Role of XBP1 in regulating the progression of non-alcoholic steatohepatitis

Qi Wang; Haoming Zhou; Qingfa Bu; Song Wei; Lei Li; Jinren Zhou; Shun Zhou; Wantong Su; Mu Liu; Zheng Liu; Mingming Wang; Ling Lu

doi:10.1016/j.jhep.2022.02.031

Role of XBP1 in regulating the progression of non-alcoholic steatohepatitis

J Hepatol. 2022 Aug;77(2):312-325. doi: 10.1016/j.jhep.2022.02.031. Epub 2022 Mar 12.

Authors

Qi Wang¹, Haoming Zhou², Qingfa Bu², Song Wei¹, Lei Li², Jinren Zhou², Shun Zhou², Wantong Su², Mu Liu², Zheng Liu², Mingming Wang², Ling Lu³

Affiliations

¹ Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China; School of Medicine, Southeast University, Nanjing, China.
² Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.
³ Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China; School of Medicine, Southeast University, Nanjing, China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. Electronic address: lvling@njmu.edu.cn.

PMID: 35292349
DOI: 10.1016/j.jhep.2022.02.031

Abstract

Background & aims: Non-alcoholic steatohepatitis (NASH) is associated with the dysregulation of lipid metabolism and hepatic inflammation, though the underlying mechanisms remain unclear. We aimed to investigate the role of X-box binding protein-1 (XBP1) in the progression of NASH.

Methods: Human liver tissues obtained from patients with NASH and controls were used to assess XBP1 expression. NASH models were developed in hepatocyte-specific Xbp1 knockout (Xbp1^ΔHep), macrophage-specific Xbp1 knockout (Xbp1^ΔMf), macrophage-specific Nlrp3 knockout, and wild-type (Xbp1^FL/FL or Nlrp3^FL/FL) mice fed with a high-fat diet for 26 weeks or a methionine/choline-deficient diet for 6 weeks.

Results: The expression of XBP1 was significantly upregulated in liver samples from patients with NASH. Hepatocyte-specific Xbp1 deficiency inhibited the development of steatohepatitis in mice fed the high-fat or methionine/choline-deficient diets. Meanwhile, macrophage-specific Xbp1 knockout mice developed less severe steatohepatitis and fibrosis than wild-type Xbp1^FL/FL mice in response to the high-fat or methionine/choline-deficient diets. Macrophage-specific Xbp1 knockout mice showed M2 anti-inflammatory polarization. Xbp1-deleted macrophages reduced steatohepatitis by decreasing the expression of NLRP3 and secretion of pro-inflammatory cytokines, which mediate M2 macrophage polarization in macrophage-specific Xbp1 knockout mice. Steatohepatitis was less severe in macrophage-specific Nlrp3 knockout mice than in wild-type Nlrp3^FL/FL mice. Xbp1-deleted macrophages prevented hepatic stellate cell activation by decreasing expression of TGF-β1. Less fibrotic changes were observed in macrophage-specific Xbp1 knockout mice than in wild-type Xbp1^FL/FL mice. Inhibition of XBP1 suppressed the development of NASH.

Conclusion: XBP1 regulates the development of NASH. XBP1 inhibitors protect against steatohepatitis. Thus, XBP1 is a potential target for the treatment of NASH.

Lay summary: XBP1 is a transcription factor that is upregulated in liver tissues of patients with non-alcoholic steatohepatitis (NASH). Conditional knockout of Xbp1 in hepatocytes resulted in decreased lipid accumulation in mice, while genetic deletion of Xbp1 in macrophages ameliorated nutritional steatohepatitis and fibrosis in mice. Pharmacological inhibition of XBP1 protects against steatohepatitis and fibrosis, highlighting a promising therapeutic strategy for NASH.

Keywords: XBP1; hepatic stellate cells; hepatocytes; macrophages; non-alcoholic steatohepatitis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Choline
Diet, High-Fat / adverse effects
Disease Models, Animal
Humans
Liver / pathology
Liver Cirrhosis / pathology
Methionine
Mice
Mice, Inbred C57BL
Mice, Knockout
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Non-alcoholic Fatty Liver Disease* / genetics
Non-alcoholic Fatty Liver Disease* / metabolism
X-Box Binding Protein 1* / genetics
X-Box Binding Protein 1* / metabolism

Substances

NLR Family, Pyrin Domain-Containing 3 Protein
X-Box Binding Protein 1
XBP1 protein, human
Xbp1 protein, mouse
Methionine
Choline