Increased de novo Lipogenesis and Delayed Conversion of Large VLDL into Intermediate Density Lipoprotein Particles Contribute to Hyperlipidemia in Glycogen Storage Disease Type 1a

Abstract

Glycogen storage disease type 1a (GSD-1a) is a metabolic disorder characterized by fasting-induced hypoglycemia, hepatic steatosis, and hyperlipidemia. The mechanisms underlying the lipid abnormalities are largely unknown. To investigate these mechanisms seven GSD-1a patients and four healthy control subjects received an infusion of [1-13 C]acetate to quantify cholesterogenesis and lipogenesis. In a subset of patients, [1-13 C]valine was given to assess lipoprotein metabolism and [2-13 C]glycerol to determine whole body lipolysis. Cholesterogenesis was 274 Ϯ 112 mg/d in controls and 641 Ϯ 201 mg/d in GSD-1a patients (p Ͻ 0.01). Plasma triglyceride-palmitate derived from de novo lipogenesis was 7.1 Ϯ 9.4 and 86.3 Ϯ 42.5 mol/h in controls and patients, respectively (p Ͻ 0.01). Production of VLDL did not show a consistent difference between the groups, but conversion of VLDL into intermediate density lipoproteins was relatively retarded in all patients (0.6 Ϯ 0.5 pools/d) compared with controls (4.3 Ϯ 1.8 pools/d). Fractional catabolic rate of intermediate density lipoproteins was lower in patients (0.8 Ϯ 0.6 pools/d) compared with controls (3.1 Ϯ 1.5 pools/d). Whole body lipolysis was similar, i.e., 4.5 Ϯ 1.9 mol/kg/ min in patients and 3.8 Ϯ 1.9 mol/kg/min in controls. Hyperlipidemia in GSD-1a is associated with strongly increased lipid production and a slower relative conversion of VLDL to LDL. (Pediatr Res 63: 702-707, 2008) G lycogen storage disease type 1a (GSD-1a, von Gierke Disease, OMIM#232200) is caused by deficiency of glucose-6-phosphatase ␣ (G6Pase-␣), which catalyzes the terminal steps in gluconeogenesis and glycogenolysis by converting glucose-6-phosphate to glucose and phosphate. G6Pase-␣ deficiency results in an inability to release glucose from liver, kidney, and possibly intestine. Phenotypical, G6Pase-␣ deficiency is characterized by growth retardation, hypoglycemia, hepatomegaly (massive hepatic steatosis) and lactic acidemia, as well as hypertriglyceridemia and hypercholesterolemia (1). Increased concentrations of cholesterol are found in both very LDL (VLDL) and LDL fractions whereas HDL cholesterol and apolipoprotein A-I concentrations are usually decreased (2,3). To control hypoglycemia in GSD-1a, patients often receive uncooked cornstarch which is accompanied by reductions in plasma lipid levels in GSD-1a (4,5). The underlying mechanisms responsible for disturbed lipid metabolism in GSD-1a are largely unknown. We have previously reported increased rates of hepatic de novo lipogenesis and cholesterogenesis in two patients with GSD-1a (6), which may drive VLDL production by the liver. Lipogenesis and cholesterogenesis have both been implicated in regulation of VLDL secretion (7-9). In addition, insulin is known to suppress hepatic VLDL production (10): prevailing low insulin concentrations in GSD-1a patients may contribute to increased VLDL production in these subjects, but quantitative data are not available. Furthermore, defective lipoprotein lipolysis might also contribute to hy...

Further delineation of the phenotype of severe congenital neutropenia type 4 due to mutations in G6PC3

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Glycogen Storage Disease Type 1: Impact of Medium-Chain Triglycerides on Metabolic Control and Growth

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