Role of hepatic glucose signaling in the development of liver disease

Yu Lei

    Research output: ThesisThesis fully internal (DIV)

    486 Downloads (Pure)

    Abstract

    The liver is a key organ in the maintenance of metabolic homeostasis and the divergent functions of the hepatocytes are tightly controlled by a wide variety of factors, including nutrients. As a consequence, sustained imbalances in hepatic nutrient availability can cause metabolic diseases and liver dysfunction. In this thesis, a mouse model for hepatic Glycogen Storage Disease type 1a (GSD Ia) was used to identify the physiological and molecular mechanisms that link intrahepatic glucose (-6-phosphate; G6P) imbalance to liver dysfunction. The work was particularly focused on Carbohydrate response element binding protein (ChREBP), a glucose-sensitive transcription factor that plays a central role in the regulation of hepatic glucose and lipid metabolism. The main findings of this research are: 1) Attenuation of ChREBP induction in GSD Ia liver aggravates hepatomegaly due to further accumulation of glycogen and lipids as a result of reduced glycolysis and suppressed VLDL-triglyceride (TG) secretion. This finding indicates that enhanced ChREBP activity limits NAFLD development in GSD Ia. 2) The hepatic G6P-ChREBP-CYP8B1 signaling axis controls both bile acid and cholesterol metabolism in mice. 3) ChREBP promotes hepatocyte proliferation in vitro but protects against oncogenic hepatocyte transformation in hepatocyte-specific GSD Ia mice. 4) Hepatocyte-specific glucose-6-phosphatase deficiency causes genomic instability and replication stress and shifts the balance between hepatocyte hyperplasia and hypertrophy during liver regeneration. 5) ChREBP protein expression tends to be positively correlated to human hepatocyte carcinoma (HCC) progression, while the glucose transporters GLUT1 and GLUT2 are positively and negatively, respectively, associated with hepatic malignancy.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • Kuipers, Folkert, Supervisor
    • Gu, Jiang, Supervisor, External person
    • Oosterveer, Maaike, Co-supervisor
    Award date10-Jun-2020
    Place of Publication[Groningen]
    Publisher
    Print ISBNs978-94-6375-923-6
    Electronic ISBNs978-94-034-2776-8
    DOIs
    Publication statusPublished - 2020

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