Publication

Altered lipid and bile acid metabolism in Glycogen Storage Disease type 1a: pathophysiological mechanisms and therapeutic opportunities

Hoogerland, J., 2020, [Groningen]: University of Groningen. 219 p.

Research output: ThesisThesis fully internal (DIV)

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  • Title and contents

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  • Chapter 1

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  • Chapter 2

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  • Chapter 6

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  • Complete thesis

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  • Propositions

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DOI

Perturbed glucose signalling in liver cells induces several metabolic responses that adversely affect health. The studies described in this thesis focus on the (patho)physiological consequences of constitutively activated hepatic glucose signalling as occurs in type 2 diabetes and Glycogen Storage Disease type 1a (GSD Ia). The main findings described in this thesis are 1) Blood glucose levels in GSD Ia affect plasma triglyceride (TG) catabolism and fatty liver disease, suggesting that impaired TG catabolism is also most evident in GSD Ia patients with poor metabolic control. 2) Hepatic Carbohydrate Response Element Binding Protein (ChREBP) activity contributes to cholesterol homeostasis in mice via a CYP8B1-dependent modulation of bile acid composition. The ChREBP-CYP8B1 signaling cascade that we identified likely contributes to altered bile acid metabolism and its (patho)physiological consequences in conditions coinciding with excessive intrahepatic glucose signaling, such as GSD I. 3) ChREBP maintains hepatic TG balance in GSD Ia and its activation limits fatty liver development. 4) De novo lipogenesis contributes only marginally to fatty liver disease in GSD Ia, and inhibition of this pathway via pharmacological FXR activation may not be sufficient to protect against hepatic lipid accumulation. These studies may provide a basis for the development of novel therapeutic strategies to reduce or prevent GSD Ia symptoms and complications. They furthermore contribute to a better understanding of the pathophysiology of other metabolic diseases in which intrahepatic glucose signaling is perturbed, such as type 2 diabetes.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
Supervisors/Advisors
Award date14-Sep-2020
Place of Publication[Groningen]
Publisher
Publication statusPublished - 2020

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