A Combination of Leucine, Metformin, and Sildenafil Treats Nonalcoholic Fatty Liver Disease and Steatohepatitis in Mice. (30th November 2016)

• Record Type: Journal Article
• Authors: Bruckbauer, Antje; Banerjee, Jheelam; Fu, Lizhi; Li, Fenfen; Cao, Qiang; Cui, Xin; Wu, Rui; Shi, Hang; Xue, Bingzhong; Zemel, Michael B.
• Other Names: Francis Heather Academic Editor.
• Is Part Of: International journal of hepatology. Volume 2016(2016)
• Publication Date: 2016-11-30
• Subjects: Hepatology -- Periodicals; Liver Diseases; Gastroenterology; Hepatology; Electronic journals; Periodicals; Periodicals; Fulltext; Internet Resources; Periodicals; 616.3
• DOI: 10.1155/2016/9185987
• Languages: English
• ISSNs: 2090-3448

Abstract

Abstract : Sirt1, AMPK, and eNOS modulate hepatic energy metabolism and inflammation and are key players in the development of NASH. L-leucine, an allosteric Sirt1 activator, synergizes with low doses of metformin or sildenafil on the AMPK-eNOS-Sirt1 pathway to reverse mild NAFLD in preclinical mouse models. Here we tested a possible multicomponent synergy to yield greater therapeutic efficacy in NAFLD/NASH. Liver cells and macrophages or an atherogenic diet induced NASH mouse model was treated with two-way and three-way combinations. The three-way combination Sild-Met-Leu increased hepatic fatty acid oxidation and reduced lipogenic gene expression and inflammatory marker in vitro . In mice, Sild-Met-Leu reduced the diet induced increases of ALT, TGF β, PAI-1, IL1 β, and TNF α, hepatic collagen expression, and nearly completely reversed hepatocyte ballooning and triglyceride accumulation, while all two-way combinations had only modest effects. Therefore, these data provide preclinical evidence for therapeutic efficacy of Sild-Met-Leu in the treatment of NAFLD and NASH.