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, 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.
Highlights
Nonalcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver disease (NAFLD), is characterized by the presence of >5% macrovesicular steatosis, inflammation, and liver cell ballooning [1]
We have previously demonstrated that leucine acts as a direct Sirt1 activator by lowering the activation energy for NAD+ and enables coactivation with other AMPK/Sirt1 activators thereby reducing the necessary concentration for each individual compound [8, 9]
Our data indicate that the triple combination of leucine, metformin, and sildenafil substantially regresses hepatic steatosis, inflammation, and fibrosis and exerts greater effects than the two-way combination, suggesting that this combination may provide a new therapeutic approach to treat NASH
Summary
Nonalcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver disease (NAFLD), is characterized by the presence of >5% macrovesicular steatosis, inflammation, and liver cell ballooning [1]. Its prevalence is increasing concomitantly with prevalence of obesity and diabetes, representing a serious public health issue [2, 3]. Treatment is presently limited to lifestyle intervention, as approved treatment options are lacking and represent a significant unmet need. Sirt regulates multiple inflammatory pathways such as NF-κB and TNFα [2]. They play an important role in the pathophysiology of NAFLD and NASH [2, 4, 5]. Liver-specific deletion of Sirt results in hepatic steatosis and inflammation in mice [6], while treatment with
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