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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 296/3/E543    most recent 90719.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Li, S. Articles by Lin, J. D. Search for Related Content PubMed PubMed Citation Articles by Li, S. Articles by Lin, J. D.

Regulation of homocysteine homeostasis through the transcriptional coactivator PGC-1

¹Life Sciences Institute and Department of Cell and Developmental Biology, ²Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan; and ³Institute of Metabolic Disease, Baylor University Medical Center, Dallas, Texas

Submitted 25 August 2008 ; accepted in final form 12 January 2009

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- coactivator (PGC)-1, a transcriptional coactivator that regulates hepatic gluconeogenesis and mitochondrial function. PGC-1 stimulates the expression of genes involved in Hcy metabolism in cultured primary hepatocytes as well as in the liver. Adenoviral-mediated expression of PGC-1 in vivo leads to elevated plasma Hcy levels. In contrast, mice deficient in PGC-1 have lower plasma Hcy concentrations. These results define a novel role for the PGC-1 coactivator pathway in the regulation of Hcy homeostasis and suggest a potential pathogenic mechanism that contributes to hyperhomocysteinemia.

transcriptional coactivator; peroxisome proliferator-activated receptor- coactivator 1; homocysteine; liver metabolism; cardiovascular disease