Hepatic glycerol shunt and glycerol-3-phosphate phosphatase control liver metabolism and glucodetoxification under hyperglycemia
Objective: Glycerol-3-phosphate (Gro3P) phosphatase (G3PP) hydrolyzes Gro3P to glycerol that exits the cell, thereby operating a “glycerol shunt”, a metabolic pathway that we identified recently in mammalian cells. We have investigated the role of G3PP and the glycerol shunt in the regulation of glu...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877822001788 |
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| author | Anfal Al-Mass Pegah Poursharifi Marie-Line Peyot Roxane Lussier Isabelle Chenier Yat Hei Leung Anindya Ghosh Abel Oppong Elite Possik Yves Mugabo Rasheed Ahmad Robert Sladek S.R. Murthy Madiraju Fahd Al-Mulla Marc Prentki |
| author_facet | Anfal Al-Mass Pegah Poursharifi Marie-Line Peyot Roxane Lussier Isabelle Chenier Yat Hei Leung Anindya Ghosh Abel Oppong Elite Possik Yves Mugabo Rasheed Ahmad Robert Sladek S.R. Murthy Madiraju Fahd Al-Mulla Marc Prentki |
| author_sort | Anfal Al-Mass |
| collection | DOAJ |
| description | Objective: Glycerol-3-phosphate (Gro3P) phosphatase (G3PP) hydrolyzes Gro3P to glycerol that exits the cell, thereby operating a “glycerol shunt”, a metabolic pathway that we identified recently in mammalian cells. We have investigated the role of G3PP and the glycerol shunt in the regulation of glucose metabolism and lipogenesis in mouse liver. Methods: We generated hepatocyte-specific G3PP-KO mice (LKO), by injecting AAV8-TBG-iCre to male G3PPfl/fl mice. Controls received AAV8-TBG-eGFP. Both groups were fed chow diet for 10 weeks. Hyperglycemia (16–20 mM) was induced by glucose infusion for 55 h. Hepatocytes were isolated from normoglycemic mice for ex vivo studies and targeted metabolomics were measured in mice liver after glucose infusion. Results: LKO mice showed no change in body weight, food intake, fed and fasted glycemia but had increased fed plasma triglycerides. Hepatic glucose production from glycerol was increased in fasted LKO mice. LKO mouse hepatocytes displayed reduced glycerol production, elevated triglyceride and lactate production at high glucose concentration. Hyperglycemia in LKO mice led to increased liver weight and accumulation of triglycerides, glycogen and cholesterol together with elevated levels of Gro3P, dihydroxyacetone phosphate, acetyl-CoA and some Krebs cycle intermediates in liver. Hyperglycemic LKO mouse liver showed elevated expression of proinflammatory cytokines and M1-macrophage markers accompanied by increased plasma triglycerides, LDL/VLDL, urea and uric acid and myocardial triglycerides. Conclusions: The glycerol shunt orchestrated by G3PP acts as a glucose excess detoxification pathway in hepatocytes by preventing metabolic disturbances that contribute to enhanced liver fat, glycogen storage, inflammation and lipid build-up in the heart. We propose G3PP as a novel therapeutic target for hepatic disorders linked to nutrient excess. |
| first_indexed | 2024-04-13T06:01:01Z |
| format | Article |
| id | doaj.art-ef4e4aa106094673b2a836cb280c8599 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-04-13T06:01:01Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-ef4e4aa106094673b2a836cb280c85992022-12-22T02:59:26ZengElsevierMolecular Metabolism2212-87782022-12-0166101609Hepatic glycerol shunt and glycerol-3-phosphate phosphatase control liver metabolism and glucodetoxification under hyperglycemiaAnfal Al-Mass0Pegah Poursharifi1Marie-Line Peyot2Roxane Lussier3Isabelle Chenier4Yat Hei Leung5Anindya Ghosh6Abel Oppong7Elite Possik8Yves Mugabo9Rasheed Ahmad10Robert Sladek11S.R. Murthy Madiraju12Fahd Al-Mulla13Marc Prentki14Department of Medicine, McGill University, Montréal, QC, Canada; Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center and CRCHUM, Montréal, QC, CanadaDepartments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center and CRCHUM, Montréal, QC, CanadaDepartments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center and CRCHUM, Montréal, QC, CanadaDepartments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center and CRCHUM, Montréal, QC, CanadaDepartments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center and CRCHUM, Montréal, QC, CanadaDepartments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center and CRCHUM, Montréal, QC, CanadaDepartments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center and CRCHUM, Montréal, QC, CanadaDepartments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center and CRCHUM, Montréal, QC, CanadaDepartments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center and CRCHUM, Montréal, QC, CanadaDepartments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center and CRCHUM, Montréal, QC, CanadaDepartments of Immunology, Microbiology, Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, KuwaitDepartment of Medicine, McGill University, Montréal, QC, CanadaDepartments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center and CRCHUM, Montréal, QC, Canada; Corresponding author. CRCHUM, Room R08-418, Tour Viger, 900 rue Saint Denis, Montreal, QC H2X 0A9, Canada.Departments of Immunology, Microbiology, Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, KuwaitDepartments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center and CRCHUM, Montréal, QC, Canada; Corresponding author. Biochemistry and Molecular Medicine, Université de Montréal CRCHUM, Room R08-412, Tour Viger, 900 rue Saint Denis Montreal, QC H2X 0A9, Canada.Objective: Glycerol-3-phosphate (Gro3P) phosphatase (G3PP) hydrolyzes Gro3P to glycerol that exits the cell, thereby operating a “glycerol shunt”, a metabolic pathway that we identified recently in mammalian cells. We have investigated the role of G3PP and the glycerol shunt in the regulation of glucose metabolism and lipogenesis in mouse liver. Methods: We generated hepatocyte-specific G3PP-KO mice (LKO), by injecting AAV8-TBG-iCre to male G3PPfl/fl mice. Controls received AAV8-TBG-eGFP. Both groups were fed chow diet for 10 weeks. Hyperglycemia (16–20 mM) was induced by glucose infusion for 55 h. Hepatocytes were isolated from normoglycemic mice for ex vivo studies and targeted metabolomics were measured in mice liver after glucose infusion. Results: LKO mice showed no change in body weight, food intake, fed and fasted glycemia but had increased fed plasma triglycerides. Hepatic glucose production from glycerol was increased in fasted LKO mice. LKO mouse hepatocytes displayed reduced glycerol production, elevated triglyceride and lactate production at high glucose concentration. Hyperglycemia in LKO mice led to increased liver weight and accumulation of triglycerides, glycogen and cholesterol together with elevated levels of Gro3P, dihydroxyacetone phosphate, acetyl-CoA and some Krebs cycle intermediates in liver. Hyperglycemic LKO mouse liver showed elevated expression of proinflammatory cytokines and M1-macrophage markers accompanied by increased plasma triglycerides, LDL/VLDL, urea and uric acid and myocardial triglycerides. Conclusions: The glycerol shunt orchestrated by G3PP acts as a glucose excess detoxification pathway in hepatocytes by preventing metabolic disturbances that contribute to enhanced liver fat, glycogen storage, inflammation and lipid build-up in the heart. We propose G3PP as a novel therapeutic target for hepatic disorders linked to nutrient excess.http://www.sciencedirect.com/science/article/pii/S2212877822001788Glycerol-3-phosphate phosphataseGlycerol shuntGlucodetoxificationLiverLipogenesisTriglycerides |
| spellingShingle | Anfal Al-Mass Pegah Poursharifi Marie-Line Peyot Roxane Lussier Isabelle Chenier Yat Hei Leung Anindya Ghosh Abel Oppong Elite Possik Yves Mugabo Rasheed Ahmad Robert Sladek S.R. Murthy Madiraju Fahd Al-Mulla Marc Prentki Hepatic glycerol shunt and glycerol-3-phosphate phosphatase control liver metabolism and glucodetoxification under hyperglycemia Molecular Metabolism Glycerol-3-phosphate phosphatase Glycerol shunt Glucodetoxification Liver Lipogenesis Triglycerides |
| title | Hepatic glycerol shunt and glycerol-3-phosphate phosphatase control liver metabolism and glucodetoxification under hyperglycemia |
| title_full | Hepatic glycerol shunt and glycerol-3-phosphate phosphatase control liver metabolism and glucodetoxification under hyperglycemia |
| title_fullStr | Hepatic glycerol shunt and glycerol-3-phosphate phosphatase control liver metabolism and glucodetoxification under hyperglycemia |
| title_full_unstemmed | Hepatic glycerol shunt and glycerol-3-phosphate phosphatase control liver metabolism and glucodetoxification under hyperglycemia |
| title_short | Hepatic glycerol shunt and glycerol-3-phosphate phosphatase control liver metabolism and glucodetoxification under hyperglycemia |
| title_sort | hepatic glycerol shunt and glycerol 3 phosphate phosphatase control liver metabolism and glucodetoxification under hyperglycemia |
| topic | Glycerol-3-phosphate phosphatase Glycerol shunt Glucodetoxification Liver Lipogenesis Triglycerides |
| url | http://www.sciencedirect.com/science/article/pii/S2212877822001788 |
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