|
 |
|
|||||||
|
|||||||||
© 2001 by the American Diabetes Association, Inc.
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
1 Groningen University Institute for Drug Exploration, Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, Academic Hospital Groningen, Groningen, the Netherlands
2 Aventis Pharma Germany, Frankfurt, Germany
3 Department of Biochemistry, Academic Medical Center, Amsterdam, the Netherlands
4 Department of Endocrinology, Academic Hospital Leiden, Leiden, the Netherlands
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.
CiteULike 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  K. W. Sloop, A. D. Showalter, A. L. Cox, J. X. C. Cao, A. M. Siesky, H. Y. Zhang, A. R. Irizarry, S. F. Murray, S. L. Booten, E. A. Finger, et al. Specific Reduction of Hepatic Glucose 6-Phosphate Transporter-1 Ameliorates Diabetes while Avoiding Complications of Glycogen Storage Disease J. Biol. Chem., June 29, 2007; 282(26): 19113 - 19121. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Rebouissou, S. Imbeaud, C. Balabaud, V. Boulanger, J. Bertrand-Michel, F. Terce, C. Auffray, P. Bioulac-Sage, and J. Zucman-Rossi HNF1{alpha} Inactivation Promotes Lipogenesis in Human Hepatocellular Adenoma Independently of SREBP-1 and Carbohydrate-response Element-binding Protein (ChREBP) Activation J. Biol. Chem., May 11, 2007; 282(19): 14437 - 14446. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. N. van der Veen, R. Havinga, V. W. Bloks, A. K. Groen, and F. Kuipers Cholesterol feeding strongly reduces hepatic VLDL-triglyceride production in mice lacking the liver X receptor {alpha} J. Lipid Res., February 1, 2007; 48(2): 337 - 347. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Grefhorst, J. Hoekstra, T. G. J. Derks, D. M. Ouwens, J. F. W. Baller, R. Havinga, L. M. Havekes, J. A. Romijn, and F. Kuipers Acute hepatic steatosis in mice by blocking {beta}-oxidation does not reduce insulin sensitivity of very-low-density lipoprotein production Am J Physiol Gastrointest Liver Physiol, September 1, 2005; 289(3): G592 - G598. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Carriere, M. Le Gall, F. Gouyon-Saumande, D. Schmoll, E. Brot-Laroche, V. Chauffeton, J. Chambaz, and M. Rousset Intestinal Glucose-dependent Expression of Glucose-6-phosphatase: INVOLVEMENT OF THE ARYL RECEPTOR NUCLEAR TRANSLOCATOR TRANSCRIPTION FACTOR J. Biol. Chem., May 20, 2005; 280(20): 20094 - 20101. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. den Boer, P.J. Voshol, F. Kuipers, L.M. Havekes, and J.A. Romijn Hepatic Steatosis: A Mediator of the Metabolic Syndrome. Lessons From Animal Models Arterioscler. Thromb. Vasc. Biol., April 1, 2004; 24(4): 644 - 649. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Leuzzi, G. Banhegyi, T. Kardon, P. Marcolongo, P.-L. Capecchi, H.-J. Burger, A. Benedetti, and R. Fulceri Inhibition of microsomal glucose-6-phosphate transport in human neutrophils results in apoptosis: a potential explanation for neutrophil dysfunction in glycogen storage disease type 1b Blood, March 15, 2003; 101(6): 2381 - 2387. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Grefhorst, B. M. Elzinga, P. J. Voshol, T. Plosch, T. Kok, V. W. Bloks, F. H. van der Sluijs, L. M. Havekes, J. A. Romijn, H. J. Verkade, et al. Stimulation of Lipogenesis by Pharmacological Activation of the Liver X Receptor Leads to Production of Large, Triglyceride-rich Very Low Density Lipoprotein Particles J. Biol. Chem., September 6, 2002; 277(37): 34182 - 34190. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Diabetes | Diabetes Care | Clinical Diabetes | Diabetes Spectrum |