The nuclear receptor CAR (NR1I3) regulates serum triglyceride levels under conditions of metabolic stress
| Autor: | David C. Lobe, John T. Moore, Jodi M. Maglich |
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| Rok vydání: | 2008 |
| Předmět: |
Agonist
Male medicine.medical_specialty medicine.drug_class Pyridines Alpha (ethology) peroxisome proliferator-activated receptor alpha Mice Obese Receptors Cytoplasmic and Nuclear QD415-436 Biology Biochemistry chemistry.chemical_compound Mice Endocrinology Stress Physiological Internal medicine Constitutive androstane receptor medicine serum triglycerides Animals PPAR alpha RNA Messenger nonalcoholic steatohepatitis Receptor Beta oxidation Constitutive Androstane Receptor Triglycerides DNA Primers Oligonucleotide Array Sequence Analysis Mice Knockout Triglyceride Base Sequence Fatty Acids non-alcoholic fatty liver disease Cell Biology Lipid Metabolism Dietary Fats Mice Inbred C57BL Nuclear receptor chemistry Liver Peroxisome proliferator-activated receptor alpha Transcription Factors |
| Zdroj: | Journal of Lipid Research, Vol 50, Iss 3, Pp 439-445 (2009) |
| ISSN: | 0022-2275 |
| Popis: | 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 PPARalpha (NR1C1). The expression of peroxisome proliferator-activated receptor alpha (PPARalpha) 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 PPARalpha mRNA as well as Cyp4a14, CPT1alpha, and cytosolic Acyl-CoA thioesterase (CTE) in the liver. These data have implications in disease therapy such as for diabetes and nonalcoholic steatohepatitis (NASH). |
| Databáze: | OpenAIRE |
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