Abstract
BackgroundSirt6 has been implicated in the regulation of hepatic lipid metabolism and the development of hepatic steatosis. The aim of this study was to address the potential role of Sirt6 in the protective effects of rosiglitazone (RGZ) on hepatic steatosis.MethodsTo investigate the effect of RGZ on hepatic steatosis, rats were treated with RGZ (4 mg·kg−1·day−1) by stomach gavage for 6 weeks. The involvement of Sirt6 in the RGZ's regulation was evaluated by Sirt6 knockdown in AML12 mouse hepatocytes.ResultsRGZ treatment ameliorated hepatic lipid accumulation and increased expression of Sirt6, peroxisome proliferator-activated receptor gamma coactivtor-1-α (Ppargc1a/PGC1-α) and Forkhead box O1 (Foxo1) in rat livers. AMP-activated protein kinase (AMPK) phosphorylation was also increased by RGZ, accompanied by alterations in phosphorylation of LKB1. Interestingly, in free fatty acid-treated cells, Sirt6 knockdown increased hepatocyte lipid accumulation measured as increased triglyceride contents (p = 0.035), suggesting that Sirt6 may be beneficial in reducing hepatic fat accumulation. In addition, Sirt6 knockdown abolished the effects of RGZ on hepatocyte fat accumulation, mRNA and protein expression of Ppargc1a/PGC1-α and Foxo1, and phosphorylation levels of LKB1 and AMPK, suggesting that Sirt6 is involved in RGZ-mediated metabolic effects.ConclusionOur results demonstrate that RGZ significantly decreased hepatic lipid accumulation, and that this process appeared to be mediated by the activation of the Sirt6-AMPK pathway. We propose Sirt6 as a possible therapeutic target for hepatic steatosis.
Highlights
Hepatic steatosis is a relatively benign and early condition of nonalcoholic fatty liver disease (NAFLD), which is strongly associated with obesity and insulin resistance [1,2]
Using a rat model of moderate obesity and insulin resistance and a cell model of hepatocyte steatosis, we report upregulation of adiponectin, Sirt6, peroxisome proliferator-activated receptor gamma coactivtor-1-a (Ppargc1a/PGC1-a) and forkhead box O1 (Foxo1), as well as increases in both LKB1 and AMPK activities upon RGZ treatment
Sirt6 knockdown abolished the effects of RGZ on hepatocyte fat accumulation and the Sirt6-AMPK pathway, suggesting that Sirt6 is involved in RGZ-mediated metabolic effects
Summary
Hepatic steatosis is a relatively benign and early condition of nonalcoholic fatty liver disease (NAFLD), which is strongly associated with obesity and insulin resistance [1,2]. TZD-activated PPARc improves insulin sensitivity in most tissues, but affects lipid metabolism in a cell- and tissue-specific manner. TZD-activated PPARc stimulates adipocyte differentiation and induces lipogenic enzymes, thereby increasing fat storage, especially into subcutaneous adipose tissue [8,9,10]. This sequestration of lipid into adipose tissue decreases circulating levels of triglyceride (TG) and free fatty acids (FFA), decreasing lipid uptake in the liver.
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