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.
Highlights
Metabolism of macronutrients including carbohydrates, amino acids and fats converges on the generation of a three-carbon moiety, glycerol, either in the free form or as glycerol-3-phosphate (Gro3P), which forms the backbone of glycerolipids in almost all the species
The present review focuses on the identification of a specific Gro3P phosphatase (G3PP) in mammalian cells and its most plausible physiological function, addressing its role in controlling glucose, lipid and energy metabolism
We present a balanced view on the physiological relevance of the various suggested substrates of this enzyme, with a discussion on the importance of G3PP in preventing glucotoxicity/nutri-stress and the control of glucose stimulated insulin secretion (GSIS) in bcells, in the regulation of lipogenesis in liver and adipose tissue, and in slowing down hepatic glucose production
Summary
Metabolism of macronutrients including carbohydrates, amino acids and fats converges on the generation of a three-carbon moiety, glycerol, either in the free form or as glycerol-3-phosphate (Gro3P), which forms the backbone of glycerolipids in almost all the species. A powerful pan-lipase inhibitor, totally inhibits GSIS as well as lipolysis, measured as free fatty acid (FFA) release, in pancreatic b-cells [22], but not glycerol release at elevated glucose concentrations (>10 mM), suggesting that pancreatic b-cells can produce glycerol from glucose, via non-lipolytic pathways [22] This observation led us to conduct a thorough search using BLAST analysis for mammalian proteins that are homologous to the known microbial (yeast and bacteria) glycerol-3-phosphate phosphatase enzymes [8, 23], and to the identification of previously described phosphoglycolate phosphatase (PGP), as the potential mammalian G3PP [22]. On the basis of available evidence, we suggest that the protein encoded by PGP in mammalian cells is poised to act on Gro3P, as its normal physiological function, but may assume a detoxification role to hydrolyze toxic phosphometabolites, such as 2-phosphoglycolate, 4-phosphoerythronate or 2-phospholactate, which may buildup in the cells under stress conditions [22, 24, 25, 32]. Significant evidence accumulated in the last five years suggests an important role for G3PP/PGP in the regulation of glucose and lipid metabolism in pancreatic islets, hepatocytes and adipocytes (Figure 1), which is summarized below
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