate residues: Selectivity induced by the methods. 2021.

  40. Venkataramanamma D, Aruna P, Singh RP. Standardization of the conditions for extraction of polyphenols from pomegranate peel. J Food Sci Technol. 2016;53(5):2497–503.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Haghighian M, Rafraf M, Moghaddam A, Hemmati S, Asghari Jafarabadi M, Pourghassem Gargari B. Pomegranate (Punica granatum L.) peel hydro alcoholic extract ameliorates cardiovascular risk factors in obese women with dyslipidemia: a double blind, randomized, placebo controlled pilot study. Eur J Integr Med. 2016;8.

  42. Lamiaa ML, Eman SA. The impact of Pomegranate Peel-fortified Cupcakes on Weight loss. Int J Pharm Res Allied Sci. 2019;8(3).

  43. Soliman NA, Mansour SW, Ammar MA, Ammar MAM. Effect of Pomegranate (Molasses, White Peel and Red Peel) extract on healthy liver and hepatotoxicity induced by Phenylhydrazine in male rats. 2022.

  44. Rahnama Z, Poozesh Jadidi R, Nasir Zadeh MR. Effect of two month aerobic training and pomegranate peel extract (PPE) supplementation on insulin resistance index levels in obese rats. J Appl Health Stud Sport Physiol. 2017;4(1):1–10.

    CAS  Google Scholar 

  45. Haghighian MK, Rafraf M, Hemmati S, Haghravan S, Asghari-Jafarabadi M. Effects of pomegranate (Punica granatum L.) peel extract supplementation on serum lipid profile and oxidative stress in obese women with knee osteoarthritis: a double blind, randomized, placebo controlled study. Adv Integr Med. 2021;8(2):107–13.

    Google Scholar 

  46. Jafari T, Fallah AA, Bahrami M, Lorigooini Z. Effects of pomegranate peel extract and vitamin E on oxidative stress and antioxidative capacity of hemodialysis patients: a randomized controlled clinical trial. J Funct Foods. 2020;72:104069.

    CAS  Google Scholar 

  47. Faddladdeen KA. Ameliorating effect of pomegranate peel extract supplement against type 1 diabetes-induced hepatic changes in the rat: biochemical, morphological and ultrastructural microscopic studies. Folia Morphol. 2021;80(1):149–57.

    CAS  Google Scholar 

  48. Alqahtani FA, Elsaid FG, Alsyaad KM. The role of olive leaves and pomegranate peel extracts on diabetes mellitus induced in male rats. Egypt J Hosp Med. 2018;71(5):3079–85.

    Google Scholar 

  49. Kamboh AA. Effect of pomegranate peel extract on some biochemical and histopathological parameters in experimental induced mice with Staphylococcus aureus. J Anim Health Prod. 2016;4(2):42–9.

    Google Scholar 

  50. Faddladdeen KA, Ojaimi AA. Protective effect of pomegranate (Punica granatum) extract against diabetic changes in adult male rat liver: histological study. J microscopy ultrastructure. 2019;7(4):165.

    Google Scholar 

  51. Arun K, Jayamurthy P, Anusha C, Mahesh S, Nisha P. Studies on activity guided fractionation of pomegranate peel extracts and its effect on antidiabetic and cardiovascular protection properties. J Food Process Preserv. 2017;41(1):e13108.

    Google Scholar 

  52. Middha SK, Usha T, Pande V. Pomegranate peel attenuates hyperglycemic effects of alloxan-induced diabetic rats. EXCLI J. 2014;13:223.

    PubMed  PubMed Central  Google Scholar 

  53. Salwe KJ, Sachdev DO, Bahurupi Y, Kumarappan M. Evaluation of antidiabetic, hypolipedimic and antioxidant activity of hydroalcoholic extract of leaves and fruit peel of Punica granatum in male Wistar albino rats. J Nat Sci biology Med. 2015;6(1):56.

    Google Scholar 

  54. Faria A, Calhau C. The bioactivity of pomegranate: impact on health and disease. Crit Rev Food Sci Nutr. 2011;51(7):626–34.

    CAS  PubMed  Google Scholar 

  55. Sumner AE, Zhou J, Doumatey A, Imoisili OE, Amoah A, Acheampong J, et al. Low HDL-Cholesterol with normal triglyceride levels is the most common lipid pattern in West Africans and African Americans with metabolic syndrome: implications for Cardiovascular Disease Prevention. CVD Prev Control. 2010;5(3):75–80.

    PubMed  PubMed Central  Google Scholar 

  56. Altunkaya A. Potential antioxidant activity of pomegranate peel and seed extracts and synergism with added phenolic antioxidants in a liposome system: a preliminary study. Ir J Agricultural food Res. 2014:121–31.

  57. Abdel-Rahim E, El-Beltagi H, Romela R, Box P. White Bean seeds and pomegranate peel and fruit seeds as hypercholesterolemic and hypolipidemic agents in albino rats. Grasas Aceites. 2013;64:1.

    Google Scholar 

  58. Sadeghipour A, Eidi M, Ilchizadeh Kavgani A, Ghahramani R, Shahabzadeh S, Anissian A. Lipid lowering effect of Punica granatum L. peel in high lipid diet fed male rats. Evidence-Based complementary and alternative medicine. 2014;2014.

  59. Lv O, Wang L, Li J, Ma Q, Zhao W. Effects of pomegranate peel polyphenols on lipid accumulation and cholesterol metabolic transformation in L-02 human hepatic cells via the PPARγ-ABCA1/CYP7A1 pathway. Food Funct. 2016;7(12):4976–83.

    CAS  PubMed  Google Scholar 

  60. Ekambaram SP, Perumal SS, Balakrishnan A. Scope of Hydrolysable Tannins as Possible Antimicrobial Agent. Phytother Res. 2016;30(7):1035–45.

  61. Dos Santos RL, Dellacqua LO, Delgado NT, Rouver WN, Podratz PL, Lima LC, et al. Pomegranate peel extract attenuates oxidative stress by decreasing coronary angiotensin-converting enzyme (ACE) activity in hypertensive female rats. J Toxicol Environ Health Part A. 2016;79(21):998–1007.

    CAS  Google Scholar 

  62. Ali MY, Jannat S, Chang MS. Discovery of Potent Angiotensin-Converting enzyme inhibitors in Pomegranate as a treatment for hypertension. Journal of Agricultural and Food Chemistry; 2023.

  63. Omar U, Aloqbi A, Yousr M, Howell NK. Punicalagin induce the production of nitric oxide and inhibit angiotensin converting enzyme in endothelial cell line EA. hy926. Univers J Public Health. 2016;4(5):268–77.

    Google Scholar 

  64. Toklu HZ, Sehirli O, Sener G, Dumlu MU, Ercan F, Gedik N, et al. Pomegranate peel extract prevents liver fibrosis in biliary-obstructed rats. J Pharm Pharmacol. 2007;59(9):1287–95.

    CAS  PubMed  Google Scholar 

  65. Liu H, Zhan Q, Miao X, Xia X, Yang G, Peng X, et al. Punicalagin prevents hepatic steatosis through improving lipid homeostasis and inflammation in liver and adipose tissue and modulating gut microbiota in western diet-fed mice. Mol Nutr Food Res. 2021;65(4):2001031.

    CAS  Google Scholar 

  66. Abozid MM, Farid H. The anti-fatty liver effects of guava leaves and pomegranate peel extracts on ethanol-exposed rats. J Biol Chem Environ Sci. 2013;8:83–104.

    Google Scholar 

  67. Nazeem MM, Moram GSE-D, Barakat HA. EFFECT OF POMEGRANATE (PUNICAGRANATUM L.)(ARILS, PEELS AND SEEDS) EXTRACTS ON FATTY LIVER IN RATS. 2018.

  68. Ayad BM, Elshawesh MA, Alatresh OK, Elgenaidi AR. PROTECTIVE EFFECT OF POMEGRANATE PEEL EXTRACT ON DIETARY-INDUCED NON-ALCOHOLIC FATTY LIVER DISEASE.

  69. Taha O, Barakat A, Abdelhakim HK, Shemis M, Zakaria Z. Hypolipidemic and anti-fatty liver effects exerted by standardized Punica granatum L. peel extract in hepg2 cell-line and high-fat diet-induced mice. Int J Pharm Pharm Sci. 2016;8:156–61.

    CAS  Google Scholar 

  70. Les F, Arbonés-Mainar JM, Valero MS, López V. Pomegranate polyphenols and urolithin A inhibit α-glucosidase, dipeptidyl peptidase-4, lipase, triglyceride accumulation and adipogenesis related genes in 3T3-L1 adipocyte-like cells. J Ethnopharmacol. 2018;220:67–74.

    CAS  PubMed  Google Scholar 

  71. Al-Shaaibi SN, Waly MI, Al-Subhi L, Tageldin MH, Al-Balushi NM, Rahman MS. Ameliorative effects of pomegranate peel extract against dietary-induced nonalcoholic fatty liver in rats. Prev Nutr food Sci. 2016;21(1):14.

    PubMed  PubMed Central  Google Scholar 

  72. Song Q, Zhang X. The role of gut–liver axis in gut microbiome dysbiosis associated NAFLD and NAFLD-HCC. Biomedicines. 2022;10(3):524.

    PubMed  PubMed Central  Google Scholar 

  73. Tiniakos DG, Vos MB, Brunt EM. Nonalcoholic fatty liver disease: pathology and pathogenesis. Annu Rev Pathol. 2010;5:145–71.

    CAS  PubMed  Google Scholar 

  74. Marjot T, Moolla A, Cobbold JF, Hodson L, Tomlinson JW. Nonalcoholic fatty liver disease in adults: current concepts in etiology, outcomes, and management. Endocr Rev. 2020;41(1):66–117.

    Google Scholar 

  75. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115(5):1343–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Johnson AR, Milner JJ, Makowski L. The inflammation highway: metabolism accelerates inflammatory traffic in obesity. Immunol Rev. 2012;249(1):218–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Oddy WH, Herbison CE, Jacoby P, Ambrosini GL, O’Sullivan TA, Ayonrinde OT, et al. The western dietary pattern is prospectively associated with nonalcoholic fatty liver disease in adolescence. Am J Gastroenterol. 2013;108(5):778–85.

    CAS  PubMed  Google Scholar 

  78. Mirmiran P, Amirhamidi Z, Ejtahed HS, Bahadoran Z, Azizi F. Relationship between Diet and non-alcoholic fatty liver disease: a review article. Iran J public health. 2017;46(8):1007–17.

    PubMed  PubMed Central  Google Scholar 

  79. Ter Horst KW, Serlie MJ. Fructose Consumption, Lipogenesis, and non-alcoholic fatty liver disease. Nutrients. 2017;9(9).

  80. Xiao Y, Huang R, Wang N, Deng Y, Tan B, Yin Y, et al. Ellagic acid alleviates oxidative stress by mediating Nrf2 signaling pathways and protects against paraquat-induced intestinal injury in piglets. Antioxidants. 2022;11(2):252.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Neyrinck AM, Van Hée VF, Bindels LB, De Backer F, Cani PD, Delzenne NM. Polyphenol-rich extract of pomegranate peel alleviates tissue inflammation and hypercholesterolaemia in high-fat diet-induced obese mice: potential implication of the gut microbiota. Br J Nutr. 2013;109(5):802–9.

    CAS  PubMed  Google Scholar 

  82. Du L, Li J, Zhang X, Wang L, Zhang W, Yang M et al. Pomegranate peel polyphenols inhibits inflammation in LPS-induced RAW264. 7 macrophages via the suppression of TLR4/NF-κB pathway activation. Food & nutrition research. 2019;63.

  83. Zhou S, Zhang Q, Gao Y, Liu F, Cao W, Li Z, et al. Sargassum fusiforme together with turmeric extract and pomegranate peel extract alleviates obesity in high fat-fed C57BL/6J mice. Food Funct. 2021;12(10):4654–69.

    CAS  PubMed  Google Scholar 

  84. Mohamed MS, Mabrok HB. Protective effect of pomegranate peel powder against gastric ulcer in rats. Biointerface Res Appl Chem. 2021;12:4888–99.

    Google Scholar 

  85. Xu Y, Li G, Zhang B, Wu Q, Wang X, Xia X. Tannin-rich pomegranate rind extracts reduce adhesion to and invasion of Caco-2 cells by Listeria monocytogenes and decrease its expression of virulence genes. J Food Prot. 2015;78(1):128–33.

    CAS  PubMed  Google Scholar 

  86. Neyrinck AM, Van H?e VF, Bindels LB, De Backer F, Cani PD, Delzenne NM. Polyphenol-rich extract of pomegranate peel alleviates tissue inflammation and hypercholesterolaemia in high-fat diet-induced obese mice: potential implication of the gut microbiota. Br J Nutr. 2013;109(5):802-9.

  87. Du L, Li J, Zhang X, Wang L, Zhang W, Yang M et al. Pomegranate peel polyphenols inhibits inflammation in LPS-induced RAW264.7 macrophages via the suppression of TLR4/NF-κB pathway activation. Food Nutr Res. 2019;63.

Download references

Acknowledgements

None.

Funding

This study was supported by MASHHAD University of Medical sciences. The funders had no role different stages of study.

Author information

Authors and Affiliations

  1. Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Hanieh Barghchi, Andisheh Norouzian Ostad, Seyede Yegane Ghelichi Kheyrabadi, Zahra Dehnavi, Seyyed Reza Sobhani & Mohsen Nematy

  2. Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran

    Hanieh Barghchi & Zahra Dehnavi

  3. Metabolic Syndrome Research Center, Department of Nutrition, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Narges Milkarizi & Mohsen Nematy

  4. Student Research Committee, North Khorasan University of Medical Sciences, Bojnourd, Iran

    Saba Belyani

  5. Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran

    Vahid Reza Askari

  6. Neurogenic Inflammation Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran

    Vahid Reza Askari

  7. Department of Radiology, Mashhad Medical Sciences Branch, Islamic Azad University, Mashhad, Iran

    Farnood Rajabzadeh

  8. Department of Gastroenterology and Hepatology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Ladan Goshayeshi

  9. Gastroenterology and Hepatology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    Ladan Goshayeshi

  10. Department of Nutrition Sciences, Varastegan Institute for Medical Sciences, Mashhad, Iran

    Maryam Razavidarmian

Authors
  1. Hanieh Barghchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Narges Milkarizi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Saba Belyani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andisheh Norouzian Ostad
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vahid Reza Askari
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Farnood Rajabzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ladan Goshayeshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Seyede Yegane Ghelichi Kheyrabadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Maryam Razavidarmian
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zahra Dehnavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Seyyed Reza Sobhani
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Mohsen Nematy
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

H.B: Investigation, methodology, project administration, conceptualization, visualization, writing - original draft; H.B & S.B: Writing - original draft; VR.A, F.R, N.M, L.G, A.NO, Z.D, SY.G & M.R: Project coworkers, review and editing; SR.S & H.B: Statistical analysis & editing, M.N: Project administration, supervision, review & editing.

Corresponding author

Correspondence to Mohsen Nematy.

Ethics declarations

Ethics approval and consent to participate

The present trial was registered at IRCT.ir (IRCT20210726051988N1). All participants completed an informed consent form.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Barghchi, H., Milkarizi, N., Belyani, S. et al. Pomegranate (Punica granatum L.) peel extract ameliorates metabolic syndrome risk factors in patients with non-alcoholic fatty liver disease: a randomized double-blind clinical trial. Nutr J 22, 40 (2023). https://0-doi-org.brum.beds.ac.uk/10.1186/s12937-023-00869-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://0-doi-org.brum.beds.ac.uk/10.1186/s12937-023-00869-2

Keywords

Nutrition Journal

ISSN: 1475-2891

Contact us