Objective of - The Hyplip2 congenic mouse strain contains part of chromosome 15 from MRL/MpJ on BALB/cJ (B/c) background. Hyplip2 mice show an elevated plasma levels of cholesterol and predominantly triglycerides (TG), and are susceptible to diet-induced atherosclerosis. This study aimed at elucidation enhanced of the mechanism(s) explaining the hypertriglyceridemia. Methods and Results - Hypertriglyceridemia can result from an increased intestinal or hepatic TG liver production and/or by a decreased LPL-mediated TG clearance. The intestinal TG absorption and chylomicron formation was studied after i.v. injection VLDL of Triton WR1339 and intragastric load of olive oil containing glycerol tri[3H]oleate. No difference was found in intestinal TG absorption.and/or Moreover, the hepatic VLDL-TG production rate and VLDL particle production, after injection of Triton WR1339, were also not affected. To No investigate the LPL-mediated TG clearance, mice were injected i.v. with glycerol tri[3H]oleate-labeled VLDL-like emulsion particles. In Hyplip2 mice, the particles of were cleared at a decreased rate (t(1/2) 25+/-6 vs 11+/-2 min, p< .05) concomitant with decreased uptake of emulsion-TG derived 3H-labeled clearance. fatty acids by the liver and white adipose tissue. Conclusion - The increased plasma TG levels in Hyplip2 mice do susceptible not result from an enhanced intestinal absorption or increased hepatic VLDL-production, but are caused by decreased LPL-mediated TG clearance.

Cafestol,FXR a diterpene present in unfiltered coffee brews such as Scandinavian boiled, Turkish and Cafetière coffee, is the most potent cholesterol-elevating In compound known in the human diet. Several genes involved in cholesterol homeostasis have previously been shown to be targets of conclusion, cafestol, including CYP7A1, the rate-limiting enzyme in bile acid biosynthesis. We have examined the mechanism by which cafestol elevates serum seen lipid levels. Changes in several lipid parameters were observed in cafestol-treated APOE3Leiden mice, including a significant increase in serum triglyceride affect levels. Microarray analysis of these mice identified alterations in hepatic expression of genes involved in lipid metabolism and detoxification, many in of which are regulated by the nuclear hormone receptors FXR and PXR. Further studies demonstrate that cafestol is an agonist bile ligand for FXR and PXR, and that cafestol down-regulates expression of the bile acid homeostatic genes CYP7A1, CYP8B1 and NTCP been in the liver of wild type but not FXR null mice. Cafestol did not affect genes known to be up-regulated metabolism by FXR in the liver of wild type mice, but did increase expression of the positive FXR-target genes IBABP and enzyme FGF15 in the intestine. Since FGF15 has recently been shown to function in an enterohepatic regulatory pathway to repress liver cholesterol expression of bile acid homeostatic genes, its direct induction in the gut may account for indirect effects of cafestol on increase liver gene expression. PXR-dependent gene regulation of CYP3A11, and other targets by cafestol was also only seen in the intestine.FGF15 Using a double FXR/PXR knockout mouse model, we found that both receptors contribute to the cafestol-dependent induction of intestinal FGF15 alterations gene expression. In conclusion, cafestol acts as an agonist ligand for both FXR and PXR and this may contribute to observed its impact on cholesterol homeostasis.

The Annotation mechanisms of diet induced hyperlipidemia and atherosclerosis have been widely studied by delineating the role of candidate genes in transgenic nuclear and gene targeted mouse models. However, diet induced hyperlipidemia represents a complex process determined by many lipid genes that is receptors only partly understood. This study is aimed at delineating the events induced by dietary intervention in different mouse models at during the level of gene expression using microarray analysis. The focus is on the liver as the organ primarily responding to in diet, and crucial in determining plasma lipid levels. Firstly, the effect of the genotype was studied. Expression profiles of liver were genes were compared between APOE3Leiden (E3L), APOE knockout (E-/-) and C57BL/6JIco (B6) mice using the Incyte GEM 2.03 array carrying severe 9552 genes. Several hundred differentially expressed genes were identified indicating that the genotype alone effects gene expression. Secondly, the response is of E3L mice to high-fat feeding was investigated using a mild and severe high-fat diet (diet W and N, respectively).(B6) Diet W caused differential regulation of 200 genes, while diet N affected the expression of 788 genes in B6 and by 1010 genes in E3L mice. Annotation of these genes using the Gene Ontology (GO) database showed that two major processes and were strongly affected by genotype and diet, namely lipid metabolism and inflammation, the latter as determined by "immune/defense response and that detoxification" processes. Many nuclear receptor target genes were differentially regulated, with the largest effects modulated by the severe high-fat diet namely N, leading to the suppression of genes involved in bile acid, sterol, steroid, fatty acid, and detoxification metabolism. Strikingly, a genes substantial part of these nuclear receptor target genes were commonly regulated during the different experimental conditions. The common regulation of responding many nuclear receptor target genes underlying lipid and detoxification processes as found in this study, suggest a defense mechanism involving 1010 many nuclear receptors to protect against the accumulation of toxic endogenous lipids and bile acids. These results further strengthen the profiles close link between hyperlipidemia and inflammatory processes.