Anti-NR1I3 monoclonal antibody Made to order

The nuclear receptor constitutive androstane receptor (CAR) (NR1I3) regulates hepatic genes involved in xenobiotic detoxification as well as genes involved in energy homeostasis. We provide data that extend the role of CAR to regulation of serum triglyceride levels under conditions of metabolic/nutritional stress. The typically high serum triglyceride levels of ob/ob mice were completely normalized when crossed onto a Car(-/-) (mice deficient for the Car gene) genetic background. Moreover, increases in serum triglycerides observed after a high-fat diet (HFD) regime were not observed in Car(-/-) animals. Conversely, pharmacological induction of CAR activity using the selective mouse CAR agonist TCPOBOP during HFD feeding resulted in a CAR-dependent increase in serum triglyceride levels. A major regulator of hepatic fatty oxidation is the nuclear receptor PPAR alpha (NR1C1). The expression of peroxisome proliferator-activated receptor alpha (PPAR alpha) target genes was inversely related to the activity of CAR. Consistent with these observations, Car(-/-) animals exhibited increased hepatic fatty acid oxidation. Treatment of mice with 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) significantly decreased expression of PPARa mRNA as well as Cyp4a14, CPT1 alpha, and cytosolic Acyl-CoA thioesterase (CTE) in the liver. These data have implications in disease therapy such as for diabetes and nonalcoholic steatohepatitis (NASH).-Maglich, J. M., D. C. Lobe, and J. T. Moore. The nuclear receptor CAR (NR1I3) regulates serum triglyceride levels under conditions of metabolic stress. J. Lipid Res. 2009. 50: 439-445.

Reduced levonorgestrel concentrations fromthe levonorgestrel contraceptive implant was previously seen when given concomitantly with efavirenz. We sought to assess whether single nucleotide polymorphisms (SNPs) in genes involved in efavirenz and nevirapine metabolismwere linked to these changes in levonorgestrel concentration. SNPs in CYP2B6, CYP2A6, NR1I2, and NR1I3 were analyzed. Associations of participant demographics and genotype with levonorgestrel pharmacokinetics were evaluated in HIV-positive women using the levonorgestrel implant plus efavirenz-or nevirapinebased antiretroviral therapy (ART), in comparison to ART-na ive women using multivariate linear regression. Efavirenz group: CYP2B6 516G>T was associated with lower levonorgestrel log(10) C-max and log(10) AUC. CYP2B6 15582C> T was associated with lower log(10) AUC. Nevirapine group: CYP2B6 516G>T was associated with higher log(10) C-max and lower log(10) C-min. Pharmacogenetic variations influenced subdermal levonorgestrel pharmacokinetics in HIV-positive women, indicating that the magnitude of the interaction with non-nucleoside reverse transcriptase inhibitors (NNRTIs) is influenced by host genetics.