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As previously reported by us, mice with targeted disruption of the CYP8B1 gene (CYP8B1 2/2 ) fail to produce cholic acid (CA), upregulate their bile acid synthesis, reduce the absorption of dietary cholesterol and, after cholesterol feeding, accumulate less liver cholesterol than wild-type (CYP8B1 1/1 ) mice. In the present study, cholesterol-enriched diet (0.5%) or administration of a synthetic liver X receptor (LXR) agonist strongly upregulated CYP7A1 expression in CYP8B1 2/2 mice, compared to CYP8B1mice. Cholesterol-fed CYP8B1 2/2 mice also showed a significant rise in HDL cholesterol and increased levels of liver ABCA1 mRNA. A combined CA (0.25%)/cholesterol (0.5%) diet enhanced absorption of intestinal cholesterol in both groups of mice, increased their liver cholesterol content, and reduced their expression of CYP7A1 mRNA. The ABCG5/G8 liver mRNA was increased in both groups of mice, but cholesterol crystals were only observed in bile from the CYP8B1 1/1 mice. The results demonstrate the cholesterol-sparing effects of CA: enhanced absorption and reduced conversion into bile acids. Farnesoid X receptor (FXR)-mediated suppression of CYP7A1 in mice seems to be a predominant mechanism for regulation of bile acid synthesis under normal conditions and, as confirmed, able to override LXR-mediated mechanisms. Interaction between FXR-and LXR-mediated stimuli might also regulate expression of liver ABCG5/G8.-Wang, J., C. Einarsson, C. Murphy, P. Parini, I. Björkhem, M. Gåfvels, and G. Eggertsen. Studies on LXR-and FXR-mediated effects on cholesterol homeostasis in normal and cholic acid-depleted mice. J. Lipid Res. 2006. 47: 421-430. Supplementary key words bile acids . farnesoid X receptor . liver X receptor . cholesterol 7a-hydroxylase . sterol 12a-hydroxylase

The microsomal triglyceride transfer protein (MTTP) is essential for formation of apolipoprotein B (apoB)-containing lipoproteins. The liver and the intestine have the highest tissue expression of MTTP and secrete triacylglycerol (TAG)-rich VLDLs and chylomicrons, respectively ( 1 ). MTTP is also expressed in other cells such as cardiomyocytes ( 2 ) and macrophages ( 3 ). The heart secretes apoB100-containing lipoproteins and it has been proposed that cardiac lipoprotein secretion protects the heart against accumulation of lipids that are toxic to the myocardium ( 4 ). This theory is supported by the fi nding that MTTP exAbstract Promoter polymorphisms in microsomal triglyceride transfer protein ( MTTP ) have been associated with decreased plasma lipids but an increased risk for ischemic heart disease (IHD), indicating that MTTP infl uences the susceptibility for IHD independent of plasma lipids. The objective of this study was to characterize the functional promoter polymorphism in MTTP predisposing to IHD and its underlying mechanism. Use of pyrosequencing technology revealed that presence of the minor alleles of the promoter polymorphisms -493G>T and -164T>C result in lower transcription of MTTP in vivo in the heart, liver, and macrophages. In vitro experiments indicated that the minor -164C allele mediates the lower gene expression and that C/ EBP binds to the polymorphic region in an allele-specifi c manner. Furthermore, homozygous carriers of the -164C were found to have increased risk for IHD as shown in a case-control study including a total of 544 IHD patients and 544 healthy control subjects. We concluded that carriers of the minor -164C allele have lower expression of MTTP in the heart, mediated at least partly by the transcription factor CCAAT/enhancer binding protein, and that reduced concentration of MTTP in the myocardium may contribute to IHD upon ischemic damage. -Aminoff, A

Pages: 25 Pages including 2 tables Abstract:2 Variations in genes associated with cholesterol homeostasis have been reported to modify the risk of developing Alzheimer disease (AD). To date there have been few investigations into variations in genes directly involved in cholesterol biosynthesis and AD. We investigated the influence of the -911C>A polymorphism (rs3761740) in the hydroxy-methyl-glutaryl CoA reductase (HMGCR) gene promoter on basal and regulated transcription, plasma cholesterol levels and the association with AD. Under in vitro conditions the A allele was found to be significantly more responsive to SREBP-2 mediated regulation than the C allele. In an age and sex matched case-control study, the genotype distribution and allele frequency of this polymorphism were not associated with AD (OR=1.03; 95% CI=0.72-1.48). However, we did find evidence supporting an interaction between the HMGCR A allele, the APOE E4 allele and an altered risk of AD (OR=2.41; 95% CI=0.93-6.22).

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