In mammals, the liver plays a central role in maintaining carbohydrate and lipid homeostasis by acting both as a major source and a major sink of glucose and lipids. In particular, when dietary carbohydrates are in excess, the liver converts them to lipids via de novo lipogenesis. The molecular checkpoints regulating the balance between carbohydrate and lipid homeostasis, however, are not fully understood. Here we identify PPP2R5C, a regulatory subunit of PP2A, as a novel modulator of liver metabolism in postprandial physiology. Inactivation of PPP2R5C in isolated hepatocytes leads to increased glucose uptake and increased de novo lipogenesis. These phenotypes are reiterated in vivo, where hepatocyte specific PPP2R5C knockdown yields mice with improved systemic glucose tolerance and insulin sensitivity, but elevated circulating triglyceride levels. We show that modulation of PPP2R5C levels leads to alterations in AMPK and SREBP-1 activity. We find that hepatic levels of PPP2R5C are elevated in human diabetic patients, and correlate with obesity and insulin resistance in these subjects. In sum, our data suggest that hepatic PPP2R5C represents an important factor in the functional wiring of energy metabolism and the maintenance of a metabolically healthy state.
After a meal, dietary glucose travels through the hepatic portal vein to the liver. A substantial part of this glucose is taken up by liver, which converts it to glycogen which is stored, and lipids which are in part stored and in part secreted as VLDL particles. The rest of the organs receive whatever glucose the liver leaves in circulation, plus the secreted lipids. Hence the liver plays a crucial role in determining the balance of sugar versus lipids in the body after a meal. This balance is very important, because too much glucose in circulation leads to diabetic complications whereas too much VLDL increases risk of atherosclerosis. Little is known about how the liver strikes this balance. We identify here a phosphatase—the PP2A holoenzyme containing the PPP2R5C regulatory subunit—as a regulator of this process. We find that knockdown of PPP2R5C in mouse liver specifically causes it to uptake elevated levels of glucose, and secrete elevated levels of VLDL into circulation. This leads to a phenotype of improved glucose tolerance and insulin sensitivity. The prediction from these functional studies in mice is that elevated levels of PPP2R5C expression should lead to insulin resistance. Indeed, we find that PPP2R5C expression levels are elevated in diabetic patients, or healthy controls with visceral obesity, raising the possibility that dysregulation of PPP2R5C expression in humans may contribute towards metabolic dysfunction.