Date on Master's Thesis/Doctoral Dissertation


Document Type

Doctoral Dissertation

Degree Name

Ph. D.


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


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.