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.
Highlights
Non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver diseases in western countries [1]
We found that T cell immunoglobulin and mucin domain 1 (Tim-1) expression was significantly upregulated in the liver of high-fat diet (HFD)-fed WT mice
Tim-1 deficiency resulted in an exacerbation of HFDinduced hepatic steatosis and inflammation, as evidenced by increased hepatocyte ballooning and excessive lipid accumulation concomitant with augmented infiltration of inflammatory cells as well as pronounced hepatic expression of LCN2 in HFD Tim-1-/mice
Summary
Non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver diseases in western countries [1]. Improving our understanding of the functions of genes/mediators that contribute to the susceptibility to and severity of NAFLD/NASH is of great consequence to both the treatment and prevention of chronic liver disease. Given the functional role of hepatic macrophages as a master regulator of immune homeostasis and a pivotal coordinator of liver inflammation, it has been postulated that macrophage activation and polarization are involved in the progression of NAFLD to NASH. It remains largely unknown how M1 versus M2 macrophages contribute to liver inflammation and fibrosis progression in advanced NASH
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