MASH is a progressive form of MASLD, characterized by chronic inflammation and fibrosis. Recent literature suggests S100A11, a stress-inducible damage associated molecular pattern (DAMP), is associated with MASH in mice and humans. However, the mechanism by which hepatic S100A11 mediates hepatic inflammation and fibrosis in MASH remains unknown. In lines with our in vitro and in vivo studies, we identified enhanced hepatocellular expression and extracellular vesicle abundance of S100A11 in lipotoxic hepatocytes. Therefore, we hypothesized lipotoxicity dependent upregulation of S100A11 to mediate hepatic inflammation and fibrosis in MASH.

To understand the association of S100A11 with pathophysiologies of MASH, we employed a whole-body knockout (KO) of S100A11 and maintained them on a diet high in fructose, fat, and cholesterol (FFC) for 24 weeks which recapitulates steatohepatitis with cardiometabolic risk factors. Liver injury, inflammation and fibrosis were measured by serum studies, histology, and gene expression analysis. S100A11 KO mice had reduced alanine transferase (ALT) compared to wildtype FFC counterpart, indicative of reduced liver injury. Blinded scoring of H&E-stained liver tissues inferred, S100A11 KO mice to have microvesicular steatosis and reduced inflammatory foci, in contrast to the macrovesicular steatosis and densely populated inflammatory foci noted in FFC controls. Assessment of Picro-Sirius Red stained liver sections, via polarized light presented S100A11 KO mice to have significantly reduced fibrosis, relative to the FFC mice. qPCR assessment of S100A11 KO liver indicated significantly reduced expression of lipogenic, inflammatory and fibrogenic markers compared to the FFC-controls. In vitro verification of de novo lipogenesis using primary hepatocytes isolated from S100A11 KO mice also demonstrated reduced de novo lipogenesis, compared to wildtype hepatocytes.

Since, whole body knockout of S100A11 ameliorated FFC diet induced MASH pathogenesis in mice, we were curious to ascertain the importance of hepatic S100A11. Hepatocyte-specific KD of S100A11 resulted in amelioration of FFC-diet induced liver injury, inflammation and fibrosis as demonstrated by lower ALT and collagen deposition quantified by Picro-Sirius red staining. RNA sequencing of S100A11 silenced liver tissues inferred upregulation of pathways regulating microvesicular steatosis and dysregulated glucose and lipid metabolism. RNA seq and qPCR assessment of liver tissues confirmed significant reduction in inflammatory and fibrogenic markers, in S100A11 KD mice livers compared to wildtype FFC controls. In conclusion, our studies suggest that S100A11 mediates liver injury and inflammation in MASH. Therefore, S100A11 may represent a new potential therapeutic target for the treatment of MASH and related liver diseases.

P. Vineeth Daniel

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