New Mammalian Glycerol-3-Phosphate Phosphatase: Role in β-Cell, Liver and Adipocyte Metabolism

Abstract

Cardiometabolic diseases, including type 2 diabetes, obesity and non-alcoholic fatty liver disease, have enormous impact on modern societies worldwide. Excess nutritional burden and nutri-stress together with sedentary lifestyles lead to these diseases. Deranged glucose, fat, and energy metabolism is at the center of nutri-stress, and glycolysis-derived glycerol-3-phosphate (Gro3P) is at the crossroads of these metabolic pathways. Cellular levels of Gro3P can be controlled by its synthesis, utilization or hydrolysis. The belief that mammalian cells do not possess an enzyme that hydrolyzes Gro3P, as in lower organisms and plants, is challenged by our recent work showing the presence of a Gro3P phosphatase (G3PP) in mammalian cells. A previously described phosphoglycolate phosphatase (PGP) in mammalian cells, with no established physiological function, has been shown to actually function as G3PP, under physiological conditions, particularly at elevated glucose levels. In the present review, we summarize evidence that supports the view that G3PP plays an important role in the regulation of gluconeogenesis and fat storage in hepatocytes, glucose stimulated insulin secretion and nutri-stress in β-cells, and lipogenesis in adipocytes. We provide a balanced perspective on the pathophysiological significance of G3PP in mammals with specific reference to cardiometabolic diseases.

Keywords: cardiometabolic diseases; glycerol-3-phosphate phosphatase; glycerolipid/free fatty acid cycle; insulin secretion; nutri-stress; obesity; phosphoglycolate phosphatase; type 2 diabetes.

Figure 1

Role of G3PP in intermediary metabolism. Glycerol-3-phosphate (Gro3P) is a central metabolite at the intersection of four important pathways in most cells: 1) glycolysis; 2) glycerolipid synthesis and the glycerolipid/free fatty acid (GL/FFA) cycle; 3) gluconeogenesis (liver and kidney) and 4) energy metabolism via electron transfer shuttle to mitochondria. Gro3P can be produced from glucose via glycolysis or from lipolysis-derived glycerol by glycerol kinase. The cellular levels and availability of Gro3P are regulated by Gro3P phosphatase (G3PP), which dephosphorylates Gro3P to form glycerol. Under conditions of excess glucose supply, a buildup of Gro3P in the cell may cause an overflow of glucose carbons into glycolysis, lipid synthesis and electron transfer, leading to accumulation of fat and also elevated production of reactive oxygen species (ROS) in mitochondria. G3PP may act as a detoxification enzyme to protect the cells from glucotoxicity, excess fat synthesis and storage and oxidative damage by hydrolyzing Gro3P to glycerol, a less harmful molecule, that exits the cell through aquaglyceroporins. α-KG, α-ketoglutarate; AQP, aquaglyceroporin; DHAP, dihydroxyacetone phosphate; ETC, electron transport chain; FFA, free fatty acid; G-6-P, glucose-6-phosphate; G3PP, glycerol-3-phosphate phosphatase; GA3P, glyceraldehyde-3-phosphate; GK, glycerol kinase; GL/FFA cycle, glycerolipid/free fatty acid cycle; Gro3P, glycerol-3-phosphate; OAA, oxaloacetate; ROS, reactive oxygen species; Succ-CoA, succinyl-CoA; TCA cycle, tricarboxylic acid cycle; TG, triglycerides.