LXR-Agonists Regulate ApoM Expression Differentially in Liver and In- testine

Abstract: Apolipoprotein M (apoM) has been suggested to play a role in reverse cholesterol transport. Here we studied the influence of liver X-receptor (LXR) agonist on the transcriptional regulation of apoM. Studies were performed in murine liver and intestinal mucosal cells in vivo and in human intestinal Caco-2 cells in vitro. The expression of apoM was analyzed by quantitative real time PCR, and compared to well-established LXR target genes. Mice fed with TO901317 for six days showed a downregulation of apoM and apoAI in the liver to 40 % and 60 % respectively and an upregulation of Cyp7A1 to 280 %. In the small intestine, however, apoM and apoAI were upregulated by 30-60 % and ABCA1 by 250-430 %. In Caco-2 cells TO901317 caused a 60 % upregulation and the natural LXR agonist 22-hydroxycholesterol a 40 % upregulation of apoM. Possible causes for the differential effects in liver and intestine are discussed

Lp(a) and the Risk for Cardiovascular Disease: Focus on the Lp(a) Paradox in Diabetes Mellitus

Lipoprotein(a) (Lp(a)) is one of the strongest causal risk factors of atherosclerotic disease. It is rich in cholesteryl ester and composed of apolipoprotein B and apo(a). Plasma Lp(a) levels are determined by apo(a) transcriptional activity driven by a direct repeat (DR) response element in the apo(a) promoter under the control of (HNF)4α Farnesoid-X receptor (FXR) ligands play a key role in the downregulation of APOA expression. In vitro studies on the catabolism of Lp(a) have revealed that Lp(a) binds to several specific lipoprotein receptors; however, their in vivo role remains elusive. There are more than 1000 publications on the role of diabetes mellitus (DM) in Lp(a) metabolism; however, the data is often inconsistent and confusing. In patients suffering from Type-I diabetes mellitus (T1DM), provided they are metabolically well-controlled, Lp(a) plasma concentrations are directly comparable to healthy individuals. In contrast, there exists a paradox in T2DM patients, as many of these patients have reduced Lp(a) levels; however, they are still at an increased cardiovascular risk. The Lp(a) lowering mechanism observed in T2DM patients is most probably caused by mutations in the mature-onset diabetes of the young (MODY) gene and possibly other polymorphisms in key transcription factors of the apolipoprotein (a) gene (APOA)