Nonalcoholic fatty liver disease (NAFLD) is a global metabolic disease that comprises a broad spectrum of liver dysfunction ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) with fibrosis. It is largely unknown how the communication between hepatocytes and non-parenchymal cells dictates the disease progression from NAFL to NASH and fibrosis. Dysregulation of protein O-GlcNAcylation in hepatocytes has been implicated in a wide range of liver diseases. In this study, we demonstrate the role of O‑GlcNAc transferase (OGT) in mediating intercellular crosstalk between hepatocytes and immune cells in NASH-fibrosis development. RNA-sequencing analysis of wildtype and hepatocyte-specific OGT knockout mice was performed and trefoil factor 2 (TFF2) was identified as one of the highly induced genes encoding secreted proteins in OGT-deficient hepatocytes. Immunohistochemistry and western blot were performed to reveal decreased OGT and increased TFF2 expression in the liver of NAFLD patients. Mechanically, OGT was found to repress TFF2 transcription in hepatocytes by modifying forkhead box protein A2 (FOXA2). Recombinant TFF2 along with NASH stimuli was applied to a 3D spheroid culture system comprised of hepatocytes and non-parenchymal cells and TFF2 was shown to promote NASH stimuli-induced triglyceride secretion and elevate the expression of pro-inflammatory and fibrogenic genes. ELISA and RT-qPCR were performed to further show that TFF2 treatment induced the expression of Th1-type cytokines (IFN-γ and TNF-α) and Th17-type cytokine (IL17) in CD4 T cells, promoting Th1 and Th17 differentiation. Collectively, these results identify an OGT-TFF2 axis that mediates the crosstalk between hepatocytes and CD4 T cells during NASH pathogenesis, revealing a potential therapeutic target for the treatment of chronic liver disease.


L. Zhang: None. Q. Wang: None. R. Desrouleaux: None. X. Yang: None.


American Diabetes Association (1-19-IBS-119 to X.Y.); National Institutes of Health (R01DK089098, P30DK34989)

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