Regulation of homocysteine homeostasis through the transcriptional coactivator PGC-1α

Li S, Arning E, Liu C, Vitvitsky V, Hernandez C, Banerjee R, Bottiglieri T, Lin JD. Regulation of homocysteine homeostasis through the transcriptional coactivator PGC-1 alpha. Am J Physiol Endocrinol Metab 296: E543-E548, 2009. First published January 21, 2009; doi:10.1152/ajpendo.90719.2008.-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)-1 alpha, a transcriptional coactivator that regulates hepatic gluconeogenesis and mitochondrial function. PGC-1 alpha 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 alpha in vivo leads to elevated plasma Hcy levels. In contrast, mice deficient in PGC-1 alpha have lower plasma Hcy concentrations. These results define a novel role for the PGC-1 alpha coactivator pathway in the regulation of Hcy homeostasis and suggest a potential pathogenic mechanism that contributes to hyperhomocysteinemia.