Pemafibrate modulates peroxisome proliferator-activated receptor alpha and prevents alcohol-associated liver disease in rats.

BACKGROUND AND AIMS: Alcohol-associated liver disease (ALD) with steatosis or steatohepatitis that could progress to liver cirrhosis is a common problem in chronic alcohol consumption. Pemafibrate is a novel, highly specific peroxisome proliferator-activated receptor-α (PPARα) modulator, which regulates the expression of the target genes related to lipid and glucose metabolism. Here, we evaluated the effect of pemafibrate to prevent ALD and steatosis in rats. METHODS: The animals were treated with liquid diet containing ethanol (36% of total calories) or an isocaloric carbohydrate diet for 4 weeks. Subsequently, both groups were fed with either 0.5% aqueous methylcellulose solution (MC) or MC containing 0.3 mg/kg body weight of pemafibrate orally twice a day along with the liquid diet for another 4 weeks. A set of animals were sacrificed at the 4th week before the start of pemafibrate treatment and the remaining animals at the end of 8 weeks. Blood and liver samples were collected for biochemical and histopathological evaluations. RESULTS: Treatment with pemafibrate prevented inflammation and steatosis in the hepatic tissue. Furthermore, pemafibrate administration markedly increased hepatic NAD and NADH levels, reduced both serum and hepatic triglyceride levels, and upregulated the expression of molecules involved in lipid metabolism. CONCLUSIONS: The results of the present study demonstrated that pemafibrate modulates target genes related to hepatic lipid metabolism and prevents deposition of fat globules in the liver during chronic alcohol feeding in rats. Therefore, pemafibrate could be used as a potent therapeutic agent to prevent steatosis and related adverse events in ALD.