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Mimetics of caloric restriction include agonists of lipid-activated nuclear receptors
- Source :
- The Journal of biological chemistry. 279(44)
- Publication Year :
- 2004
-
Abstract
- The obesity epidemic in industrialized countries is associated with increases in cardiovascular disease (CVD) and certain types of cancer. In animal models, caloric restriction (CR) suppresses these diseases as well as chemical-induced tissue damage. These beneficial effects of CR overlap with those altered by agonists of nuclear receptors (NR) under control of the fasting-responsive transcriptional co-activator, peroxisome proliferator-activated co-activator 1alpha (PGC-1alpha). In a screen for compounds that mimic CR effects in the liver, we found statistically significant overlaps between the CR transcript profile in wild-type mice and the profiles altered by agonists of lipid-activated NR, including peroxisome proliferator-activated receptor alpha (PPARalpha), liver X receptor, and their obligate heterodimer partner, retinoid X receptor. The overlapping genes included those involved in CVD (lipid metabolism and inflammation) and cancer (cell fate). Based on this overlap, we hypothesized that some effects of CR are mediated by PPARalpha. As determined by transcript profiling, 19% of all gene expression changes in wild-type mice were dependent on PPARalpha, including Cyp4a10 and Cyp4a14, involved in fatty acid omega-oxidation, acute phase response genes, and epidermal growth factor receptor but not increases in PGC-1alpha. CR protected the livers of wild-type mice from damage induced by thioacetamide, a liver toxicant and hepatocarcinogen. CR protection was lost in PPARalpha-null mice due to inadequate tissue repair. These results demonstrate that PPARalpha mediates some of the effects of CR and indicate that a pharmacological approach to mimicking many of the beneficial effects of CR may be possible.
- Subjects :
- Male
medicine.medical_specialty
Receptors, Cytoplasmic and Nuclear
Inflammation
Retinoid X receptor
Biochemistry
Mice
Risk Factors
Internal medicine
medicine
Animals
Homeostasis
PPAR alpha
Epidermal growth factor receptor
Receptor
Liver X receptor
Molecular Biology
Transcription factor
Caloric Restriction
Liver X Receptors
biology
Lipid metabolism
Cell Biology
Lipid Metabolism
Orphan Nuclear Receptors
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
DNA-Binding Proteins
Mice, Inbred C57BL
Endocrinology
Nuclear receptor
Liver
Cardiovascular Diseases
biology.protein
Trans-Activators
Female
medicine.symptom
Cell Division
Transcription Factors
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 279
- Issue :
- 44
- Database :
- OpenAIRE
- Journal :
- The Journal of biological chemistry
- Accession number :
- edsair.doi.dedup.....62e5d167f05f6f01b4b2ea064ded6ff2