Tim-1 Deficiency Aggravates High-Fat Diet-Induced Steatohepatitis in Mice.

Abstract

Non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) is commonly associated with obesity and characterized by excessive lipid accumulation and liver inflammation. The T cell immunoglobulin and mucin domain 1 (Tim-1), also known as hepatitis A virus cellular receptor 1 (Havcr-1) and kidney injury molecule 1 (Kim-1), has been shown to affect innate immunity-driven proinflammatory cascade in liver ischemia-reperfusion injury. However, its contribution to obesity-related NAFLD/NASH remains unknown. Thus, this study was designed to evaluate the role of Tim-1 in obesity-related liver inflammation and injury in wild-type (WT) and Tim-1-deficient (Tim-1-/-) C57BL/6J mice fed a high-fat diet (HFD) for 5-6 months. HFD feeding induced steatosis and upregulated Tim-1 gene expression in the liver of WT mice. Surprisingly, Tim-1-/- mice on HFD diet exhibited an exacerbation of hepatic steatosis, accompanied with an elevation of protein levels of fatty acid translocase CD36 and sterol regulatory element binding protein 1 (SREBP1). Tim-1 deficiency also enhanced HFD-induced liver inflammation and injury, as evidenced by augmented increase in hepatic expression of pro-inflammatory factor lipocalin 2 and elevated serum alanine transaminase (ALT). In addition, gene expression of type I, III and IV collagens and liver fibrosis were greatly enhanced in HFD Tim-1-/- mice compared with HFD WT mice. HFD-induced hepatic expression of YM-1, a specific mouse M2 macrophage marker, was further upregulated by deletion of Tim-1. Together, these results show that Tim-1 deficiency aggravates the effects of HFD diet on lipid accumulation and liver fibrosis, most likely through enhanced infiltration and activation of inflammatory cells.

• Authors: Jasmine George, Yuanyuan Zhang, Jacob Sloan, Joya M Sims, John D Imig, Xueying Zhao
• Journal: Frontiers in immunology (Front Immunol) Vol. 12 Pg. 747794 ( 2021) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 34675931 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2021 George, Zhang, Sloan, Sims, Imig and Zhao.

Chemical References

• Havcr1 protein, mouse
• Hepatitis A Virus Cellular Receptor 1

Topics

• Animals
• Diet, High-Fat (adverse effects)
• Hepatitis A Virus Cellular Receptor 1 (deficiency, immunology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Non-alcoholic Fatty Liver Disease (immunology, pathology)