title: Regulation of homocysteine homeostasis through the transcriptional coactivator PGC-1alpha.
abstract: Plasma homocysteine (Hcy) is an independent risk factor for cardiovascular disease. Hcy is a nonprotein amino acid derivative that is generated from the methionine cycle, which provides the methyl group for essentially all biological methylation reactions. Although plasma Hcy levels are elevated in patients with cardiovascular disease, the mechanisms that regulate Hcy homeostasis remain poorly defined. In this study, we found that the expression of key enzymes involved in Hcy metabolism is induced in the liver in response to fasting. This induction coincides with increased expression of peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha, a transcriptional coactivator that regulates hepatic gluconeogenesis and mitochondrial function. PGC-1alpha stimulates the expression of genes involved in Hcy metabolism in cultured primary hepatocytes as well as in the liver. Adenoviral-mediated expression of PGC-1alpha in vivo leads to elevated plasma Hcy levels. In contrast, mice deficient in PGC-1alpha have lower plasma Hcy concentrations. These results define a novel role for the PGC-1alpha coactivator pathway in the regulation of Hcy homeostasis and suggest a potential pathogenic mechanism that contributes to hyperhomocysteinemia.
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
authors.forename: Siming
authors.initials: S
authors.lastname: Li
authors.forename: Erland
authors.initials: E
authors.lastname: Arning
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.forename: Victor
authors.initials: V
authors.lastname: Vitvitsky
authors.forename: Carlos
authors.initials: C
authors.lastname: Hernandez
authors.forename: Ruma
authors.initials: R
authors.lastname: Banerjee
authors.forename: Teodoro
authors.initials: T
authors.lastname: Bottiglieri
authors.forename: Jiandie D
authors.initials: JD
authors.lastname: Lin
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation / Q000502:physiology; D022781:Hepatocytes / Q000502:physiology; D006706:Homeostasis / Q000502:physiology*; D006710:Homocysteine / Q000097:blood*; D020138:Hyperhomocysteinemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D008099:Liver / Q000166:cytology / Q000502:physiology; D008297:Male; D008715:Methionine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000502:physiology; D014161:Transduction, Genetic
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D006710:Homocysteine; D008715:Methionine