Efficacy of Berberine in Patients with Non-Alcoholic Fatty Liver Disease

RESEARCH ARTICLE Efficacy of Berberine in Patients with NonAlcoholic Fatty Liver Disease Hong-Mei Yan1☯, Ming-Feng Xia1☯, Yan Wang2, Xin-Xia Chang1, Xiu-Zhong Yao3, ShengXiang Rao3, Meng-Su Zeng3, Yin-Fang Tu4, Ru Feng2, Wei-Ping Jia4, Jun Liu5, Wei Deng6, Jian-Dong Jiang2*, Xin Gao1* 1 Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200032, China, 2 Institute of Materia Medica, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing, 100050, China, 3 Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China, 4 Department of Endocrinology and Metabolism, The Sixth People’s Hospital, Shanghai Jiaotong University, Shanghai, 200233, China, 5 Department of Endocrinology and Metabolism, The Fifth People’s Hospital, Fudan University, Shanghai, 200240, China, 6 School of public health, Fudan University, Shanghai, 200032, China ☯ These authors contributed equally to this work. * (XG); (JJ) OPEN ACCESS Citation: Yan H-M, Xia M-F, Wang Y, Chang X-X, Yao X-Z, Rao S-X, et al. (2015) Efficacy of Berberine in Patients with Non-Alcoholic Fatty Liver Disease. PLoS ONE 10(8): e0134172. doi:10.1371/journal. pone.0134172 Editor: Jianping Ye, Pennington Biomedical Research Center, UNITED STATES Received: March 17, 2015 Accepted: June 26, 2015 Published: August 7, 2015 Copyright: © 2015 Yan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: Data are uploaded to Figshare at the following DOIs: http://dx.doi.org/10. 6084/m9.figshare.1434011; http://dx.doi.org/10.6084/ m9.figshare.1434010; http://dx.doi.org/10.6084/m9. figshare.1434009. Funding: This work was supported by grants from the Major State Basic Research Development Program of China (2012CB524906 to Gao X.; http:// www.973.gov.cn/Default_3.aspx), National Natural Science Foundation of China (81270933 to Gao X.), Major State Basic Research Development Program of China (2011CB504004 to Gao X.), the Science and Technology Commission of Shanghai Municipality Abstract Objectives A randomized, parallel controlled, open-label clinical trial was conducted to evaluate the effect of a botanic compound berberine (BBR) on NAFLD. Methods A randomized, parallel controlled, open-label clinical trial was conducted in three medical centers (NIH Registration number: NCT00633282). A total of 184 eligible patients with NAFLD were enrolled and randomly received (i) lifestyle intervention (LSI), (ii) LSI plus pioglitazone (PGZ) 15mg qd, and (iii) LSI plus BBR 0.5g tid, respectively, for 16 weeks. Hepatic fat content (HFC), serum glucose and lipid profiles, liver enzymes and serum and urine BBR concentrations were assessed before and after treatment. We also analyzed hepatic BBR content and expression of genes related to glucose and lipid metabolism in an animal model of NAFLD treated with BBR. Results As compared with LSI, BBR treatment plus LSI resulted in a significant reduction of HFC (52.7% vs 36.4%, p = 0.008), paralleled with better improvement in body weight, HOMA-IR, and serum lipid profiles (all p<0.05). BBR was more effective than PGZ 15mg qd in reducing body weight and improving lipid profile. BBR-related adverse events were mild and mainly occurred in digestive system. Serum and urine BBR concentrations were 6.99ng/ml and 79.2ng/ml, respectively, in the BBR-treated subjects. Animal experiments showed that BBR located favorably in the liver and altered hepatic metabolism-related gene expression. PLOS ONE | DOI:10.1371/journal.pone.0134172 August 7, 2015 1 / 16 Effects of Berberine on NAFLD (07JC14011 to Gao X.), the National Ministry of Education Program (985 III-YFX0302 to Gao X.) and Shanghai Municipal Health Bureau Foundation (12GWZX0103 to Gao X.), National Natural Science Foundation of China for Young Scholar (81200627 to Yan HM., 81100602 to Chang XX., 81300682 to Xia MF.), Foundation of Fudan University, China (20520133483 to Yan HM., 20520133383 to Chang XX.). Conclusion BBR ameliorates NAFLD and related metabolic disorders. The therapeutic effect of BBR on NAFLD may involve a direct regulation of hepatic lipid metabolism. Trial Registration ClinicalTrials.gov NCT00633282 Competing Interests: The authors have declared that no competing interests exist. Introduction Non-Alcoholic Fatty Liver Disease (NAFLD) is characterized by hepatic fat accumulation, insulin resistance and usually impaired glucose and lipid metabolism, which is currently a leading cause of chronic liver diseases [1]. It has been a significant health problem that affects 20– 30% of the general population, among whom 5–20% developed liver cirrhosis during a 10-year period [2]. Besides, NAFLD predicts both type 2 diabetes (T2DM) and cardiovascular diseases [3], and the metabolic complex of NAFLD has attracted extensive attentions [4]. Several pharmacologic interventions have been attempted to treat NAFLD, and the agents targeting insulin resistance such as thiazolidinediones [5,6,7] have yielded promising results. Berberine (BBR) is an active single compound isolated from Rhizoma Coptidis with a welldefined chemical structure. Recently, several studies from both clinic [8,9] and laboratory [10,11,12] reported that BBR had antidiabetic and antihyperlipidemic effects. Zhang Y et al. demonstrated that BBR had a robust glucose-lowering effect, accompanying with a significantly increase of glucose disposal rate through a randomized, double-blind, and placebo-controlled clinical trial [13]. Insulin resistance is frequently associated with hyperglycemia and dyslipidemia, and the ectopic liver fat accumulation played a key role in the development of insulin resistance [14]. In our previous study, BBR significantly decreased hepatic fat content (HFC) in high fat diet induced rats of NAFLD by reducing methylation of the MTTP promoter [15]. Therefore, we speculate that BBR may reverse many of the metabolic abnormalities associated with NAFLD by reducing the HFC. However, the effects and underlying mechanisms of BBR on hepatic steatosis and its associated metabolic abnormalities have never been investigated in patients with NAFLD. In the present study, we carried out a randomized, multicenter, controlled, open-label clinical trial to investigate the efficacy and safety of BBR in NAFLD patients, and also explore the mechanism of BBR’s effect in an animal model of NAFLD. Methods Patients A randomized, parallel controlled, open-label clinical trial was conducted in three medical centers for treating NAFLD patients with impaired glucose regulation (IGR) or T2DM with LSI in combination with pioglitazone (PGZ) or BBR in three centers (NIH Registration number: NCT00633282). The trial design conformed to the revised CONSORT standards for reporting randomized tri (...truncated)