High Cholesterol And Fenofibrate Stimulate Bile Acid Synthesis Via LXR,PPARα Respectively In Rats

Objective: Bile acids are formed in the liver from cholesterol and their synthesis represents an important pathway for elimination of cholesterol from body. There are two major biosynthetic pathway in liver: classic (or neutral) and alternative (or acidic) pathway. Cholesterol is either catalyzed to 7α-hydroxycholesterol by the rate-limiting enzyme CYP7A1 in the endoplasmic reticulum or converted into 27-hydroxycholesterol by CYP27A1 in the mitochondria. The 7α-, or 27-hydroxycholesterol is hydroxylated and links to HsCoA. Then the product tri- and dihydroxycholestanoyl-CoA (THC-CoA and DHC-CoA) enter into peroxisome forβ-oxidation which involves four steps and three enzymes: Trihydroxycoprostanoyl-CoA oxidase (Acox2) for oxidation, D-3-Hydroxyacyl-CoA dehydratase /D-3- Hydroxyacyl-CoA dehydrogenase (D-bifunctional protein, DBP) for hydration and dehydrogenation and SCPx thiolase for thiolysis. In the end, they are converted to cholic acid (CA) or chenodeoxycholic acid (CDCA). The sterol 12α-hydroxylase (CYP8B1) is a hepatic microsomal enzyme that catalyzes the conversion of cholic acid to chenodeoxycholic acid. This conversion determines the ratio of cholic acid to chenodeoxycholic acid.