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Disturbed lipid metabolism in glycogen storage disease type 1

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Abstract

Glycogen storage disease type 1 (GSD1) is an inborn error of metabolism caused by deficiency of glucose-6-phosphatase, the enzyme catalysing the conversion of glucose-6-phosphate (G6P) to glucose. GSD1 is associated with severe hyperlipidaemia and hepatic steatosis. The underlying mechanisms responsible for these abnormalities in lipid metabolism are only partly known. This review summarises data available on hyperlipidaemia and steatosis in GSD1 and postulates new hypotheses for unresolved issues. Evidence indicates that lipid clearance from the blood compartment is decreased in GSD1. Furthermore, in two GSD1 a patients synthesis of palmitate, an indicator of de novo lipogenesis, and cholesterol were found to be increased 40-fold and 7-fold, respectively. Elevated hepatic G6P levels may play a regulatory role in lipid synthesis via activation of transcription of lipogenic genes. In addition, accelerated glycolysis will supply acetyl-CoA molecules required for lipogenesis. It is as yet unclear whether hepatic secretion of lipids in the form of very low density lipoprotein-triglycerides (VLDL-TG) is altered in GSD1 patients: we recently found unaffected VLDL-TG secretion rates in an acute animal model of GSD1b. Hepatic steatosis, which is invariably present in GSD1 is probably mainly caused by an increased free fatty acid flux from adipose tissue to the liver and, to a limited extent, by increased de novo lipogenesis.Conclusion: future studies, using novel stable isotope methodologies, are warranted to further clarify the disturbances in lipid and lipoprotein metabolism in glycogen storage disease type 1 and the role of glucose-6-phosphate herein.

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Abbreviations

G6P :

glucose-6-phosphate

G6Pase :

glucose-6-phosphatase

GSD1 :

glycogen storage disease type 1

LDL :

low density lipoprotein

LPL :

lipoprotein lipase

SREBP :

sterol regulatory element-binding protein

VLDL :

very low density lipoprotein

VLDL-TG :

very low density lipoprotein-triglycerides

FFA :

face fatty acids

ER :

endoplasmic reticulum

References

  1. Bandsma RHJ, Rake JP, Visser G, Neese RA, Hellerstein MK, van Duyvenvoorde W, Princen HMG, Stellaard F, Smit GPA, Kuipers F (2002) Increased lipogenesis and resistance of lipoproteins to oxidative modification in two patients with Glycogen Storage Disease type 1a. J Ped 140: 256–260

    Article  CAS  Google Scholar 

  2. Binkiewicz A, Senior B (1973) Decreased ketogenesis in von Gierke's disease (type I glycogenosis). J Pediatr 83: 973–978

    Article  CAS  PubMed  Google Scholar 

  3. Brown AM, Wiggins D, Gibbons GF (1999) Glucose phosphorylation is essential for the turnover of neutral lipid and the second stage assembly of triacylglycerol-rich ApoB-containing lipoproteins in primary hepatocyte cultures. Arterioscler Thromb Vasc Biol 19: 321–329

    Article  CAS  PubMed  Google Scholar 

  4. Chen YT, Cornblath M, Sidbury JB (1984) Cornstarch therapy in type I glycogen-storage disease. N Engl J Med 310: 171–175

    Article  CAS  PubMed  Google Scholar 

  5. Doiron B, Cuif MH, Chen R, Kahn A (1996) Transcriptional glucose signaling through the glucose response element is mediated by the pentose phosphate pathway. J Biol Chem 271: 5321–5324

    Article  CAS  PubMed  Google Scholar 

  6. Fernandes J, Pikaar NA (1969) Hyperlipemia in children with liver glycogen disease. Am J Clin Nutr 22: 617–627

    CAS  PubMed  Google Scholar 

  7. Fernandes J, Alaupovic P, Wit JM (1989) Gastric drip feeding in patients with glycogen storage disease type I: its effects on growth and plasma lipids and apolipoproteins. Pediatr Res 25: 327–331

    Article  CAS  PubMed  Google Scholar 

  8. Foretz M, Guichard C, Ferre P, Foufelle F (1999) Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes. Proc Natl Acad Sci U S A 96: 12737–12742

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Forget PP, Fernandes J, Haverkamp-Begemann P (1974) Triglyceride clearing in glycogen storage disease. Pediatr Res 8: 114–119

    Article  CAS  PubMed  Google Scholar 

  10. Foufelle F, Gouhot B, Pegorier JP, Perdereau D, Girard J, Ferre P (1992) Glucose stimulation of lipogenic enzyme gene expression in cultured white adipose tissue. A role for glucose 6-phosphate. J Biol Chem 267: 20543–20546

    CAS  PubMed  Google Scholar 

  11. Frayn KN, Coppack SW, Fielding BA, Humphreys SM (1995) Coordinated regulation of hormone-sensitive lipase and lipoprotein lipase in human adipose tissue in vivo: implications for the control of fat storage and fat mobilization. Adv Enzyme Regul 35: 163–178

    Article  CAS  PubMed  Google Scholar 

  12. Gerin I, Veiga-da-Cunha M, Achouri Y, Collet JF, Van Schaftingen E (1997) Sequence of a putative glucose 6-phosphate translocase, mutated in glycogen storage disease type Ib. FEBS Lett 419: 235–238

    Article  CAS  PubMed  Google Scholar 

  13. Greene HL, Slonim AE, O'Neill JA Jr, Burr IM (1976) Continuous nocturnal intragastric feeding for management of type 1 glycogen-storage disease. N Engl J Med 294: 423–425

    Article  CAS  PubMed  Google Scholar 

  14. Greene HL, Swift LL, Knapp HR (1991) Hyperlipidemia and fatty acid composition in patients treated for type IA glycogen storage disease. J Pediatr 119: 398–403

    Article  CAS  PubMed  Google Scholar 

  15. Havel RJ, Balasse EO, Williams HE, Kane JP, Segel N (1969) Splanchnic metabolism in von Gierke's disease (glycogenosis type I). Trans Assoc Am Physicians 82: 305–323

    CAS  PubMed  Google Scholar 

  16. Hellerstein MK, Neese RA (1992) Mass isotopomer distribution analysis: a technique for measuring biosynthesis and turnover of polymers. Am J Physiol 263: E988-E1001

    CAS  PubMed  Google Scholar 

  17. Horton JD, Shimomura I (1999) Sterol regulatory element-binding proteins: activators of cholesterol and fatty acid biosynthesis. Curr Opin Lipidol 10: 143–150

    Article  CAS  PubMed  Google Scholar 

  18. Howell RR (1978) The glycogen storage diseases. In: Stanbury JB, Wyngaarden JB, Frederickson DS (eds) The metabolic basis of inherited disease. McGraw-Hill, New York, pp 143–146

    Google Scholar 

  19. Howell RR, Ashton DM, Wyngaarden JB (1962) Glucose-6-phosphatase deficiency in glycogen storage disease: studies on the interrelationship of carbohydrate, lipid and purine abnormalities. Pediatrics 29: 553–565

    CAS  PubMed  Google Scholar 

  20. Ihara K, Kuromaru R, Hara T (1998) Genomic structure of the human glucose 6-phosphate translocase gene and novel mutations in the gene of a Japanese patient with glycogen storage disease type Ib. Hum Genet 103: 493–496

    Article  CAS  PubMed  Google Scholar 

  21. Jakovcic S, Khachadurian AK Hsia DY (1966) The hyperlipidemia in glycogen storage disease. J Lab Clin Med 68: 769–779

    CAS  PubMed  Google Scholar 

  22. Jas FR, Bruni N, Montano S, Zitoun C, Mithieux G (1999) The glucose-6 phosphatase gene is expressed in human and rat small intestine: regulation of expression in fasted and diabetic rats. Gastroenterology 117: 132–139

    Article  Google Scholar 

  23. Koo SH, Dutcher AK, Towle HC (2001) Glucose and insulin function through two distinct transcription factors to stimulate expression of lipogenic enzyme genes in liver. J Biol Chem 276: 16033–16039

    Article  PubMed  Google Scholar 

  24. Levy E, Thibault LA, Roy CC, Bendayan M, Lepage G, Letarte J (1988) Circulating lipids and lipoproteins in glycogen storage disease type I with nocturnal intragastric feeding. J Lipid Res 29: 215–226

    CAS  PubMed  Google Scholar 

  25. Levy E, Letarte J, Lepage G, Thibault L, Roy CC (1987) Plasma and lipoprotein fatty acid composition in glycogen storage disease type I. Lipids 22: 381–385

    Article  CAS  PubMed  Google Scholar 

  26. Levy E, Thibault L, Roy CC, Letarte J, Lambert M, Seidman EG (1990) Mechanisms of hypercholesterolaemia in glycogen storage disease type I: defective metabolism of low density lipoprotein in cultured skin fibroblasts. Eur J clin Invest 20: 253–260

    Article  CAS  PubMed  Google Scholar 

  27. Levy E, Thibault L, Turgeon J, Roy CC, Gurbindo C, Lepage G, Godard M, Rivard GE, Seidman E (1993) Beneficial effects of fish-oil supplements on lipids, lipoproteins, and lipoprotein lipase in patients with glycogen storage disease type I. Am J Clin Nutr 57: 922–929

    CAS  PubMed  Google Scholar 

  28. Lewis GF, Uffelman KD, Szeto LW, Steiner G (1993) Effects of acute hyperinsulinaemia on VLDL triglyceride and VLDL ApoB production in normal weight and obese individuals. Diabetes 42: 833–842

    Article  CAS  PubMed  Google Scholar 

  29. Malmström R, Packard CJ, Caslake M, Bedford D, Stewart P, Yki-Järvinen H, Shepherd J, Taskinen MJ (1998) Effects of insulin and acipimox on VLDL1 and VLDL2 apolipoprotein B production in normal subjects. Diabetes 47: 779–787

    Article  PubMed  Google Scholar 

  30. McAdams AJ, Hug G, Bove KE (1974) Glycogen storage disease, types I to X: criteria for morphologic diagnosis. Hum Pathol 5: 463–487

    Article  CAS  PubMed  Google Scholar 

  31. McGarry J, Brown N (1997) The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis. Eur J Biochem 244: 1–14

    Article  CAS  PubMed  Google Scholar 

  32. Michels VV, Beaudet AL, Potts VE, Montandon CM (1982) Glycogen storage disease: long-term follow-up of nocturnal intragastric feeding. Clin Genet 21: 136–140

    Article  CAS  PubMed  Google Scholar 

  33. Mourrieras F, Foufelle F, Foretz M, Morin J, Bouche S, Ferre P (1997) Induction of fatty acid synthase and S14 gene expression by glucose, xylitol and dihydroxyacetone in cultured rat hepatocytes is closely correlated with glucose 6-phosphate concentrations. Biochem J 326: 345–349

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Oberhaensli RD, Rajagopalan B, Taylor DJ, Radda GK, Collins JE, Leonard JV (1988) Study of liver metabolism in glucose-6-phosphatase deficiency (glycogen storage disease type 1A) by P-31 magnetic resonance spectroscopy. Pediatr Res 23: 375–380

    Article  CAS  PubMed  Google Scholar 

  35. Riches FM, Watts GF, Naoumova RP, Kelly JM, Croft KD, Thompson GR (1997) Direct association between the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 and plasma mevalonic acid and lathosterol concentrations in man. Atherosclerosis 135: 83–91

    Article  CAS  PubMed  Google Scholar 

  36. Shelly LL, Lei KL, Pan CJ, Sakata SF, Ruppert S, Schutz G, Chou JY (1993) Isolation of the gene for murine glucose-6-phosphatase, the enzyme deficient in glycogen storage disease type 1A. J Biol Chem 268: 21482–21485

    CAS  PubMed  Google Scholar 

  37. Shimomura I, Bashmakov Y, Ikemoto S, Horton JD, Brown MS, Goldstein JL (1999) Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. Proc Natl Acad Sci U S A 96: 13656–13661

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Smit GPA (1993) The long-term outcome of patients with glycogen storage disease type Ia. Eur J Pediatr 152[Supplement]: S52-S55

    Article  PubMed  Google Scholar 

  39. Talente GM, Coleman RA, Alter C, Baker L, Brown BI, Cannon RA, Chen YT, Crigler JF Jr, Ferreira P, Haworth JC (1994) Glycogen storage disease in adults. Ann Intern Med 120: 218–226

    Article  CAS  PubMed  Google Scholar 

  40. Wang SL, Du EZ, Martin TD, Davis RA (1997) Coordinate regulation of lipogenesis, the assembly and secretion of apolipoprotein B-containing lipoproteins by sterol response element binding protein 1. J Biol Chem 272: 19351–19358

    Article  CAS  PubMed  Google Scholar 

  41. Watts GF, Naoumova R, Cummings MH, Umpleby AM (1995) Direct correlation between cholesterol synthesis and hepatic secretion of apolipoprotein B-100 in normolipidemic subjects. Metabolism 44: 1052–1057

    Article  CAS  PubMed  Google Scholar 

  42. Bandsma RHJ, Wiegman CH, Herling AW, Burger HJ, ter Harmsel A, Meijer AJ, Romijn JA, Reijngoud DJ, Kuipers F (2001) Acute inhibition of glucose-6-phosphatase translocator activity leads to increasedde novo lipogenesis and development of hepatic steatosis without affecting VLDL production in rats. Diabetes 50: 2591–2597

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Centre for Liver, Digestive and Metabolic Diseases, Room Y2117, CMCIV, University Hospital Groningen, Hanzeplein 1, PO Box 30.001, 9700 RB, Groningen, The Netherlands

    Robert H. J. Bandsma & Folkert Kuipers

  2. Department of Paediatrics, University Children’s Hospital, Groningen, The Netherlands

    G. Peter A. Smit

Authors
  1. Robert H. J. Bandsma
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  2. G. Peter A. Smit
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  3. Folkert Kuipers
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Correspondence to Robert H. J. Bandsma.

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Published online: 13 July 2002

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Bandsma, R.H.J., Smit, G.P.A. & Kuipers, F. Disturbed lipid metabolism in glycogen storage disease type 1. Eur J Pediatr 161, S65–S69 (2002). https://doi.org/10.1007/BF02679998

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  • DOI: https://doi.org/10.1007/BF02679998

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