3 years ago

ApoE is a major determinant of hepatic bile acid homeostasis in mice

ApoE plays a central role in lipid transport and cholesterol metabolism with surplus cholesterol being removed from the liver through bile acid (BA) synthesis. Furthermore, BAs are of critical importance in fat absorption by forming intestinal lipid-bile salt mixed micelles. To define ApoE's role in BA homeostasis the metabolism of cholesterol and BA was investigated in liver tissue and gallbladder bile of ApoE-deficient mice given a Chow or high-cholesterol/high-fat diet (HCHF) diet for 6 months. When compared to wild-type mice muricholic-(MCA) and chenodeoxycholic acid-(CDCA) increased approximately 15-, 82-, 22- and 38-fold, respectively in hepatic tissue of ApoE-deficient mice given a Chow or HCHF diet. Moreover, ApoE-deficient mice on a HCHF diet increased the amounts of hepatic free cholesterol, MCA and CDCA by 61%, 61% and 50% (P<.05%). Conversely, total cholesterol and cholesterol esters were unchanged and the bile acids THDCA, TDCA and HDCA decreased to 1/3 as compared to the Chow diet (P<.05). Additionally, RT-qPCR assays revealed induced expression of the bile acid receptor (Fxr) and associated transcription factors, i.e. Fxr, Lrh, Lxra and Srebp1c. Transcript expression of Cyp2a12, Cyp1b1 Cyp2e1, Cyp3a16 and Cyp4a10 was also induced. Note Cyp4a10 catalyzes ω-hydroxylation of arachidonic acid to epoxy- and hydroxyeicosatrienoic acids to control vascular tone. Altogether, MCA and CDCA synthesis is selectively induced in ApoE-deficient mice. These hydrophilic BA alter micellar size and structure to lower intestinal cholesterol solubilization. Furthermore, CDCA and MCA are potent FXR-agonist and antagonist, respectively and function in a regulatory loop to mitigate impaired ApoE function.

Publisher URL: www.sciencedirect.com/science

DOI: S0955286317303480

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