Betulinic Acid Improves Nonalcoholic Fatty Liver Disease Through YY1/FAS Signaling Pathway

Background: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in the worldwide. It is known for excessive accumulation of triglyceride in hepatocytes in the absence of excess alcohol intake. Betulinic acid (BA) is a naturally occurring plant-derived pentacyclic triterpenoid discovered in birch trees and present in many other botanical sources. Methods: High-fat diet (HFD) mice and methionine-choline deficient diet-fed (MCD) mice were used as NAFLD animal models. The molecular mechanism was investigated using mouse liver primary cells and hepatocyte lineage. Findings Here we show that BA-treated HFD mice and MCD mice were resistant to steatosis in the liver than vehicle-treated mice. BA extremely reduced hepatic lipogenesis, inflammation and fibrosis. BA decreased the free fatty acid-induced lipid accumulation in primary hepatocytes and HepG2 cells. Furthermore , we showed that BA could improve lipogenesis through the yin-yang 1( YY1 )/ fatty acid synthase (FAS) pathway in vitro. Interpretation: Our findings establish a novel role for BA in reversing hepatic steatosis and non-alcoholic steatohepatitis. Funding Statement: This study was supported by the National Natural Science Foundation of China (No. 81570719, 81670797, 81770863), partly supported by Key Laboratory for Endocrine and Metabolic Diseases, Chinese Ministry of Public Health (No. 1994DP131044), Ministry of Science & Technology Innovation Fund and projects (No.2011YQ030114), Shanghai Talent development fund (2018091), the Basic Important Program (No.10JC141100), the Sector Funds of Ministry of Health (No. 201002002), and the National Key New Drug Creation and Manufacturing Program by Ministry of Science and Technology (No. 2012ZX09303006-001). This study was supported by the Fund of Shanghai Municipal Education Commission and Shanghai Education Development Foundation (No. 14SG17). Declaration of Interests: The authors declare no competing financial interests. Ethics Approval Statement: All animal protocols used in this study were approved by and conducted in accordance with the guidelines of the Animal Ethical Committee of Ruijin Hospital of Shanghai Jiaotong University.