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Impaired Very‐Low‐Density Lipoprotein catabolism links hypoglycemia to hypertriglyceridemia in Glycogen Storage Disease type Ia
Author(s) -
Hoogerland Joanne A.,
Peeks Fabian,
Hijmans Brenda S.,
Wolters Justina C.,
Kooijman Sander,
Bos Trijnie,
Bleeker Aycha,
Dijk Theo H.,
Wolters Henk,
Gerding Albert,
Eunen Karen,
Havinga Rick,
Pronk Amanda C. M.,
Rensen Patrick C. N.,
Mithieux Gilles,
Rajas Fabienne,
Kuipers Folkert,
Reijngoud DirkJan,
Derks Terry G. J.,
Oosterveer Maaike H.
Publication year - 2021
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1002/jimd.12380
Subject(s) - endocrinology , medicine , hypertriglyceridemia , very low density lipoprotein , lipolysis , hypoglycemia , glycogen storage disease , catabolism , dyslipidemia , glycogen , chylomicron , triglyceride , adipose tissue , lipoprotein , insulin , diabetes mellitus , cholesterol , metabolism
Prevention of hypertriglyceridemia is one of the biomedical targets in Glycogen Storage Disease type Ia (GSD Ia) patients, yet it is unclear how hypoglycemia links to plasma triglyceride (TG) levels. We analyzed whole‐body TG metabolism in normoglycemic (fed) and hypoglycemic (fasted) hepatocyte‐specific glucose‐6‐phosphatase deficient (L‐ G6pc −/− ) mice. De novo fatty acid synthesis contributed substantially to hepatic TG accumulation in normoglycemic L‐ G6pc −/− mice. In hypoglycemic conditions, enhanced adipose tissue lipolysis was the main driver of liver steatosis, supported by elevated free fatty acid concentrations in GSD Ia mice and GSD Ia patients. Plasma very‐low‐density lipoprotein (VLDL) levels were increased in GSD Ia patients and in normoglycemic L‐ G6pc −/− mice, and further elevated in hypoglycemic L‐ G6pc −/− mice. VLDL‐TG secretion rates were doubled in normo‐ and hypoglycemic L‐ G6pc −/− mice, while VLDL‐TG catabolism was selectively inhibited in hypoglycemic L‐ G6pc −/− mice. In conclusion, fasting‐induced hypoglycemia in L‐ G6pc −/− mice promotes adipose tissue lipolysis and arrests VLDL catabolism. This mechanism likely contributes to aggravated liver steatosis and dyslipidemia in GSD Ia patients with poor glycemic control and may explain clinical heterogeneity in hypertriglyceridemia between GSD Ia patients.