Farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor, plays an important role in the regulation of cholesterol and more specifically high-density lipoprotein (HDL) homeostasis. Activation of FXR is reported to lead to both proand anti-atherosclerotic effects. In the present study we analyzed the impact of different FXR agonists on cholesterol homeostasis, plasma lipoprotein profiles, and transhepatic cholesterol efflux in C57BL/6J mice and cynomolgus monkeys and atherosclerosis development in cholesteryl ester transfer protein transgenic (CETPtg) low-density lipoprotein receptor (LDLR) (Ϫ/Ϫ) mice. In C57BL/6J mice on a high-fat diet the synthetic FXR agonists isopropyl 3-(3,benzoic acid (PX20606) demonstrated potent plasma cholesterollowering activity that affected all lipoprotein species, whereas 3-[2-ethenyl]benzoic acid (GW4064) and 6-ethyl chenodeoxycholic acid (6-ECDCA) showed only limited effects. In FXR wild-type mice, but not FXR(Ϫ/Ϫ) mice, the more efficacious FXR agonists increased fecal cholesterol excretion and reduced intestinal cholesterol (re)uptake. In CETPtg-LDLR(Ϫ/Ϫ) mice PX20606 potently lowered total cholesterol and, despite the observed HDL cholesterol (HDLc) reduction, caused a highly significant decrease in atherosclerotic plaque size. In normolipidemic cynomolgus monkeys PX20606 and 6-ECDCA both reduced total cholesterol, and PX20606 specifically lowered HDL 2c but not HDL 3c or apolipoprotein A1. That pharmacological FXR activation specifically affects this cholesterol-rich HDL 2 subclass is a new and highly interesting finding and sheds new light on FXR-dependent HDLc lowering, which has been perceived as a major limitation for the clinical development of FXR agonists.

The farnesoid X receptor (FXR) is expressed predominantly in tissues exposed to high levels of bile acids and controls bile acid and lipid homeostasis. FXR−/− mice develop hepatocellular carcinoma (HCC) and show an increased prevalence for intestinal malignancies, suggesting a role of FXR as a tumor suppressor in enterohepatic tissues. The N-myc downstream-regulated gene 2 (NDRG2) has been recognized as a tumor suppressor gene, which is downregulated in human hepatocellular carcinoma, colorectal carcinoma and many other malignancies.We show reduced NDRG2 mRNA in livers of FXR−/− mice compared to wild type mice and both, FXR and NDRG2 mRNAs, are reduced in human HCC compared to normal liver. Gene reporter assays and Chromatin Immunoprecipitation data support that FXR directly controls NDRG2 transcription via IR1-type element(s) identified in the first introns of the human, mouse and rat NDRG2 genes. NDRG2 mRNA was induced by non-steroidal FXR agonists in livers of mice and the magnitude of induction of NDRG2 mRNA in three different human hepatoma cell lines was increased when ectopically expressing human FXR. Growth and metastasis of SK-Hep-1 cells was strongly reduced by non-steroidal FXR agonists in an orthotopic liver xenograft tumor model. Ectopic expression of FXR in SK-Hep1 cells reduced tumor growth and metastasis potential of corresponding cells and increased the anti-tumor efficacy of FXR agonists, which may be partly mediated via increased NDRG2 expression. FXR agonists may show a potential in the prevention and/or treatment of human hepatocellular carcinoma, a devastating malignancy with increasing prevalence and limited therapeutic options.

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The transient appearance of P-selectin on the surface of endothelial cells helps recruit leukocytes into sites of inflammation. The tight control of cell surface P-selectin on these cells depends on regulated exocytosis of WeibelPalade bodies where the protein is stored and on its rapid endocytosis. After endocytosis, P-selectin is either sorted via endosomes and the Golgi apparatus for storage in Weibel-Palade bodies or targeted to lysosomes for degradation. A potential player in this complex endocytic itinerary is SNX17, a member of the sorting nexin family, which has been shown in a yeast two-hybrid assay to bind P-selectin. Here, we show that overexpression of SNX17 in mammalian cells can influence two key steps in the endocytic trafficking of P-selectin. First, it promotes the endocytosis of P-selectin from the plasma membrane. Second, it inhibits the movement of P-selectin into lysosomes, thereby reducing its degradation.

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Background: Implantable cardioverter defibrillator (ICD) implantation is a common approach in patients at high risk of sudden cardiac death. To check for normal function, it is necessary to test the ICD. For this purpose, repetitive induction and termination of ventricular fibrillation by direct current shocks is required. This may lead to minor myocardial damage. Cardiac troponin T (cTnT) and I (cTnI) are specific markers for the detection of myocardial injury. Because these proteins usually are undetectable in healthy individuals, they are excellent markers for detecting minimal myocardial damage. The objective of this study was to evaluate the effect of defibrillation of induced ventricular fibrillation on markers of myocardial damage. Methods: This study included 14 patients who underwent ICD implantation and intraoperative testing. We measured cTnT, cTnI, creatine kinase MB (CK-MB) mass, CK activity, and myoglobin before and at definite times after intraoperative shock application. Results: Depending on the effectiveness of shocks and the energy applied, the cardiac-specific markers cTnT and cTnI, as well as CK-MB mass, showed a significant increase compared with the baseline value before testing and peaked for the most part 4 h after shock application. In contrast, the increases in CK activity and myoglobin were predominantly detectable in patients who received additional external shocks. Conclusions: ICD implantation and testing leads to a short release of cardiac markers into the circulation. This release seems to be of cytoplasmic origin and depends on the number and effectiveness of the shocks applied.