Impaired Very-Low-Density Lipoprotein catabolism links hypoglycemia to hypertriglyceridemia in Glycogen Storage Disease type Ia

Joanne A Hoogerland; Fabian Peeks; Brenda S Hijmans; Justina C Wolters; Sander Kooijman; Trijnie Bos; Aycha Bleeker; Theo H van Dijk; Henk Wolters; Albert Gerding; Karen van Eunen; Rick Havinga; Amanda C M Pronk; Patrick C N Rensen; Gilles Mithieux; Fabienne Rajas; Folkert Kuipers; Dirk-Jan Reijngoud; Terry G J Derks; Maaike H Oosterveer

doi:10.1002/jimd.12380

Impaired Very-Low-Density Lipoprotein catabolism links hypoglycemia to hypertriglyceridemia in Glycogen Storage Disease type Ia

Joanne A Hoogerland, Fabian Peeks, Brenda S Hijmans, Justina C Wolters, Sander Kooijman, Trijnie Bos, Aycha Bleeker, Theo H van Dijk, Henk Wolters, Albert Gerding, Karen van Eunen, Rick Havinga, Amanda C M Pronk, Patrick C N Rensen, Gilles Mithieux, Fabienne Rajas, Folkert Kuipers, Dirk-Jan Reijngoud, Terry G J Derks, Maaike H Oosterveer^*

^*Corresponding author for this work

Center for Liver, Digestive and Metabolic Diseases (CLDM)

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Prevention of hypertriglyceridemia is one of the biomedical targets in Glycogen Storage Disease type 1a (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 -patients. Plasma 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. This article is protected by copyright. All rights reserved.

Original language	English
Pages (from-to)	879–892
Number of pages	14
Journal	Journal of Inherited Metabolic Disease
Volume	44
Issue number	4
Early online date	7-Apr-2021
DOIs	https://doi.org/10.1002/jimd.12380
Publication status	Published - Jul-2021

Keywords

Glycogen Storage Disease type Ia
hepatic steatosis
hypertriglyceridemia
metabolic control
translational research

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Hoogerland, J. A., Peeks, F., Hijmans, B. S., Wolters, J. C., Kooijman, S., Bos, T., Bleeker, A., van Dijk, T. H., Wolters, H., Gerding, A., van Eunen, K., Havinga, R., Pronk, A. C. M., Rensen, P. C. N., Mithieux, G., Rajas, F., Kuipers, F., Reijngoud, D.-J., Derks, T. G. J., & Oosterveer, M. H. (2021). Impaired Very-Low-Density Lipoprotein catabolism links hypoglycemia to hypertriglyceridemia in Glycogen Storage Disease type Ia. Journal of Inherited Metabolic Disease, 44(4), 879–892. https://doi.org/10.1002/jimd.12380

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title = "Impaired Very-Low-Density Lipoprotein catabolism links hypoglycemia to hypertriglyceridemia in Glycogen Storage Disease type Ia",

abstract = "Prevention of hypertriglyceridemia is one of the biomedical targets in Glycogen Storage Disease type 1a (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 -patients. Plasma 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. This article is protected by copyright. All rights reserved.",

keywords = "Glycogen Storage Disease type Ia, hepatic steatosis, hypertriglyceridemia, metabolic control, translational research",

author = "Hoogerland, {Joanne A} and Fabian Peeks and Hijmans, {Brenda S} and Wolters, {Justina C} and Sander Kooijman and Trijnie Bos and Aycha Bleeker and {van Dijk}, {Theo H} and Henk Wolters and Albert Gerding and {van Eunen}, Karen and Rick Havinga and Pronk, {Amanda C M} and Rensen, {Patrick C N} and Gilles Mithieux and Fabienne Rajas and Folkert Kuipers and Dirk-Jan Reijngoud and Derks, {Terry G J} and Oosterveer, {Maaike H}",

year = "2021",

month = jul,

doi = "10.1002/jimd.12380",

language = "English",

volume = "44",

pages = "879–892",

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Hoogerland, JA , Peeks, F, Hijmans, BS, Wolters, JC, Kooijman, S, Bos, T , Bleeker, A, van Dijk, TH, Wolters, H, Gerding, A, van Eunen, K , Havinga, R, Pronk, ACM, Rensen, PCN, Mithieux, G, Rajas, F, Kuipers, F , Reijngoud, D-J , Derks, TGJ & Oosterveer, MH 2021, 'Impaired Very-Low-Density Lipoprotein catabolism links hypoglycemia to hypertriglyceridemia in Glycogen Storage Disease type Ia', Journal of Inherited Metabolic Disease, vol. 44, no. 4, pp. 879–892. https://doi.org/10.1002/jimd.12380

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T1 - Impaired Very-Low-Density Lipoprotein catabolism links hypoglycemia to hypertriglyceridemia in Glycogen Storage Disease type Ia

AU - Hoogerland, Joanne A

AU - Peeks, Fabian

AU - Hijmans, Brenda S

AU - Wolters, Justina C

AU - Kooijman, Sander

AU - Bos, Trijnie

AU - Bleeker, Aycha

AU - van Dijk, Theo H

AU - Wolters, Henk

AU - Gerding, Albert

AU - van Eunen, Karen

AU - Havinga, Rick

AU - Pronk, Amanda C M

AU - Rensen, Patrick C N

AU - Mithieux, Gilles

AU - Rajas, Fabienne

AU - Kuipers, Folkert

AU - Reijngoud, Dirk-Jan

AU - Derks, Terry G J

AU - Oosterveer, Maaike H

PY - 2021/7

Y1 - 2021/7

N2 - Prevention of hypertriglyceridemia is one of the biomedical targets in Glycogen Storage Disease type 1a (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 -patients. Plasma 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. This article is protected by copyright. All rights reserved.

AB - Prevention of hypertriglyceridemia is one of the biomedical targets in Glycogen Storage Disease type 1a (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 -patients. Plasma 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. This article is protected by copyright. All rights reserved.

KW - Glycogen Storage Disease type Ia

KW - hepatic steatosis

KW - hypertriglyceridemia

KW - metabolic control

KW - translational research

U2 - 10.1002/jimd.12380

DO - 10.1002/jimd.12380

M3 - Article

C2 - 33739445

SN - 0141-8955

VL - 44

SP - 879

EP - 892

JO - Journal of Inherited Metabolic Disease

JF - Journal of Inherited Metabolic Disease

IS - 4

ER -

Impaired Very-Low-Density Lipoprotein catabolism links hypoglycemia to hypertriglyceridemia in Glycogen Storage Disease type Ia

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