Hepatic gluconeogenesis is enhanced by phosphatidic acid which remains uninhibited by insulin in lipodystrophic Agpat2-/- mice [Metabolism]

January 14th, 2014 by Sankella, S., Garg, A., Horton, J. D., Agarwal, A. K.

In this study we examined the role of phosphatidic acid (PA) in hepatic glucose production (HGP) and development of hepatic insulin resistance in mice that lack AGPAT2. Liver LPA and PA levels were increased ~2-fold and ~5-fold respectively in male Agpat2-/- mice compared to WT mice. In the absence of AGPAT2, the liver can synthesize PAs by activating diacylglycerol kinase or phospholipase D, both of which were elevated in the livers of Agpat2-/- mice. We found that PAs C16:0/18:1 and C18:1/20:4 enhanced HGP in primary WT hepatocytes, an effect that was further enhanced in primary hepatocytes from Agpat2-/- mice. LPAs C16:0 and C18:1 failed to increase HGP in primary hepatocytes. The activation of HGP was accompanied by an upregulation of the key gluconeogenic enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. This activation was suppressed by insulin in the WT primary hepatocytes but not in the Agpat2-/- primary hepatocytes. Thus, the lack of normal insulin signaling in Agpat2-/- livers allows unrestricted PA-induced gluconeogenesis significantly contributing to the development of hyperglycemia in these mice.