Submitted on August 25, 2008
Revised on January 12, 2009
Accepted on January 12, 2009
Regulation of homocysteine homeostasis through the transcriptional coactivator PGC-1
Siming Li1, Erland Arning2, Chang Liu2, Victor Vitvitsky3, Carlos Hernandez1, Ruma Banerjee1, Teodoro Bottiglieri2, and Jiandie Lin1*
1 University of Michigan Medical Center
2 Baylor University Medical Center
3 University of Nebraska
* To whom correspondence should be addressed. E-mail: jdlin{at}umich.edu.
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 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 role for the PGC-1 coactivator pathway in the regulation of Hcy homeostasis and suggest a potential pathogenic mechanism that contributes to hyperhomocysteinemia.
