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

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

Molecular Metabolism (Dec 2022)

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

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

Affiliations

Anfal Al-Mass: Department 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, Canada
Pegah Poursharifi: Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center and CRCHUM, Montréal, QC, Canada
Marie-Line Peyot: Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center and CRCHUM, Montréal, QC, Canada
Roxane Lussier: Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center and CRCHUM, Montréal, QC, Canada
Isabelle Chenier: Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center and CRCHUM, Montréal, QC, Canada
Yat Hei Leung: Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center and CRCHUM, Montréal, QC, Canada
Anindya Ghosh: Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center and CRCHUM, Montréal, QC, Canada
Abel Oppong: Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center and CRCHUM, Montréal, QC, Canada
Elite Possik: Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center and CRCHUM, Montréal, QC, Canada
Yves Mugabo: Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center and CRCHUM, Montréal, QC, Canada
Rasheed Ahmad: Departments of Immunology, Microbiology, Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait
Robert Sladek: Department of Medicine, McGill University, Montréal, QC, Canada
S.R. Murthy Madiraju: Departments 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.
Fahd Al-Mulla: Departments of Immunology, Microbiology, Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait
Marc Prentki: Departments 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.

Journal volume & issue: Vol. 66
p. 101609

Abstract

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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.

Published in Molecular Metabolism

ISSN: 2212-8778 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine
Website: https://www.journals.elsevier.com/molecular-metabolism/

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