Transgenic expression of CYP7A1 in LDL receptor-deficient mice blocks diet-induced hypercholesterolemia

• Published in: Journal of lipid research Vol. 47; no. 7; pp. 1513 - 1520
• Main Authors: Ratliff, Eric P., Gutierrez, Alejandra, Davis, Roger A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2006; American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Animals; ATP-Binding Cassette Transporters - metabolism; bile acids; cholesterol; Cholesterol 7-alpha-Hydroxylase - genetics; Cholesterol 7-alpha-Hydroxylase - metabolism; Cholesterol, Dietary - metabolism; cholesterol-7α-hydroxylase; Diet, Atherogenic; DNA-Binding Proteins - metabolism; Gene Expression; Hypercholesterolemia - etiology; Hypercholesterolemia - metabolism; Hypercholesterolemia - prevention & control; Intestinal Absorption; Liver - metabolism; Liver X Receptors; low density lipoprotein receptors; Membrane Transport Proteins - genetics; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Niemann-Pick C1-Like 1 protein; Orphan Nuclear Receptors; Proprotein Convertase 9; proprotein convertase subtilisin/kexin type 9; Proprotein Convertases; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, LDL - deficiency; Receptors, LDL - genetics; Receptors, LDL - metabolism; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Serine Endopeptidases - genetics; Sterol Regulatory Element Binding Protein 2 - genetics; cholesterol-7α-hydroxylase; low density lipoprotein receptors; proprotein convertase subtilisin/kexin type 9; cholesterol; Niemann-Pick C1-Like 1 protein; bile acids
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M600120-JLR200

Constitutive expression of a cholesterol-7α-hydroxylase (CYP7A1) transgene in LDL receptor-deficient mice blocked the ability of a cholesterol-enriched diet to increase plasma levels of apolipoprotein B-containing lipoproteins. LDL receptor-deficient mice expressing the CYP7A1 transgene exhibited complete resistance to diet-induced hypercholesterolemia and to the accumulation of cholesterol in the liver. Hepatic mRNA expression of liver X receptor-inducible ABCG5 and ABCG8 was decreased in CYP7A1 transgenic, LDL receptor-deficient mice fed a cholesterol-enriched diet. Thus, increased biliary cholesterol excretion could not account for the maintenance of cholesterol homeostasis. CYP7A1 transgenic, LDL receptor-deficient mice fed the cholesterol-enriched diet exhibited decreased jejunal Niemann-Pick C1-Like 1 protein (NPC1L1) mRNA expression, an important mediator of intestinal cholesterol absorption. A taurocholate-enriched diet also decreased NPC1L1 mRNA expression in a farnesoid X receptor-independent manner. Reduced expression of NPC1L1 mRNA was associated with decreased cholesterol absorption (∼20%; P < 0.05) exhibited by CYP7A1 transgenic LDL receptor-deficient mice fed the cholesterol-enriched diet. The combined data show that enhanced expression of CYP7A1 is an effective means to prevent the accumulation of cholesterol in the liver and of atherogenic apolipoprotein B-containing lipoproteins in plasma.