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

Abstract

Constitutive expression of a cholesterol-7a-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 receptorinducible ABCG5 and ABCG8 was decreased in CYP7A1 transgenic, LDL receptor-deficient mice fed a cholesterolenriched 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 (z20%; 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, E. P., A. Gutierrez, and R. A. Davis. Hepatic expression of cholesterol-7a-hydroxylase (CYP7A1), the enzyme regulating the conversion of cholesterol to bile acids, plays a crucial role in eliminating excess cholesterol from the body (reviewed in 1). Studies in rats show that biliary excretion of bile acids and cholesterol accounts for z85% of the cholesterol eliminated from the body (2). The ability of the cholesterol-to-bile acid pathway to vary in parallel with changes in the endogenous cholesterol pool plays an important role in maintaining whole body cholesterol homeostasis (3, 4). In rodents such as mice and rats, sterol-mediated activation of the nuclear liver X receptor (LXR) increases CYP7A1 gene expression and, thus, provides a mechanism to maintain cholesterol homeostasis (5, 6). In contrast to the rat and mouse CYP7A1 genes, the human CYP7A1 gene does not display LXRmediated enhancement of transcription (7,8).By altering hepatic expression of sterol-regulatory element binding protein (SREBP)-mediated genes, CYP7A1 has a marked influence on many processes that control lipoprotein production as well as LDL receptor-dependent removal from plasma (9, 10). Hepatic expression of CYP7A1 indirectly controls plasma LDL levels by influencing the expression of LDL receptors (11). Studies showing that the expression of CYP7A1 in nonhepatic CHO cells enhanced the expression of LDL receptors further indicate the critical role for cholesterol catabolism in maintaining cholesterol homeostasis (9). Transgenic expression of CYP7A1 in hepatoma cells (10), CHO cells (12), and macrophages (13) also acti...

Dietary herring improves plasma lipid profiles and reduces atherosclerosis in obese low-density lipoprotein receptor-deficient mice

“…In the transcriptome study performed on a subset of the mice (n=3 per diet group) we found that hepatic Cyp7a1 transcript levels were higher in the herring-fed compared with the beef-fed mice (24). That Cyp7a1 is a promising candidate as a mediator for the herring-induced effects is supported by the finding that Ldlr -/-mice overexpressing Cyp7a1 were resistant to diet-induced hypercholesterolemia (40).…”

Loss of small heterodimer partner expression in the liver protects against dyslipidemia

“…Overexpression of CYP7A1 blocks the increase in hepatic lipids that occurs when LDLR 2/2 mice are fed a Western diet (14). The LDLR 2/2 SHP 2/2 mice did not have reduced hepatic lipid levels nor altered patterns of cholesterol regulated gene expression.…”

“…Similarly, there is also an inverse correlation between CYP7A1 expression and plasma cholesterol levels in primates (13). In mice, transgenic overexpression of CYP7A1 blocks diet-induced hypercholesterolemia and atherosclerosis (14,15). The loss of SHP repression of CYP7A1 expression could thus be predicted to have beneficial effects on LDL cholesterol levels.…”

Activation of farnesoid X receptor prevents atherosclerotic lesion formation in LDLR−/− and apoE−/− mice

“…Adenovirusmediated overexpression of CYP7A1 in the hamster reduces plasma LDL cholesterol in direct proportion to the magnitude of increase in cholesterol-7-a-hydroxylase activity (27). Similarly, transgenic overexpression of CYP7A1 blocks dietinduced atherosclerosis in wild-type and LDLR 2/2 mice (28,29). Generally in these studies, CYP7A1 has been expressed at ?10-fold elevated levels over the already high levels present in the mice.…”