Therapeutic Role of Ursolic Acid on Ameliorating Hepatic Steatosis and Improving Metabolic Disorders in High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease Rats

Songtao Li,Yemei Wang,Fanyu Meng,Man Meng,Xiaoxia Li,Xilu Liao,Ying Li,Changhao Sun,Fuchuan Guo,Zongxiang Sun,Carlos M Rodriguez-Ortigosa

doi:10.1371/journal.pone.0086724

Abstract

BackgroundNon-alcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases around the world, and is closely associated with obesity, diabetes, and insulin resistance. Ursolic acid (UA), an ubiquitous triterpenoid with multifold biological roles, is distributed in various plants. This study was conducted to investigate the therapeutic effect and potential mechanisms of UA against hepatic steatosis in a high-fat diet (HFD)-induced obese non-alcoholic fatty liver disease (NAFLD) rat model.Methodology/Principal FindingsObese NAFLD model was established in Sprague-Dawley rats by 8-week HFD feeding. Therapeutic role of UA was evaluated using 0.125%, 0.25%, 0.5% UA-supplemented diet for another 6 weeks. The results from both morphologic and histological detections indicated that UA significantly reversed HFD-induced hepatic steatosis and liver injury. Besides, hepatic peroxisome proliferator-activated receptor (PPAR)-α was markedly up-regulated at both mRNA and protein levels by UA. Knocking down PPAR-α significantly inhibited the anti-steatosis role of UA in vitro. HFD-induced adverse changes in the key genes, which participated in hepatic lipid metabolism, were also alleviated by UA treatment. Furthermore, UA significantly ameliorated HFD-induced metabolic disorders, including insulin resistance, inflammation and oxidative stress.Conclusions/SignificanceThese results demonstrated that UA effectively ameliorated HFD-induced hepatic steatosis through a PPAR-α involved pathway, via improving key enzymes in the controlling of lipids metabolism. The metabolic disorders were accordingly improved with the decrease of hepatic steatosis. Thereby, UA could be a promising candidate for the treatment of NAFLD.

Highlights

Non-alcoholic fatty liver disease (NAFLD) encompasses a cluster of liver disorders, ranging from accumulation of fat in liver to nonalcoholic steatohepatitis, with some people progressing to fibrosis, cirrhosis and liver failure
Conclusions/Significance: These results demonstrated that Ursolic acid (UA) effectively ameliorated high-fat diet (HFD)-induced hepatic steatosis through a peroxisome proliferator-activated receptor (PPAR)-a involved pathway, via improving key enzymes in the controlling of lipids metabolism
Using a well-accepted HFD-induced NAFLD rat model, we reported the therapeutic role of UA for the first time on alleviating hepatic steatosis and liver injury, and further improving metabolic disorders, including serum lipid disorder, insulin resistance, inflammation and oxidative stress

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) encompasses a cluster of liver disorders, ranging from accumulation of fat in liver (steatosis) to nonalcoholic steatohepatitis (necrosis and inflammation), with some people progressing to fibrosis, cirrhosis and liver failure. Because of its high prevalence in conjunction with obesity, diabetes, and insulin resistance, NAFLD is being increasingly appreciated as a hepatic manifestation of the metabolic syndrome and represents a major cause of liver-related morbidity and mortality [1,2,3]. Improvement of hepatic lipid metabolism and attenuation of fat accumulation have been shown to have therapeutic potential in preventing the progression of NAFLD and alleviating insulin resistance, inflammation and oxidative stress. This study was conducted to investigate the therapeutic effect and potential mechanisms of UA against hepatic steatosis in a high-fat diet (HFD)-induced obese non-alcoholic fatty liver disease (NAFLD) rat model

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