Hepatic protein phosphatase 1 regulatory subunit 3B (Ppp1r3b) promotes hepatic glycogen synthesis and thereby regulates fasting energy homeostasis

Abstract

Maintenance of whole-body glucose homeostasis is critical to glycemic function. Genetic variants mapping to chromosome 8p23.1 in genome-wide association studies have been linked to glycemic traits in humans. The gene of known function closest to the mapped region, <i>PPP1R3B</i> (protein phosphatase 1 regulatory subunit 3B), encodes a protein (G_L) that regulates glycogen metabolism in the liver. We therefore sought to test the hypothesis that hepatic <i>PPP1R3B</i> is associated with glycemic traits. We generated mice with either liver-specific deletion (<i>Ppp1r3b</i>^Δ<i>^hep</i> ) or liver-specific overexpression of <i>Ppp1r3b</i> The <i>Ppp1r3b</i> deletion significantly reduced glycogen synthase protein abundance, and the remaining protein was predominantly phosphorylated and inactive. As a consequence, glucose incorporation into hepatic glycogen was significantly impaired, total hepatic glycogen content was substantially decreased, and mice lacking hepatic <i>Ppp1r3b</i> had lower fasting plasma glucose than controls. The concomitant loss of liver glycogen impaired whole-body glucose homeostasis and increased hepatic expression of glycolytic enzymes in <i>Ppp1r3b</i>^Δ<i>^hep</i> mice relative to controls in the postprandial state. Eight hours of fasting significantly increased the expression of two critical gluconeogenic enzymes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, above the levels in control livers. Conversely, the liver-specific overexpression of <i>Ppp1r3b</i> enhanced hepatic glycogen storage above that of controls and, as a result, delayed the onset of fasting-induced hypoglycemia. Moreover, mice overexpressing hepatic Ppp1r3b upon long-term fasting (12-36 h) were protected from blood ketone-body accumulation, unlike control and <i>Ppp1r3b</i>^Δ<i>^hep</i> mice. These findings indicate a major role for <i>Ppp1r3b</i> in regulating hepatic glycogen stores and whole-body glucose/energy homeostasis.