Tim-1 Deletion Amplifies Body Weight Gain and Steatosis in Early Metabolic-Dysfunction Associated Fatty Liver Disease

Metabolic-dysfunction associated fatty liver disease (MAFLD)/metabolic-dysfunction associated steatohepatitis (MASH) 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 an early stage of MAFLD/MASH. Male wildtype (WT) mice and Tim-1 knockout (KO) mice within the ages of 8-12 weeks old were fed with low-fat diet (LFD, 9% fat) or high fat diet (HFD, 42% fat) for 10 weeks. Body weight, liver weight, and liver index (Iiver weight/body weight) were recorded and compared among four groups: LFD-WT (n=8), HFD-WT (n=7), LFD-KO (n=6) and HFD-KO (n=6). The expression levels of ADRP (Adipose Differentiation-Related Protein), a lipid coating and lipid storage protein, and LCN2 (lipocalin-2), a biomarker for liver injury were examined by Western blotting. Serum alanine aminotransferase (ALT) concentration was further determined to evaluate liver function. 42% HFD feeding for 10 weeks significantly increased body weight in WT mice (HFD-WT: 36.4 ± 1.7 g vs. LFD-WT: 30.4 ± 0.9 g, P< 0.01). While Tim-1 deletion did not alter body weight in LFD-KO mice (30.6 ± 0.5 g), HFD-induced body weight increase was greatly enhanced in HFD-KO mice (44.4 ± 1.2 g, P< 0.001 vs. HFD-WT). Moreover, Tim-1 deletion resulted in a substantial amplification of liver steatosis in HFD-fed mice. The livers of the HFD-KO mice were paler in color and heavier (liver weight: 3.24 ± 0.22 g and liver index: 7.49 ± 0.93, P< 0.0001) compared with HFD-WT livers (liver weight: 1.66 ± 0.15 g and liver index: 4.54 ± 0.65). HFD-induced lipid accumulation was confirmed by a robust upregulation of the hepatic lipid storage protein, ADRP, which was increased by 11- and 24-fold in HFD-treated WT and KO livers, compared to their normal controls. Moreover, HFD feeding greatly increased hepatic expression of pro-inflammatory factor LCN2 in HFD-treated KO livers compared to HFD-WT livers (P< 0.01). Serum ALT levels were massively increased in HFD-treated KO mice (77.47 ± 13.03 IU/L, P< 0.0001) compared to HFD-treated WT mice (5.042 ± 2.055 IU/L), indicating an exacerbation of liver dysfunction by Tim-1 deletion. Together, these results show that Tim-1 deficiency worsens HFD-induced body weight gain and liver steatosis and dysfunction, 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 MAFLD/MASH. This abstract was presented at the American Physiology Summit 2026 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.