PPP1R3B is a metabolic switch that shifts hepatic energy storage from lipid to glycogen
Obesity is a growing worldwide epidemic that carries numerous metabolic complications including increased risk of type 2 diabetes (T2D), cardiovascular disease (CVD), and non-alcoholic fatty liver disease (NAFLD). Multiple genome-wide association studies (GWAS) have associated the PPP1R3B locus with cardiometabolic traits including fasting glucose and insulin levels (T2D traits), plasma lipids (CVD traits), and indications of hepatic steatosis and liver damage (NAFLD traits)1-5. The PPP1R3B gene encodes the glycogen regulatory protein PPP1R3B (also known as GL) which has an established role in liver glycogen metabolism and plasma glucose homeostasis6,7. The metabolic and NAFLD GWAS single nucleotide polymorphisms (SNPs) in this region, which are all in high linkage disequilibrium, result in increased liver PPP1R3B expression and hepatic glycogen accumulation, but have provided conflicting results on the impacts on hepatic steatosis and liver damage. Here we investigate the consequences of both Ppp1r3b overexpression and deletion in mouse and cell models and find that dysregulated Ppp1r3b expression in either direction promotes metabolic dysfunction and liver injury. Hepatocyte overexpression of Ppp1r3b increases hepatic glycogen storage, prolongs fasting blood glucose levels, and confers protection from hepatic steatosis, but increases plasma ALT in aged animals. Conversely, deletion of hepatocyte Ppp1r3b eliminates hepatic glycogen, causes impaired glucose disposal, and results in hepatic steatosis with age or high sucrose diet. We investigated the metabolic pathways contributing to steatosis and found that Ppp1r3b deletion and diminished glycogenesis diverts the storage of exogenous glucose to hepatic triglycerides (TG), and stored liver lipids are preferentially used for energy during fasting through lipid oxidation and ketogenesis. Further, we interrogated two large human biobank cohorts and found carriers of SNPs associated with increased PPP1R3B expression have increased plasma glucose, decreased hepatic fat, and lower plasma lipids, while putative loss-of-function (pLoF) variant carriers have increased hepatic fat and elevated plasma ketones and lipids, consistent with the results seen in our mouse models. These findings suggest hepatic PPP1R3B serves as a metabolic switch favoring hepatic energy storage as glycogen instead of TG.