Title

The role of O-GlcNAc transferase in liver fibrosis

Date of Award

Spring 2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cellular and Molecular Physiology

First Advisor

Yang, Xiaoyong

Abstract

The liver is a key metabolic tissue that is constantly challenged with various insults. Liver fibrosis is the common pathway for chronic liver injury, yet the treatment for liver fibrosis remains experimental. O-linked β-D-N-acetylglucosamine modification (O-GlcNAcylation) is a nutrient- and stress-sensing post-translational modification that regulates a variety of cellular events. Here I report that O-GlcNAc transferase (OGT) protects hepatocytes against necroptosis and initiation of liver fibrosis. Liver-specific OGT knockout (OGT-LKO) mice show fast-developed liver fibrosis and inflammation. The deletion of OGT induces global transcriptome changes in hepatocytes. OGT-deficient hepatocytes undergo excessive necroptosis and show elevated expression of key genes in the necroptotic pathway. Primary hepatic stellate cells are activated in OGT-LKO mice, which is mediated at least in part by the trefoil factor 2 (TFF2) released from OGT-deficient hepatocytes. Decreased O-GlcNAc levels are observed in humans and mice with chronic liver injury. Collectively, these findings reveal that OGT is critical for governing the survival and death of hepatocytes, thereby preventing the initiation of liver fibrosis. This report also identifies a critical role of TFF2 in mediating intercellular signaling between hepatocytes and hepatic stellate cells.

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