Abstract
The incidence of nonalcoholic steatohepatitis (NASH) is increasing worldwide, including in Asian countries. We reported that the hepatic expression of bile salt export pump (BSEP) was downregulated in patients with NASH, suggesting that BSEP is involved in the pathogenesis of NASH. To identify the underlying mechanism, we analyzed Bsep heterozygous knock-out (Bsep+/- mice) and wild-type (WT) C57BL/6J mice fed a high-fat diet (HFD) (32.0% animal fat) or normal diet. We examined histological changes, levels of hepatic lipids and hepatic bile acids, and expression of genes related to bile acid and cholesterol metabolism. HFD-fed Bsep+/- mice exhibited milder hepatic steatosis and less weight gain, compared to HFD-fed WT mice. The concentrations of total bile acid, triglycerides, and cholesterols were reduced in the liver of HFD-fed Bsep+/- mice. Regarding hepatic bile acid metabolism, the expression levels of Farnesoid X receptor (Fxr) and Multidrug resistance-associated protein 2 were significantly upregulated in HFD-fed Bsep+/- mice, compared to HFD-fed WT mice. Furthermore, several alterations were observed in upstream cholesterol metabolism in the liver. The expression levels of bile acid metabolism-related genes were also altered in the intestine of HFD-fed Bsep+/- mice. In conclusion, HFD-fed Bsep+/- mice exhibited significant alterations of the expression levels of genes related to bile acid and lipid metabolism in both the liver and ileum, resulting in alleviated steatosis and less weight gain. These results suggest the importance of BSEP for maintenance of bile acid and cholesterol metabolism. Further investigations of the involvement of BSEP in the pathogenesis of NASH will provide greater insight and facilitate the development of novel therapeutic modalities.
Highlights
The incidence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide, including in Asian countries [1,2,3,4]
We previously reported that the intrahepatic expression of the bile salt export pump (BSEP) was downregulated during progression of NAFLD, suggesting that BSEP is involved in the pathogenesis of nonalcoholic steatohepatitis (NASH) [27]
Because patients with NASH have reduced but not absent expression of BSEP [27], we used Bsep+/- mice fed an high-fat diet (HFD) to evaluate the role of BSEP in the pathogenesis of NASH
Summary
The incidence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide, including in Asian countries [1,2,3,4]. NASH is progressive and is considered a causative factor of cirrhosis, hepatocellular carcinoma, and systemic metabolic disorders [5,6,7]. Bile acid has been recognized as a ligand of nuclear receptor farnesoid X receptor (FXR) [8,9,10]; it is considered a central factor in systemic metabolic pathways, including glucose and lipid metabolism [11,12,13,14]. NAFLD and NASH are closely related to systemic metabolism. We previously reported that the intrahepatic expression of the bile salt export pump (BSEP) was downregulated during progression of NAFLD, suggesting that BSEP is involved in the pathogenesis of NASH [27]. We investigated the role of BSEP in the pathogenesis of NASH by using mice with a Bsep modification
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