Phosphoglycerate Mutase 5 Expression Modulates Hepatocellular Steatosis

Phosphoglycerate Mutase 5 (PGAM5) is a serine/threonine phosphatase that plays a role in oxidant injury sensing, mitochondrial biogenesis, mitophagy, and multiple cell death pathways. Pgam5 null mice are protected from high-fat diet induced obesity. This metabolic phenotype was attributed to upregulation of adaptive thermogenesis in brown adipose tissue, but hepatocyte specific lipid metabolism has not been evaluated. We hypothesize that hepatic PGAM5 expression level modulates hepatic steatosis. Using primary cultures of Pgam5 knockout hepatocytes, we have shown that palmitate induced steatosis is attenuated and that treatment with the long-chain fatty acid impairs oxygen consumption rate specifically reducing the maximal respiratory capacity. Further, over-expression of PGAM5 in human hepatoma cells exacerbates palmitate induced steatosis. Cumulatively, these results suggest that PGAM5 regulates hepatic lipogenesis and mitochondrial long-chain fatty acid beta-oxidation.