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Abstract
Sirtuin (SIRT) is known to prevent nonalcoholic fatty liver disease (NAFLD); however, the role of SIRT4 in the progression of hepatic fibrosis remains unknown. We hypothesize that EX-527, a selective SIRT1 inhibitor, can inhibit the progression of high-fat diet (HFD)-induced hepatic fibrosis. We found that SIRT4 expression in the liver of NAFLD patients is significantly lower than that in normal subjects. In this study, EX-527 (5 µg/kg), administered to HFD rats twice a week for ten weeks, reduced the serum levels of triglyceride (TG), total cholesterol, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) and attenuated hepatic fibrosis evidenced by Masson’s trichrome and hepatic fat by oil red-O staining. EX-527 upregulated SIRT2, SIRT3, and SIRT4 expression in the liver of HFD fed rats but downregulated transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) expression. It decreased proinflammatory cytokine production and hydroxyproline levels in the serum and SMAD4 expression and restored apoptotic protein (Bcl-2, Bax, and cleaved caspase-3) expression. These data propose a critical role for the SIRT4/SMAD4 axis in hepatic fibrogenesis. SIRT4 upregulation has the potential to counter HFD-induced lipid accumulation, inflammation, and fibrogenesis. We demonstrate that EX-527 is a promising candidate in inhibiting the progression of HFD-induced liver fibrosis.
Highlights
Advanced liver fibrosis can progress to cirrhosis and lead to serious complications in liver disease.Among the liver diseases, nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in Western countries [1]
We explored the effect of EX-527, a SIRT1-selective inhibitor, on the progression of high-fat diet (HFD)-induced fatty liver or fibrosis in Zucker diabetic fatty (ZDF) rats
It was reported that the expression of SIRT4 mRNA and protein is increased in patients with NAFLD, which suggested that SIRT4 might promote the progress of NAFLD [21]
Summary
Advanced liver fibrosis can progress to cirrhosis and lead to serious complications in liver disease.Among the liver diseases, nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in Western countries [1]. Advanced liver fibrosis can progress to cirrhosis and lead to serious complications in liver disease. Fat accumulation characterized by an increase in intrahepatic triglyceride content in the liver is a major cause of NAFLD development [3]. Elevated fasting blood glucose and obesity are risk factors for NAFLD, nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. The correlation between obesity and the progression of type 2 diabetes and liver fibrosis is reported [2,3,4]. Obesity is one of the key parameters for the increase in development of liver fibrosis. Pharmaceutical interventions are important for NAFLD and complications such as liver fibrosis and steatosis. Treatment of obesity with suitable drug therapies will be needed to inhibit the progression of hepatic fibrosis
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