Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease. NAFLD progresses from benign steatosis to steatohepatitis (NASH) to cirrhosis and is linked to hepatocellular carcinoma. No targeted treatment is currently approved for NAFLD/NASH. We previously showed that fat-specific protein 27 (FSP27), a lipid droplet-associated protein that controls triglyceride turnover in the hepatocyte, is required for fasting- and diet-induced triglyceride accumulation in the liver. However, silencing Fsp27 with antisense oligonucleotides (ASOs) did not improve hepatosteatosis in genetic nor nutritional mouse models of obesity. Herein, we tested the therapeutic potential of ASO-Fsp27 when used in combination with the PPARα agonist fenofibrate. C57BL/6 mice were fed a high-trans-fat, high-cholesterol, high-fructose diet for eight weeks to establish NASH, then kept on diet for six additional weeks while dosed with ASOs and fenofibrate, alone or in combination. Data show that ASO-Fsp27 and fenofibrate synergize to promote resistance to diet-induced obesity and hypertriglyceridemia and to reverse hepatic steatosis, inflammation, oxidative stress, and fibrosis. This multifactorial improvement of liver disease noted when combining both drugs suggests that a course of treatment that includes both reduced FSP27 activity and activation of PPARα could provide therapeutic benefit to patients with NAFLD/NASH.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease
To determine the effects of a combined therapy (Fsp27 silencing and PPAR activation) on diet-induced steatohepatitis, we fed C57BL/6 mice a high-trans-fat, highcholesterol, high-fructose diet that has been shown to result in severe hepatosteatosis and mild hepatic inflammation and fibrosis [18, 19, 21, 23]
Consistent with these data, analysis of body composition by NMR revealed a significant decrease in fat mass upon treatment with either fenofibrate or antisense oligonucleotide (ASO)-Fsp27, in comparison with control NAFLD progresses from benign steatosis to steatohepatitis (NASH)-fed mice, but combined treatment led to a synergistic reduction in fat mass, again similar to that in mice switched to chow diet (Fig. 1C)
Summary
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease. We tested the therapeutic potential of ASO-Fsp when used in combination with the PPAR agonist fenofibrate. Data show that ASO-Fsp and fenofibrate synergize to promote resistance to diet-induced obesity and hypertriglyceridemia and to reverse hepatic steatosis, inflammation, oxidative stress, and fibrosis. This multifactorial improvement of liver disease noted when combining both drugs suggests that a course of treatment that includes both reduced FSP27 activity and activation of PPAR could provide therapeutic benefit to patients with NAFLD/ NASH.—Rajamoorthi, A., N. Amelioration of diet-induced steatohepatitis in mice following combined therapy with ASO-Fsp and fenofibrate.
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