Nuclear Receptor Corepressor SMRT Regulates Mitochondrial Oxidative Metabolism and Mediates Aging-Related Metabolic Deterioration
Autor: | Frank B. Hu, Ronald M. Evans, Lu Qi, Russell R. Nofsinger, Cem Z. Görgün, Sihao Liu, Chih-Hao Lee, Shannon M. Reilly, Prerna Bhargava, Matthew R. Gangl |
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Rok vydání: | 2010 |
Předmět: |
Premature aging
Aging medicine.medical_specialty Physiology TBL1X Peroxisome Proliferator-Activated Receptors Receptors Cytoplasmic and Nuclear Peroxisome proliferator-activated receptor Biology Mitochondrion Polymerase Chain Reaction Polymorphism Single Nucleotide Article Epigenesis Genetic Mice 03 medical and health sciences 0302 clinical medicine Internal medicine medicine Animals Humans Nuclear Receptor Co-Repressor 2 Molecular Biology 030304 developmental biology Nuclear receptor co-repressor 2 chemistry.chemical_classification 0303 health sciences Gene Expression Profiling Age Factors Cell Biology Mitochondria Cell biology Endocrinology Diabetes Mellitus Type 2 Nuclear receptor chemistry 030220 oncology & carcinogenesis Adiponectin Signal transduction Corepressor Signal Transduction |
Zdroj: | Cell Metabolism. 12:643-653 |
ISSN: | 1550-4131 |
Popis: | SummaryThe transcriptional corepressor SMRT utilizes two major receptor-interacting domains (RID1 and RID2) to mediate nuclear receptor (NR) signaling through epigenetic modification. The physiological significance of such interaction remains unclear. We find SMRT expression and its occupancy on peroxisome proliferator-activated receptor (PPAR) target gene promoters are increased with age in major metabolic tissues. Genetic manipulations to selectively disable RID1 (SMRTmRID1) demonstrate that shifting SMRT repression to RID2-associated NRs, notably PPARs, causes premature aging and related metabolic diseases accompanied by reduced mitochondrial function and antioxidant gene expression. SMRTmRID1 cells exhibit increased susceptibility to oxidative damage, which could be rescued by PPAR activation or antioxidant treatment. In concert, several human Smrt gene polymorphisms are found to nominally associate with type 2 diabetes and adiponectin levels. These data uncover a role for SMRT in mitochondrial oxidative metabolism and the aging process, which may serve as a drug target to improve health span. |
Databáze: | OpenAIRE |
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