Human peroxisome proliferator-activated receptor alpha (PPARalpha) supports the induction of peroxisome proliferation in PPARalpha-deficient mouse liver
| Autor: | Papreddy Kashireddy, Yongjun Tan, Jianchi Feng, Yuzhi Jia, Douglas E. Hughes, Frank J. Gonzalez, M. Sambasiva Rao, Robert H. Costa, Kirstin Meyer, Songtao Yu, Wen Qing Cao, Anjana V. Yeldandi, Janardan K. Reddy |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
medicine.medical_specialty
Peroxisome proliferator-activated receptor gamma CD36 Peroxisome Proliferation Peroxisome proliferator-activated receptor Receptors Cytoplasmic and Nuclear Biology Retinoid X receptor digestive system Biochemistry Mice Internal medicine medicine Peroxisomes Animals Humans RNA Messenger Receptor Molecular Biology chemistry.chemical_classification Mice Knockout food and beverages nutritional and metabolic diseases Cell Biology Peroxisome Cell biology Mice Inbred C57BL Endocrinology Pyrimidines chemistry Gene Expression Regulation Liver cardiovascular system biology.protein lipids (amino acids peptides and proteins) Peroxisome proliferator-activated receptor alpha Oxidation-Reduction Cell Division Transcription Factors |
| Zdroj: | The Journal of biological chemistry. 276(45) |
| ISSN: | 0021-9258 |
| Popis: | Peroxisome proliferators, which function as peroxisome proliferator-activated receptor alpha (PPARalpha) agonists, induce peroxisomal, microsomal, and mitochondrial fatty acid oxidation enzymes, in conjunction with peroxisome proliferation, in liver cells. Sustained activation of PPARalpha leads to the development of liver tumors in rats and mice. The assertion that synthetic PPARalpha ligands pose negligible carcinogenic risk to humans is attributable, in part, to the failure to observe peroxisome proliferation in human hepatocytes. To explore the mechanism(s) of species-specific differences in response to PPARalpha ligands, we determined the functional competency of human PPARalpha in vivo and compared its potency with that of mouse PPARalpha. Recombinant adenovirus that expresses human or mouse PPARalpha was produced and administered intravenously to PPARalpha-deficient mice. Human as well as mouse PPARalpha fully restored the development of peroxisome proliferator-induced immediate pleiotropic responses, including peroxisome proliferation and enhanced expression of genes involved in lipid metabolism as well as nonperoxisomal genes, such as CD36, Ly-6D, Rbp7, monoglyceride lipase, pyruvate dehydrogenase kinase-4, and C3f, that have been identified recently to be up-regulated in livers with peroxisome proliferation. These studies establish that human PPARalpha is functionally competent and is equally as dose-sensitive as mouse PPARalpha in inducing peroxisome proliferation within the context of mouse liver environment and that it can heterodimerize with mouse retinoid X receptor, and this human PPARalpha-mouse retinoid X receptor chimeric heterodimer transcriptionally activates mouse PPARalpha target genes in a manner qualitatively similar to that of mouse PPARalpha. |
| Databáze: | OpenAIRE |
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