Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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ATP-Binding Cassette Transporters / metabolism
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Animals
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Cholesterol 7-alpha-Hydroxylase / genetics*
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Cholesterol 7-alpha-Hydroxylase / metabolism*
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Cholesterol, Dietary / metabolism
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DNA-Binding Proteins / metabolism
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Diet, Atherogenic
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Gene Expression
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Hypercholesterolemia / etiology
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Hypercholesterolemia / metabolism
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Hypercholesterolemia / prevention & control*
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Intestinal Absorption
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Liver / metabolism
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Liver X Receptors
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Membrane Transport Proteins / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Orphan Nuclear Receptors
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Proprotein Convertase 9
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Proprotein Convertases
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Cytoplasmic and Nuclear / metabolism
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Receptors, LDL / deficiency*
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Receptors, LDL / genetics
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Receptors, LDL / metabolism
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Serine Endopeptidases / genetics
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Sterol Regulatory Element Binding Protein 2 / genetics
Substances
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ATP-Binding Cassette Transporters
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Cholesterol, Dietary
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DNA-Binding Proteins
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Liver X Receptors
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Membrane Transport Proteins
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Npc1l1 protein, mouse
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Orphan Nuclear Receptors
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RNA, Messenger
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Receptors, Cytoplasmic and Nuclear
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Receptors, LDL
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Recombinant Proteins
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Srebf2 protein, mouse
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Sterol Regulatory Element Binding Protein 2
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Cholesterol 7-alpha-Hydroxylase
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Cyp7a1 protein, mouse
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Pcsk9 protein, mouse
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Proprotein Convertase 9
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Proprotein Convertases
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Serine Endopeptidases