Human cholesterol 7α-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype

Abstract

Bile acid synthesis plays a critical role in the maintenance of mammalian cholesterol homeostasis. The CYP7A1 gene encodes the enzyme cholesterol 7α-hydroxylase, which catalyzes the initial step in cholesterol catabolism and bile acid synthesis. We report here a new metabolic disorder presenting with hyperlipidemia caused by a homozygous deletion mutation in CYP7A1. The mutation leads to a frameshift (L413fsX414) that results in loss of the active site and enzyme function. High levels of LDL cholesterol were seen in three homozygous subjects. Analysis of a liver biopsy and stool from one of these subjects revealed double the normal hepatic cholesterol content, a markedly deficient rate of bile acid excretion, and evidence for upregulation of the alternative bile acid pathway. Two male subjects studied had hypertriglyceridemia and premature gallstone disease, and their LDL cholesterol levels were noticeably resistant to 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. One subject also had premature coronary and peripheral vascular disease. Study of the kindred, which is of English and Celtic background, revealed that individuals heterozygous for the mutation are also hyperlipidemic, indicating that this is a codominant disorder

Disruption of the Murine Protein Kinase Cβ Gene Promotes Gallstone Formation and Alters Biliary Lipid and Hepatic Cholesterol Metabolism

“…The reduction in CYP7A1 gene expression in PKC␤ Ϫ/Ϫ mice is likely responsible for increased susceptibility to gallstone formation as compared with WT mice. Human CYP7A1 deficiency is known to promote premature gallstone formation (51,52), whereas CYP7A1 transgenic mice provide resistance to gallstone formation (53). Several human studies also suggest that an A to C nucleotide substitution in position Ϫ204 of the CYP7A1 promoter is associated with variation in plasma LDL cholesterol concentrations (54,55).…”

The sterol transporting heterodimer ABCG5/ABCG8 requires bile salts to mediate cholesterol efflux

“…When bile salt micelles indeed play an indispensable role in sterol uptake from Abcg5/g8 one would expect this to have consequences for sterol absorption in the intestine as well. Indeed, patients with a defect in 7-a-hydroxylase activity leading to strongly decreased levels of bile salts show increased levels of plant sterols in plasma [29].…”

The adipokine Retnla modulates cholesterol homeostasis in hyperlipidemic mice

“…The classical pathway accounts for the majority of total bile acid synthesis and is mediated by cholesterol-7-ahydroxylase (CYP7A1), the first and rate-limiting enzyme of the pathway 30 . Both gain-and loss-of-function studies have demonstrated that CYP7A1 plays an important role in the pathogenesis of hypercholesterolaemia and atherosclerosis [31][32][33] .…”

“…Patients with CYP7A1 deficiency have been shown to develop elevated plasma LDL cholesterol levels and hepatic cholesterol contents, gallstones and premature atherosclerosis 33 .…”