Genetic variants mapping to chromosome 8p23.1 have been associated with multiple metabolic traits in humans, including plasma constituents (glucose, lactate, insulin, HDL and non-HDL cholesterol), and hepatic steatosis with genome-wide significance. The closest gene of known function, PPP1R3B, (Protein Phosphatase 1 Regulatory Subunit 3B), encodes a protein (GL) that is known to regulate glycogen metabolism. We sought to test the hypothesis that hepatic PPP1R3B is the causal gene underlying the human genetic association with these metabolic attributes and to understand the mechanisms. We generated two separate mice with liver-specific deletion (Ppp1r3bΔhep) or liver-specific overexpression of Ppp1r3b. Hepatic deletion of Ppp1r3b significantly reduced glycogen levels and glycogen synthase activity in the liver, impairing fasting glucose homeostasis, and prompting early onset of non-carbohydrate metabolite utilization to sustain energy under long term fasting. Conversely, mice with overexpression of hepatic Ppp1r3b maintained augmented glycogen storage capacity, with larger glycogen pool creating a buffer towards delayed onset of hypoglycemia. Mice harboring deletion of hepatic Ppp1r3b exhibited glucose intolerance and insulin resistance, with increased hepatic triglyceride content, leading to hepatic steatosis, under chronic high sucrose feeding. In contrast, mice overexpressing hepatic Ppp1r3b remained glucose responsive, and insulin sensitive, and were protected from hepatic steatosis under chronic sucrose diet feeding. These studies implicate a major role of Ppp1r3b in glycogen and lipid homeostasis in the liver, and provide concrete evidence for its pleiotropic effect on metabolic state in a mammalian system, consistent with the human GWAS association.
Ph. D. University of Pennsylvania 2017. Department: Cell and Molecular Biology. Supervisor: Daniel J. Rader. Includes bibliographical references.