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  • FXR activation promotes intestinal cholesterol excretion and attenuates hyperlipidemia in SR-B1-deficient mice fed a high-fat and high-cholesterol diet.

FXR activation promotes intestinal cholesterol excretion and attenuates hyperlipidemia in SR-B1-deficient mice fed a high-fat and high-cholesterol diet.

Physiological reports (2020-03-15)
Amar B Singh, Bin Dong, Fredric B Kraemer, Jingwen Liu
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Cyp7a1 Antibody, clone 15B9.1, clone 15B9.1, from mouse
Sigma-Aldrich
Anti-β-Actin antibody, Mouse monoclonal, clone AC-15, purified from hybridoma cell culture