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.

Hepatic glycerol shunt and glycerol-3-phosphate phosphatase control liver metabolism and glucodetoxification under hyperglycemia

“…Glucose derived Gro3P via glycolysis is needed for glycerolipid synthesis at large and TG in particular, and also for shuttling electrons from cytosol to mitochondria via the Gro3P shuttle. Thus, regulation of the cytosolic concentration of Gro3P offers a control mechanism with simultaneous three-dimensional effect on glucose, lipid and energy metabolism, as Gro3P is at the nexus of these pathways [ 19 , 22 ]. Excess supply of glucose can drive elevated production of Gro3P intracellularly and this together with increased availability of FFA, can lead to TG synthesis through the lipogenic arm of the GL/FFA cycle [ 11 , 12 ].…”

“…Hydrolytic control of intracellular Gro3P by G3PP adds another layer of metabolic regulation that was not recognized previously in mammalian cells. G3PP was initially identified as phosphoglycolate phosphatase with its gene name as PGP , but we and others showed that its actual primary physiological function involves Gro3P hydrolysis, although it can hydrolyze some other phospho-metabolites produced in particular during cellular stress [ 18 , 20 , [22] , [23] , [24] ]. Our earlier in vitro studies support a role for G3PP in liver glucose and lipid metabolism and showed an inverse relationship between G3PP expression and lipogenesis in isolated rat hepatocytes [ 18 ] and that the impact of G3PP activity on metabolism is more evident at high glucose concentrations when intracellular Gro3P rises to sufficiently high levels to become available for G3PP [ 18 ].…”

Proanthocyanidins Restore the Metabolic Diurnal Rhythm of Subcutaneous White Adipose Tissue According to Time-Of-Day Consumption

“…In fact, after feeding, glucose and fatty acids are taken up by WAT to synthesize acetyl-CoA for fatty acid synthesis [ 36 ]. Glycerol, another product of glycolysis, is needed for TAG formation in WAT when it is converted into glycerol-3-phosphate [ 37 ]. Lactate, for which we also found its acrophase in the dark phase, increases its production in WAT after glucose intake [ 36 , 37 ].…”

“…Glycerol, another product of glycolysis, is needed for TAG formation in WAT when it is converted into glycerol-3-phosphate [ 37 ]. Lactate, for which we also found its acrophase in the dark phase, increases its production in WAT after glucose intake [ 36 , 37 ]. Moreover, we expected to find 3-OHB increased during the light phase because of its association with β-oxidation [ 23 ].…”

Lipolysis and gestational diabetes mellitus onset: a case-cohort genome-wide association study in Chinese

“…According to the law of causality, the relation between genotypes and phenotypes is affected by only a few potential confounders, of which the most important is population stratification (PS). It can be estimated by the distinctions of observing genotypes among populations [ 79 ]. For SNPs/InDels, PS was calculated using the linkage-disequilibrium-pruned (LD-pruned) (window size 1500 variant count, step size 150 variant count, and pairwise r 2 < 0.2) variant set on autosomal chromosomes [ 53 , 54 ].…”