Transgenic expression of CYP7A1 in LDL receptor-deficient mice blocks diet-induced hypercholesterolemia.
Constitutive expression of a cholesterol-7alpha-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 ( approximately 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.
Ratliff
Eric P
EP
Heart Institute, BioScience Center, San Diego State University, CA 92182, USA.
Gutierrez
Alejandra
A
Davis
Roger A
RA
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics* / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004036:Diet, Atherogenic; D015870:Gene Expression; D006937:Hypercholesterolemia / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D007408:Intestinal Absorption; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D026901:Membrane Transport Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D057093:Orphan Nuclear Receptors; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics
D018528:ATP-Binding Cassette Transporters; D002791:Cholesterol, Dietary; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D026901:Membrane Transport Proteins; C482445:Npc1l1 protein, mouse; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL; D011994:Recombinant Proteins; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases