Abstract
Obeticholic acid (OCA) activates the farnesoid X receptor (FXR) to lower circulating total cholesterol (TC) and high density lipoprotein‐cholesterol (HDL‐C) concentrations and to stimulate fecal cholesterol excretion in mice by increasing hepatic SR‐B1 expression. Here we show that hepatic SR‐B1 depletion by an adenovirus expressing Sr‐b1 shRNA (Ad‐shSR‐B1) attenuated these beneficial effects of OCA in mice on a chow diet. The mRNA levels of ABC cholesterol transporter genes (Abca1, Abcg1, Abcg5, and Abcg8) were unchanged in the liver of hepatic SR‐B1‐depleted mice regardless of OCA treatment; however, a modest increase in Abca1, Abcg5, and Abcg8 mRNA levels was observed in the ileum of vehicle‐treated control mice and Abca1 and Abcg8 mRNA levels were increased more by OCA administration. OCA treatment of Sr‐b1 knock out (KO) mice (Sr‐b1‐/‐) fed a normal chow diet (NCD) displayed a similar lack of transhepatic cholesterol movement, as well as a modest increase in the levels of ileum cholesterol transporter expression. However, OCA treatment of Sr‐b1 KO mice fed a cholesterol‐enriched diet reduced circulating cholesterol and increased fecal cholesterol output to comparable degrees to that of wild‐type (WT) mice, and these effects were accompanied by substantial elevations of mRNA levels of Abca1, Abcg1, Abcg5, and Abcg8 in the ileum of Sr‐b1 KO mice. Our studies suggest that FXR activation stimulates intestinal cholesterol excretion and reduces diet‐induced hyperlipidemia through increased expression of ileal cholesterol transporters when hepatic SR‐B1‐mediated cholesterol movement is absent.
Highlights
The farnesoid X receptor (FXR) is a nuclear hormone receptor that is activated by bile acids (BAs) and highly expressed in the liver and other tissues (Forman et al, 1995)
Our results revealed a surprising finding that, in the absence of scavenger receptor class B type 1 (SR-B1), FXR activation in the setting of a high-fat/high-cholesterol diet still reduced serum cholesterol and increased fecal cholesterol elimination and this occurred through the upregulation of cholesterol transporter gene expression in the ileum, a response which appeared to compensate for the loss of SR-B1-facilitated transhepatic cholesterol movement
These results demonstrated that FXR activation by Obeticholic acid (OCA) upregulates hepatic SR-B1 expression, which may account for the reduction of plasma high density lipoprotein-cholesterol (HDL-C) and the increase in fecal cholesterol excretion in hyperlipidemic WT mice as previously reported (Trigatti, Rigotti, & Krieger, 2000)
Summary
The farnesoid X receptor (FXR) is a nuclear hormone receptor that is activated by bile acids (BAs) and highly expressed in the liver and other tissues (Forman et al, 1995). Activation of hepatic FXR modulates the expression of many hepatic genes involved in lipoprotein metabolism, including scavenger receptor class B type 1 (SR-B1), ApoC-II, ApoC-III, and ApoA-I (Lee et al, 2006; Zhang et al, 2006) and induces high-density lipoprotein-mediated transhepatic cholesterol efflux in mice and monkeys (Hambruch et al, 2012). FXR activation in rodents has been shown to protect from atherosclerosis (Hartman et al, 2009) and nonalcoholic fatty liver disease (NAFLD) (Kong, Luyendyk, Tawfik, & Guo, 2009; Zhang, Wang, Liu, & Harnish, 2009). Despite the established connection of increased SR-B1 expression and enhanced transhepatic cholesterol excretion upon FXR activation by OCA or other FXR agonists, up to today, no studies have investigated the impact of SR-B1 deficiency on FXR-mediated regulation of plasma and hepatic lipid metabolism. Our results revealed a surprising finding that, in the absence of SR-B1, FXR activation in the setting of a high-fat/high-cholesterol diet still reduced serum cholesterol and increased fecal cholesterol elimination and this occurred through the upregulation of cholesterol transporter gene expression in the ileum, a response which appeared to compensate for the loss of SR-B1-facilitated transhepatic cholesterol movement
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