title: A Combination of Leucine, Metformin, and Sildenafil Treats Nonalcoholic Fatty Liver Disease and Steatohepatitis in Mice.
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 markerin vitro. In mice, Sild-Met-Leu reduced the diet induced increases of ALT, TGFβ, PAI-1, IL1β, and TNFα, 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.
authors.affiliation: NuSirt Biopharma Inc., 11020 Solway School Rd, Knoxville, TN 37931, USA.
authors.forename: Antje
authors.identifier: 0000-0002-1177-033X
authors.initials: A
authors.lastname: Bruckbauer
authors.affiliation: NuSirt Biopharma Inc., 11020 Solway School Rd, Knoxville, TN 37931, USA.
authors.forename: Jheelam
authors.identifier: 0000-0003-0036-5352
authors.initials: J
authors.lastname: Banerjee
authors.affiliation: Center for Obesity Reversal, Department of Biology, Georgia State University, 33 Gilmer Street SE, Atlanta, GA 30302, USA.
authors.forename: Lizhi
authors.initials: L
authors.lastname: Fu
authors.affiliation: Center for Obesity Reversal, Department of Biology, Georgia State University, 33 Gilmer Street SE, Atlanta, GA 30302, USA.
authors.forename: Fenfen
authors.initials: F
authors.lastname: Li
authors.affiliation: Center for Obesity Reversal, Department of Biology, Georgia State University, 33 Gilmer Street SE, Atlanta, GA 30302, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Center for Obesity Reversal, Department of Biology, Georgia State University, 33 Gilmer Street SE, Atlanta, GA 30302, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Cui
authors.affiliation: Center for Obesity Reversal, Department of Biology, Georgia State University, 33 Gilmer Street SE, Atlanta, GA 30302, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Wu
authors.affiliation: Center for Obesity Reversal, Department of Biology, Georgia State University, 33 Gilmer Street SE, Atlanta, GA 30302, USA.
authors.forename: Hang
authors.initials: H
authors.lastname: Shi
authors.affiliation: Center for Obesity Reversal, Department of Biology, Georgia State University, 33 Gilmer Street SE, Atlanta, GA 30302, USA.
authors.forename: Bingzhong
authors.identifier: 0000-0002-7857-1343
authors.initials: B
authors.lastname: Xue
authors.affiliation: NuSirt Biopharma Inc., 11020 Solway School Rd, Knoxville, TN 37931, USA.
authors.forename: Michael B
authors.identifier: 0000-0003-4104-5750
authors.initials: MB
authors.lastname: Zemel