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Curcumin Lowers Serum Lipids and Uric Acid in Subjects With Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial

Panahi, Yunes PhD; Kianpour, Parisa PharmD; Mohtashami, Reza MD; Jafari, Ramezan MD; Simental-Mendía, Luis E. MD; Sahebkar, Amirhossein PharmD, PhD

Journal of Cardiovascular Pharmacology: September 2016 - Volume 68 - Issue 3 - p 223–229
doi: 10.1097/FJC.0000000000000406
Original Article
Free

Background: Nonalcoholic fatty liver disease (NAFLD) is one of the most common hepatic diseases in the general adult population. Dyslipidemia, hyperuricemia, and insulin resistance are common risk factors and accompanying features of NAFLD. Curcumin is a dietary natural product with beneficial metabolic effects relevant to the treatment of NAFLD.

Aim: To assess the effects of curcumin on metabolic profile in subjects with NAFLD.

Methods: Patients diagnosed with NAFLD (grades 1–3; according to liver sonography) were randomly assigned to curcumin (1000 mg/d in 2 divided doses) (n = 50) or control (n = 52) group for a period of 8 weeks. All patients received dietary and lifestyle advises before the start of trial. Anthropometric measurements, lipid profile, glucose, insulin, glycated hemoglobin, and uric acid concentrations were measured at baseline and after 8 weeks of follow-up.

Results: Eighty-seven subjects (n = 44 and 43 in the curcumin and control group, respectively) completed the trial. Supplementation with curcumin was associated with a reduction in serum levels of total cholesterol (P < 0.001), low-density lipoprotein cholesterol (P < 0.001), triglycerides (P < 0.001), non–high-density lipoprotein cholesterol (P < 0.001), and uric acid (P < 0.001), whereas serum levels of high-density lipoprotein cholesterol and glucose control parameters remained unaltered. Curcumin was safe and well tolerated during this study.

Conclusion: Results of the present trial suggest that curcumin supplementation reduces serum lipids and uric acid concentrations in patients with NAFLD.

*Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran;

Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran;

Medicine Quran and Health Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran;

§Baqiyatallah University of Medical Sciences, Tehran, Iran;

Biomedical Research Unit, Mexican Social Security Institute, Durango, Mexico;

Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; and

**Metabolic Research Centre, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia.

Reprints: Amirhossein Sahebkar, PharmD, PhD, Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran, PO Box: 91779-48564, Iran (e-mail: sahebkara@mums.ac.ir) or Parisa Kianpour, PharmD, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, PO Box: 19945-581, Iran (e-mail: pk.pioneer1@yahoo.com)

The authors report no conflicts of interest.

Trial registry number: IRCT2015122525641N2.

Received February 19, 2016

Accepted April 05, 2016

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INTRODUCTION

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease that encompasses a wide spectrum of disorders including hepatic steatosis, nonalcoholic steatohepatitis, liver fibrosis, and cirrhosis.1 Recently, NAFLD has come to be one of the most common hepatic diseases and a major reason for impaired liver function in the general adult population.2 In particular, the NAFLD is a common comorbidity of type 2 diabetes and obesity.2 Moreover, it has been reported that a high percentage of patients with NAFLD exhibit features of metabolic syndrome.3 Insulin resistance, which is the hallmark of metabolic syndrome, has been associated with hyperinsulinemia, impaired glucose tolerance, diabetes, hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), elevated blood pressure, visceral fat accumulation, hyperuricemia, and other cardiometabolic abnormalities that are involved in the pathogenesis of NAFLD.4,5

Curcumin is an orange-yellow pigment present in the Curcuma longa L. (turmeric) that is frequently used as a dietary spice in Asian countries for hundreds of years.6 Numerous pharmacological properties of this polyphenol have been described such as anti-inflammatory, antioxidant and anticancer, antiatherosclerotic, cardioprotective, lipid-modifying, antirheumatic, and antidepressant effects among others.7–20 Curcumin exhibits several pharmacological activities owing to its capacity to interact with different molecular targets including enzymes, receptors, transcription factors, growth factors, hormones, cytokines, adipokines, and adhesion molecules.21 Since beneficial effects of curcumin on metabolic syndrome has been reported,8,9,20 this phytochemical may improve the metabolic features of NAFLD particularly those related to lipid and glucose metabolism. Nevertheless, the effect of curcumin supplementation on cardiometabolic features of NAFLD has not yet been investigated in clinical trials. Hence, the objective of the present study was to assess the effects of curcumin on metabolic profile of subjects with NAFLD.

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MATERIALS AND METHODS

Subjects

The study population comprised subjects with NAFLD (grades 1–3; according to liver sonography) who were selected from adults referring to the Gastroenterology and Hepatology Clinic of the Baqiyatallah Hospital (Tehran, Iran). Exclusion criteria were pregnancy or breastfeeding, NAFLD secondary to alcohol consumption, smoking, consumption of hypoglycemic, hypolipidemic, and anti-inflammatory medications as well as any drug known to affect hepatic function, and presence of hepatitis, coronary, renal, pulmonary, and thyroid diseases. All patients received dietary and lifestyle advises before the start of trial.

Eligible subjects were randomly assigned to curcumin (1000 mg/d in 2 divided doses) (n = 50) or control (n = 52) group. Curcumin was administered for 8 weeks in the form of 500 mg capsules, and patients were advised to take the capsules after meal. Administered curcumin had a phytosomal formulation (Meriva; Indena S.p.A, Milan, Italy) that contained a complex of curcumin and soy phosphatidylcholine in a 1:2 weight ratio, and 2 parts of microcrystalline to improve flowability, with an overall content of curcumin in the final product of around 20%.22 An inert substance (lactose) was used as placebo.

The study protocol was given approval by the institutional Ethics Committee and written informed consent was obtained from participants. The clinical trial protocol has been registered under the Iranian Registry of Clinical Trials (IRCT) ID: IRCT2015122525641N2.

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Anthropometric Measurements

Height and weight of subjects were measured with the accuracy of 0.1 cm and 0.1 kg, respectively. Measurements were performed in the standing position, with minimal clothing and no shoes at baseline and the eighth week. Body mass index was calculated as weight (kg) divided by height (m) squared.

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Blood Sampling and Biochemical Measurements

Fasted blood samples were collected from a cubital vein at baseline and after 8 weeks of supplementation. Blood samples were centrifuged for 10 minutes at a speed of 1500–2000 rpm to separate the serum. Serum samples were kept at −80°C until analyses. Serum levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, glucose, and uric acid were measured at baseline and at the end of study using routine enzymatic assays with commercial kits (Pars Azmoon, Tehran, Iran). Serum insulin and hemoglobin A1C (HbA1C) levels were determined using immunoassay and ion exchange chromatography techniques, respectively. Homeostasis model of assessment-insulin resistance (HOMA-IR) (fasting insulin μU/mL × fasting glucose mmol/L/22.5),23 HOMA-estimated β-cell function (HOMA-β) [(20 × fasting insulin μU/mL)/(fasting glucose mmol/L − 3.5)]23 and the quantitative insulin sensitivity check index {1/[log (fasting insulin µU/mL) + log (fasting glucose mg/dL)]}24 were calculated according to the previously described formulae.

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Liver Doppler Sonography

Sonography of the liver was performed in the supine position when the patient was fasted for 8–12 hours before the examination. The examination was performed using 3.5-or 5-MHz convex probe on a Mindray DC-8 diagnostic ultrasound system (convex 3.5–5.0 MHz). Echogenicity of the liver, the presence or absence of bulky tumors cystic or solid and calcification was assessed. Hepatic steatosis was graded as 0 (lack of fat accumulation), 1 (mild increase in echogenicity with normal visualization of the diaphragm and intrahepatic vessel borders), 2 (moderate increase in echogenicity with slightly impaired visualization of the diaphragm and intrahepatic vessel borders), and 3 (severe increase in echogenicity with markedly impaired visualization of the diaphragm, intrahepatic vessel borders, and the posterior portion of the right hepatic lobe).

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Statistical Analysis

Statistical analyses were performed using the SPSS software version 11.5 (SPSS Inc., Chicago, IL). Data were expressed as mean ± SD or number (%). Within-group comparisons were performed using paired samples t test (for normally distributed data) or Wilcoxon signed-ranks test (for nonnormally distributed data). Between-group comparisons were performed using independent samples t test (for normally distributed data) or Mann–Whitney U test (for nonnormally distributed data). Categorical variables were compared using Fisher's exact test. A univariate general linear model was constructed to adjust the findings for baseline differences. A P value of <0.05 was considered as statistically significant in all analyses.

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RESULTS

Baseline Characteristics

Eighty-six subjects completed the study. There were 6 dropouts in the curcumin group and 9 in the placebo group. All dropouts were because of stopping the medication owing to the self-perception of lack of benefit (Fig. 1). Dropout rate did not differ between the study groups (P = 0.579). The study groups were comparable in terms of age, gender, body mass index, waist circumference, smoking history and frequency of type 2 diabetes, coronary heart disease, obesity, hypertension, hyperlipidemia, and hypertension (Table 1). However, there were significant baseline differences in systolic blood pressure and diastolic blood pressure between the study groups (Table 1). In addition, serum levels of total cholesterol (P < 0.001), LDL-C (P < 0.001), non–HDL-C (P < 0.001), and triglycerides (P = 0.032) were significantly higher in the curcumin versus control group at baseline (Table 1).

FIGURE 1

FIGURE 1

TABLE 1

TABLE 1

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Effect of Curcumin on Serum Lipids and Uric Acid Levels

Curcumin supplementation was associated with significant reductions in serum levels of total cholesterol (P < 0.001), LDL-C (P < 0.001), HDL-C (P = 0.017), triglycerides (P < 0.001), non–HDL-C (P < 0.001), and uric acid (P < 0.001). In the control group, serum levels of total cholesterol (P = 0.035), LDL-C (P < 0.001), non–HDL-C (P = 0.027), and uric acid were increased by the end of trial, whereas no significant change in serum levels of triglycerides and HDL-C was observed (P > 0.05) (Table 2). Comparison of magnitude of changes revealed improvement of serum lipids and uric acid levels with curcumin (P < 0.001), apart from HDL-C levels, which remained unaffected by curcumin (P > 0.05) (Table 3).

TABLE 2

TABLE 2

TABLE 3

TABLE 3

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Effect of Curcumin on Glycemic Indices

Serum fasting plasma glucose (FPG) and HbA1C levels were significantly decreased by the end of trial in both curcumin [P = 0.035 (FPG) and P = 0.004 (HbA1C)] and control [P = 0.018 (FPG) and P = 0.011 (HbA1C)] groups. However, no change in serum insulin levels was observed in either of the study groups (P > 0.05). Likewise, HOMA-IR, HOMA-β, and quantitative insulin sensitivity check indices remained unaltered in both groups (Table 2). Comparison of change values between the study groups did not reveal any significant difference in any of the assessed parameters (Table 3).

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Regression Analysis

Univariate general linear model was performed to adjust the significant findings for baseline differences as referred above. Reductions in serum total cholesterol, LDL-C, non–HDL-C, triglycerides, and uric acid levels by curcumin remained significant after adjustment for baseline values of the respective parameter (P < 0.05).

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Safety

Curcumin was safe and well tolerated in this trial. There was no report of severe adverse events.

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DISCUSSION

Findings of the present study suggested that short-term curcumin supplementation improves lipids profile and uric acid concentrations in patients with NAFLD. NAFLD is the result of hepatic fat accumulation in patients without a history of excessive alcohol consumption.25 Although the pathogenesis of this liver disease is complex and still poorly understood, the hypothesis of “2-hit” model has been raised. In this regard, the “first-hit” involves an excessive triglyceride accumulation in the liver that leads to steatosis. Afterward, the “second-hit” may induce liver injury through inflammation and oxidative stress, resulting in stetatohepatitis.26

The hepatoprotective and hypolipidemic effects of curcumin have been reported in several animal studies.27,28 Curcumin has been reported to ameliorate histopathological changes and prevent and reduce cholesterol, triglycerides, and free fatty acid levels in the liver tissue. Moreover, curcumin supplementation significantly reduces circulating concentrations of lipids.29 The molecular mechanisms described for the lipid-modifying effects of curcumin include increased activity of fatty acid β-oxidation and suppression of fatty acid synthase, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and acyl coenzyme A cholesterol acyltransferase activities that result in liver protection.30 Furthermore, there is evidence indicating that curcumin supplementation mitigates the expression of lipogenic genes, thereby lowering plasma triglycerides and cholesterol concentrations.21,31–34 It is worth noting that the lipid-modifying effects of curcumin have been demonstrated beyond experimental studies, and recent evidence from randomized controlled trials has confirmed the efficacy of curcumin supplementation in correcting dyslipidemia. In particular, the lowering effect of curcumin on triglycerides, which are major lipid species involved in hepatic steatosis, should be noticed as an important mechanism justifying the use of this phytochemical for NAFLD treatment. Randomized controlled trials in patients with obesity,31 metabolic syndrome,20 type 2 diabetes,35 and even in healthy individuals36 have shown efficient reductions in serum triglycerides following curcumin supplementation. In a trial in patients with coronary artery disease, although curcumin supplementation reduced serum levels of total cholesterol, LDL-C, and triglycerides, these differences did not reach statistical significance compared with placebo, possibly because of the small size of the study.22 A meta-analysis of 5 randomized controlled trials did not suggest a significant lipid-lowering activity of curcumin.37 However, this meta-analysis was based on a limited number of studies and individuals, and most of the included studies were conducted with unformulated curcumin, which is considered to have a low systemic bioavailability. Because most of the randomized controlled trials showing positive effects of curcumin on serum lipids have been published after the above-mentioned meta-analysis, an updated analysis is strongly suggested to avoid any underestimation of the effects of curcumin on lipid indices. Lipid-modifying effects of curcumin have been shown at varying doses and treatment durations, which is dependent on the formulation used, and the underlying pathophysiologic condition on which the lipid-modifying effects is explored.

Several observational studies have reported a significant association between elevated uric acid levels and NAFLD.38–41 In addition, it has been demonstrated that uric acid promotes both lipoprotein oxidation and inflammation,42,43 2 factors that are associated with the “second-hit” of NAFLD pathogenesis.44 Consistent with the present results, a previous study in animal models of NAFLD showed improvement of hepatic steatosis and reduction of uric acid levels following hypouricemic therapy with allopurinol and benzbromarone.45 Therefore, the evidence supports the hypothesis that uric acid might play a causal role in the pathogenesis of NAFLD because it exerts prooxidant and proinflammatory effects through activation of mitogen-activated protein kinase and nuclear factor κB pathways38 and increasing the production of monocyte chemotactic protein-1.42

Although a reduction in plasma levels of glucose and HbA1c and enhancement of insulin sensitivity have been previously shown following curcumin supplementation,35 we could not verify those positive effects on glucose homeostasis in the present study. This discrepancy could be explained by the short period of treatment, which might have been insufficient to reflect the improvement in glucose control. Moreover, this study was not primarily designed to evaluate the antidiabetic effects of curcumin, and diabetic subjects did not constitute a major proportion of studied population. Nevertheless, the overall results suggested a therapeutic effect of curcumin in patients with NAFLD, which is consistent with previous experimental studies exploring the hepatoprotective effects of this phytochemical. In a nonalcoholic steatohepatitis (NASH) mouse model on methionine-deficient and choline-deficient diet, curcumin treatment has been shown to exert antioxidant effects, and reduce hepatic fibrosis, necroinflammation, and levels of alanine aminotransferase.46 In rabbits with high fat-induced NASH, curcumin treatment reduced NASH grade and aminotransferase levels.47 Another important reported effect of curcumin is inhibition of hepatic stellate cell activation, which is a major step in the development of NASH from NAFLD.48 Hepatoprotective effects of curcumin have also been shown in several other experimental models of liver injury induced by different types of hepatotoxic agents such as carbon tetrachloride, thioacetamide, and iron.49 In most of the performed studies, attenuation of hepatic inflammation and oxidative stress, reduction of transaminases, and improvement of liver histology were reported.49

Severe adverse events were not found following curcumin treatment and it was safe and well tolerated in our trial that is in accordance with previous studies involving humans.21,50–53

The main limitation of the present study was the short-term of curcumin therapy; however, significant effects on metabolic profile were revealed during 8 weeks of treatment with this phytochemical. In addition, this study was not a priori designed to recruit subjects with dyslipidemia, hyperglycemia, and/or hyperuricemia. Although these metabolic abnormalities are predisposing factors for NAFLD, they are not present in all subjects with NAFLD.

In conclusion, results of the present study showed that short-term curcumin supplementation reduces serum lipids and uric acid concentrations in individuals with NAFLD. Although this polyphenol may eventually be implemented as a safe and effective addition to the therapeutic regimen of patients with NAFLD management, future studies are required to verify the present findings in hyperuricemic and dyslipidemic populations. Finally, proof-of-concept studies are warranted to further scrutinize the effects of lecithinized curcumin on glucose control in diabetic subjects.

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ACKNOWLEDGMENTS

The authors are grateful for the supports provided by the Baqiyatallah University of Medical Sciences (Tehran, Iran) and Indena SpA (Milan, Italy).

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Keywords:

curcumin; cholesterol; triglycerides; hyperglycemia; urate

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