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 Co-Chair (if applicable)

McClain, Craig J.

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.

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