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, (protein phosphatase 1 regulatory subunit 3B), encodes a protein (G) that regulates glycogen metabolism in the liver. We therefore sought to test the hypothesis that hepatic is associated with glycemic traits. We generated mice with either liver-specific deletion ( ) or liver-specific overexpression of The 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 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 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 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 mice. These findings indicate a major role for in regulating hepatic glycogen stores and whole-body glucose/energy homeostasis.

Relationship between genetic variation at PPP1R3B and levels of liver glycogen and triglyceride

“…Overexpression of PPP1R3B in livers of mice and rats is associated with increased hepatic glycogen content . Similarly, we found that adenovirus‐mediated expression of PPP1R3B at supraphysiological levels in livers of mice caused a dramatic increase in liver weight and hepatic glycogen content (Fig.…”

“…To test the hypothesis that hepatic x‐ray attenuation associated with rs4841132‐A is attributed to an increase in hepatic glycogen content caused by increased expression of PPP1R3B , we examined the hepatic glycogen and TG levels in livers of mice that either lack (KO) or overexpress PPP1R3B. As we were performing these studies, Rader and his colleagues developed liver‐specific Ppp1r3b KO mice . These mice had reduced hepatic glycogen attributed to a reduction in incorporation of glucose into glycogen.…”

“…These data support the hypothesis that genetic variation in PPP1R3B primarily affects hepatic glycogen levels and has little effect on HTGC. Overexpression of PPP1R3B in livers of rats and mice robustly increased hepatic glycogen content. In agreement with these past studies, we found that hepatic overexpression of PPP1R3B in mice caused a marked increase in hepatic glycogen content, and increased plasma markers of liver damage, likely reflecting a glycogen‐mediated hepatopathy.…”

“…As we were performing these studies, Rader and his colleagues developed liver-specific Ppp1r3b KO mice. (26) These mice had reduced hepatic glycogen attributed to a reduction in incorporation of glucose into glycogen. Mice also had lower blood glucose levels on both an ad lib diet and after a 4-hour fast.…”

Functions and therapeutic potential of protein phosphatase 1: Insights from mouse genetics

“…1, Table 3). Interestingly, phenylalanine mutation of GL at tyrosine 284 prevented the allosteric inhibitory binding of phospho-glycogen-phosphorylase to GL, resulting in the dephosphorylation and activation of glycogen synthase [103,104]. Thus, knockin mice that express mutant GL Y284F displayed an enhanced hepatic glycogen synthase activity and improved glucose tolerance, supporting the notion that pharmacological inhibition of this particular GL:phospho-glycogen-phosphorylase interaction can be used to combat diabetic hyperglycaemia [93,103,105,106].…”