Acute Inhibition of Glucose-6-Phosphate Translocator Activity Leads to Increased De Novo Lipogenesis and Development of Hepatic Steatosis Without Affecting VLDL Production in Rats
- Robert H.J. Bandsma1,
- Coen H. Wiegman1,
- Andreas W. Herling2,
- Hans-Joerg Burger2,
- Anke ter Harmsel1,
- Alfred J. Meijer3,
- Johannes A. Romijn4,
- Dirk-Jan Reijngoud1 and
- Folkert Kuipers1
- 1Groningen University Institute for Drug Exploration, Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, Academic Hospital Groningen, Groningen, the Netherlands
- 2Aventis Pharma Germany, Frankfurt, Germany
- 3Department of Biochemistry, Academic Medical Center, Amsterdam, the Netherlands
- 4Department of Endocrinology, Academic Hospital Leiden, Leiden, the Netherlands
Abstract
Glucose-6-phosphatase (G6Pase) is a key enzyme in hepatic glucose metabolism. Altered G6Pase activity in glycogen storage disease and diabetic states is associated with disturbances in lipid metabolism. We studied the effects of acute inhibition of G6Pase activity on hepatic lipid metabolism in nonanesthetized rats. Rats were infused with an inhibitor of the glucose-6-phosphate (G6P) translocator (S4048, 30 mg · kg–1 · h–1) for 8 h. Simultaneously, [1-13C]acetate was administered for determination of de novo lipogenesis and fractional cholesterol synthesis rates by mass isotopomer distribution analysis. In a separate group of rats, Triton WR 1339 was injected for determination of hepatic VLDL-triglyceride production. S4048 infusion significantly decreased plasma glucose (−11%) and insulin (−48%) levels and increased hepatic G6P (201%) and glycogen (182%) contents. Hepatic triglyceride contents increased from 5.8 ± 1.4 μmol/g liver in controls to 20.6 ± 5.5 μmol/g liver in S4048-treated animals. De novo lipogenesis was increased >10-fold in S4048-treated rats, without changes in cholesterol synthesis rates. Hepatic mRNA levels of acetyl-CoA carboxylase and fatty acid synthase were markedly induced. Plasma triglyceride levels increased fourfold, but no differences in plasma cholesterol levels were seen. Surprisingly, hepatic VLDL-triglyceride secretion was not increased in S4048-treated rats. These studies demonstrate that inhibition of the G6Pase system leads to acute stimulation of fat synthesis and development of hepatic steatosis, without affecting hepatic cholesterol synthesis and VLDL secretion. The results emphasize the strong interactions that exist between hepatic carbohydrate and fat metabolism.
Footnotes
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Address correspondence and reprint requests to Robert Bandsma, Department of Pediatrics, Room Y2117, CMCIV, Academic Hospital Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB Groningen, the Netherlands. E-mail: r.h.j.bandsma{at}med.rug.nl.
H.-J.B. and A.W.H. are employed by and hold stock in Aventis Pharma Germany.
R.H.J.B. and C.H.W contributed equally to this study.
Received for publication 7 August 2000 and accepted in revised form 10 August 2001.
ACC, acetyl-CoA carboxylase; ALAT, alanine aminotransferase; apoB, apolipoprotein B; ASAT, aspartate aminotransferase; CPT-I, carnitine palmitoyltransferase I; ER, endoplasmic reticulum; FAS, fatty acid synthase; FFA, free fatty acid; GSD, glycogen storage disease; GSD-1, GSD type I; G6P, glucose-6-phosphate; G6Pase, glucose-6-phosphatase; HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA; MIDA, mass isotopomer distribution analysis; MTP, microsomal triglyceride transfer protein; m/z, mass/charge ratio; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; SREBP, sterol regulatory element binding protein.
