Date on Master's Thesis/Doctoral Dissertation
8-2017
Document Type
Doctoral Dissertation
Degree Name
Ph. D.
Department
Pharmacology and Toxicology
Degree Program
Pharmacology and Toxicology, PhD
Committee Chair
Feng, Wenke
Committee Member
McClain, Craig J.
Committee Member
Cai, Zhao-Hui Son Lu
Committee Member
Song, Zhao-Hui
Committee Member
Fernandez-Botran, G. Rafel
Author's Keywords
alcoholic liver disease; gut-liver axis; intestinal HIF-1α; DSS-induced colitis; probiotics
Abstract
Hypoxia inducible factor 1 α (HIF1α) is an oxygen-responsive subunit. HIF-1α plays a pivotal role in many pathophysiological processes. In addition to oxygen availability, HIF-1α can be regulated by multiple other factors in response to various pathophysiological processes. Previous studies showed that hepatic HIF-1α could be beneficial or harmful in experimental alcoholic liver disease (ALD). However, the role of intestinal HIF-1α in ALD has not yet been studied. Given the critical role of the gut-liver axis in ALD, it is important to elucidate the role of intestinal epithelial HIF-1α in ALD. In the first chapter, we used wide type (WT) and intestinal epithelial-specific HIF-1α knockout (IEhif-1α-/-) mice to build chronic ALD model. Alcohol feeding significantly increased serum levels of ALT and LPS, hepatic triglyceride concentration, and liver injury in the IEhif-1α-/- mice compare with WT mice. Alcohol exposure resulted in greater reduction of the expression of intestinal epithelial tight junction proteins and antimicrobial substance in IEhif-1α-/- mice. Bacterial analysis of the fecal samples showed an increased dysbiosis with a significantly decreased firmicutes/bacteroidetes ratio in IEhif-1α-/- mice compared to the WT mice exposed to alcohol. In the second chapter, we used a more severe intestinal damage model- dextran sodium sulfate (DSS) induced colitis with binge ALD model in the same mice. DSS treatment alone did not affect liver function in both WT and IEhif-1α-/- mice. However, serum ALT, AST and LPS levels were significantly elevated in DSS + alcohol treatment groups, and these elevations were more pronounced in IEhif-1α-/- mice. DSS induced a marked increase in CRAMP expression in WT mice. However, this elevation was impaired in the IEhif-1α-/- mice. EtOH exposure eliminated the increased of CRAMP both in WT and IEhif-1α-/- mice. Therefore, we used global CAMP-/- mice to identify our hypothesis. As we expected, binge alcohol on colitis enhance liver injury in CAMP-/-mice compared with WT mice. In summary, our results demonstrate that intestinal HIF1α is required for the adaptation response to alcohol exposure-induced changes in intestinal microbiota and barrier function associated with elevated endotoxemia and hepatic steatosis and injury.
Recommended Citation
Shao, Tuo, "The role of HIF-1α in intestinal epithelial barrier function in alcoholic liver disease." (2017). Electronic Theses and Dissertations. Paper 2742.
https://doi.org/10.18297/etd/2742
