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

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(Delta Hep)), macrophage-specific Xbp1 knockout (Xbp1(Delta Mf)), 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-beta 1. 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. (c) 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.

Automated summary

The transcription factor XBP1 plays a critical role in the development of NASH, with its upregulation in liver tissues of NASH patients. Conditional knockout of Xbp1 in hepatocytes reduces lipid accumulation, while genetic deletion of Xbp1 in macrophages ameliorates steatohepatitis and fibrosis. Pharmacological inhibition of XBP1 shows promising therapeutic potential for NASH.