The intrahepatic expression levels of bile acid transporters are inversely correlated with the histological progression of nonalcoholic fatty liver disease

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Abstract
Nonalcoholic fatty liver disease (NAFLD) presents as a spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). The latter is progressive, and its pathogenesis remains poorly understood. Recently, bile acid (BA) metabolism has become a therapeutic focus in NASH patients. The aim of the present study was to explore changes in bile acid metabolism in NAFLD patients in the context of disease progression. We prospectively enrolled patients with clinically suspected NAFLD. Patients taking ursodeoxycholic acid were excluded. The intrahepatic expression levels of genes associated with BA metabolism were determined by quantitative PCR and immunohistochemistry. Seventy-eight patients (male:female = 49:29) histologically diagnosed with NAFLD were analyzed. The expression levels of farnesoid X receptor, liver receptor homolog 1, and small heterodimer partner, key proteins in BA synthesis, significantly decreased as the NAFLD activity score (NAS) increased in either males or females. The levels of cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme of BA synthesis, were not changed. Notably, the expression levels of a main export transporter, bile salt export pump (BSEP), significantly decreased as the NAS and the each NAS component increased in both genders. The decreases of BSEP levels were also observed by immunohistochemistry, particularly in areas with pronounced fatty changes in cases with high NAS. The expression levels of the BA export transporter BSEP were inversely correlated with NAS in NAFLD patients. Such down-regulation may cause excessive BA levels in hepatocytes, leading to cell injury. Our findings may afford new insights into the pathogenesis of NASH.

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