ORCID
https://orcid.org/0000-0001-9728-7914
Date of Award
Summer 8-15-2018
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Cardiovascular, neurodegenerative, and metabolic diseases are prevalent, highly morbid medical problems. Remarkably, increasing evidence implicates fasting as a promising treatment for these and other disorders. However, clinical implementation of fasting is unsustainable for most, and is in some cases, dangerous. To exploit the promising therapeutic effects of fasting, it is imperative to more fully understand the molecular mechanisms of fasting, pinpoint the most crucial fasting responses that are sufficient to mitigate disease, and identify pharmacological tools to leverage these pathways.
As a central regulator of the multiple metabolic switches that take place during fasting, the liver is a promising site of manipulation to achieve fasting-like effects. The most crucial and tightly regulated readout of an organismճ nutrient status is blood glucose concentration, which is sensed and maintained by the liver via bidirectional transport of sugar through the GLUT family of carbohydrate transporters. Here, we interrogate the role of GLUT8, an abundant and undercharacterized hepatic GLUT isoform, in the mediating the hepatic fasting response. To that end, we used both genetic and pharmacological approaches in mice and cultured hepatocyte models. We demonstrate a novel role for GLUT8 in maintenance of mitochondrial homeostasis and regulation of the fasting transcription factor PPAR alpha. Furthermore, we identify GLUT8 as a transporter of the therapeutic disaccharide, trehalose, and demonstrate its necessity for trehalose-mediated activation of the AMPK/mTORC-ULK1-autophagy hepatic fasting response. Finally, we propose hepatic fasting as a novel means for achieving therapeutic benefits of organismal fasting, using pressure overload heart failure as a representative fasting-responsive disease. Genetic activation of the hepatic fasting master regulator Sirt1 and treatment with the pharmacological hepatic fasting mimetic, trehalose, demonstrate that hepatic fasting activation is sufficient to protect against pressure overload left ventricular hypertrophy and systolic dysfunction in a mouse model of transverse aortic constriction-mediated pressure overload. Notably, the effects of trehalose require signaling through hepatic Transcription Factor EB (TFEB), highlighting an important pathway for future lines of investigation.
Together, these studies delineate the role of GLUT8 and its manipulation via trehalose to modulate hepatic fasting response pathways. Moreover, we identify hepatic glucose pseudo-fasting as a novel target pathway for the treatment of fasting-responsive diseases.
Language
English (en)
Chair and Committee
Brian Kelle J. DeBosch Moley
Committee Members
Dan Ory, Paul Hruz, Brian Finck,
Recommended Citation
Mayer, Allyson Leigh, "Glucose Transporters in Hepatic Fasting Metabolism: Implications for Cardiometabolic Disease" (2018). Arts & Sciences Electronic Theses and Dissertations. 1640.
https://openscholarship.wustl.edu/art_sci_etds/1640
Comments
Permanent URL: 2019-01-20