Tim-1 Deletion Exacerbates Hepatic Inflammation and Injury in Nonalcoholic Fatty Liver Disease

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) has been shown to affect innate immunity-driven proinflammatory cascade in liver ischemia-reperfusion injury. This study was designed to evaluate the role of Tim-1 in liver inflammation and damage in NAFLD/NASH. Male wildtype (WT) and Tim-1 knockout (Tim-1 -/- ) mice at the age of 6-8 weeks were fed with standard chow or high fat diet (HFD, containing 42% fat) for 5-6 months. Dual immunofluorescence staining was performed to evaluate the expression level and pattern of matrix metalloproteinase 9 (MMP-9) and lipocalin-2, a reliable indicator of liver inflammation and damage. The expression level of CHOP (GADD153/DDIT3), a major regulator of endoplasmic reticulum (ER) stress-mediated apoptosis, was further examined by Western blotting. While Tim-1 deletion had no effects on body weight gain and blood glucose in mice fed with chow or HFD diet, there was a greater increase in liver weight and liver index (liver weight to body weight ratio) in HFD-fed Tim-1 -/- mice compared with HFD WT animals. Accordingly, HFD-induced hepatocyte ballooning and lipid accumulation were more prominent in Tim-1 -/- livers. Moreover, immunostaining analysis revealed an enhancement of MMP-9 signal in lipocalin-2-positve neutrophils and macrophages in HFD Tim-1 -/- mouse livers. Compared to normal controls, HFD feeding substantially increased hepatic CHOP by 3-fold in WT and 6.7-fold in Tim-1 -/- mice ( P < 0.05 vs. HFD-WT). Together, these results show that Tim-1 deficiency aggravates HFD-induced liver inflammation and damage, suggesting a regulatory role for Tim-1 in HFD-induced steatohepatitis. Tim-1 might be considered as a target for the prevention and treatment of NAFLD/NASH. This research was supported by the NIH, the NCRR, and the Research Centers in Minority Institutions Program under grants R16GM149499, 8G12MD007602, and U54MD007602. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.