Molecular Analysis of Cholestyramine Treatment in Hamster Model Identified CYP51 as Cholestyramine‐Responsive Gene

Abstract

Cholestyramine (CA) is a bile acid sequestrant widely used as a cholesterol‐lowering drug to treat hypercholesterolemia, one of the major risk factors for cardiovascular disease. Despite the wide usage of CA, its effect on cholesterol and lipid metabolism at molecular level and over long term remains unclear. The current study aimed to further understand CA's molecular effect on cholesterol and lipid metabolism. Male golden Syrian hamsters were fed diets containing 36 kcal% fat with or without 1% CA, or chow for 35 days. As expected, CA supplementation inhibited the increases in liver weight, VLDL, LDL, hepatic cholesterol and bile acids induced by high‐fat diet. CA significantly increased excretion of bile acids, while cholesterol excretion was unchanged. Interestingly, gene expression assay identified that cholesterol synthesis‐related Cytochrome p450, Family 51 (CYP51) but not HMG‐CoA reductase (HMG‐CoAR) mRNA expression was significantly increased in CA treated group. Cholesterol, bile acids and lipid metabolism associated gene (LDL receptor, CYP7A1, LXRα, and ABCG5/8) expressions were also significantly altered by CA. In summary, CYP51 was identified as a novel enzyme regulated by CA ingestion in hamster model. CYP51 and not HMG‐CoAR up‐regulation was employed to maintain plasma cholesterol in hamster model. CYP51 may warrant further consideration as potential target for management of hypercholesterolemia in human.