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

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 ± 112 mg/d in controls and 641 ± 201 mg/d in GSD-1a patients ( p < 0.01). Plasma triglyceride-palmitate derived from de novo lipogenesis was 7.1 ± 9.4 and 86.3 ± 42.5 μmol/h in controls and patients, respectively ( p < 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 ± 0.5 pools/d) compared with controls (4.3 ± 1.8 pools/d). Fractional catabolic rate of intermediate density lipoproteins was lower in patients (0.8 ± 0.6 pools/d) compared with controls (3.1 ± 1.5 pools/d). Whole body lipolysis was similar, i.e. , 4.5 ± 1.9 μmol/kg/min in patients and 3.8 ± 1.9 μmol/kg/min in controls. Hyperlipidemia in GSD-1a is associated with strongly increased lipid production and a slower relative conversion of VLDL to LDL.