Mechanisms of liver injury in high fat sugar diet fed mice that lack hepatocyte X-box binding protein 1

Xiaoying Liu*, Sarah A. Taylor, Kyle D. Gromer, Danny Zhang, Susan C. Hubchak, Brian E. LeCuyer, Takao Iwawaki, Zengdun Shi, Don C. Rockey, Richard M. Green

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of liver diseases in the United States and can progress to cirrhosis, end-stage liver disease and need for liver transplantation. There are limited therapies for NAFLD, in part, due to incomplete understanding of the disease pathogenesis, which involves different cell populations in the liver. Endoplasmic reticulum stress and its adaptative unfolded protein response (UPR) signaling pathway have been implicated in the progression from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH). We have previously shown that mice lacking the UPR protein X-box binding protein 1 (XBP1) in the liver demonstrated enhanced liver injury and fibrosis in a high fat sugar (HFS) dietary model of NAFLD. In this study, to better understand the role of liver XBP1 in the pathobiology of NAFLD, we fed hepatocyte XBP1 deficient mice a HFS diet or chow and investigated UPR and other cell signaling pathways in hepatocytes, hepatic stellate cells and immune cells. We demonstrate that loss of XBP1 in hepatocytes increased inflammatory pathway expression and altered expression of the UPR signaling in hepatocytes and was associated with enhanced hepatic stellate cell activation after HFS feeding. We believe that a better understanding of liver cell-specific signaling in the pathogenesis of NASH may allow us to identify new therapeutic targets.

Original languageEnglish (US)
Article numbere0261789
JournalPloS one
Volume17
Issue number1 January
DOIs
StatePublished - Jan 2022

Funding

2R01DK093807(RMG), R01DK121997 (RMG), The Max Goldenberg Foundation (RMG), North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (SAT), 1K08DK121937 (SAT), R01DK113159 (DCR), P30DK123704 (DCR) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

ASJC Scopus subject areas

  • General

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