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Silencing of S100A11 Attenuates Murine Metabolic Dysfunction-associated Steatohepatitis

ABSTRACT: S100A11 is an alarmin known to be upregulated in MASH; however, its role in MASH pathophysiology remains incompletely defined. In MASH, insulin resistance and subsequent impaired hepatic carbohydrate and lipid metabolism significantly increase de novo lipogenesis causing hepatic steatosis and lipotoxicity. S100A11 promotes steatosis in cell lines. Therefore, we hypothesized that S100A11 drives MASH by upregulating lipid synthesis in the liver. We employed whole body S100A11 knockout (S100a11-/-) mice and liver specific knockdown mice and a MASH inducing diet to address this hypothesis. S100a11-/- mice demonstrated reduced steatosis, inflammation and fibrosis compared to wild type controls. Hepatotropic AAV8 mediated S100A11 silencing in mouse livers significantly attenuated steatosis, inflammation, and fibrosis. Significant dysregulation of carbohydrate and lipid metabolism was identified by Ingenuity Pathway Analysis of bulk-RNA sequencing of S100a11 silenced mouse livers. Candidate gene approach in these pathways identified hexokinase 2 (HK2) as significantly downregulated in the S100a11 knockdown mouse livers. Since hexokinases regulate the crucial stage of glucose flux into downstream metabolic processes, including de novo lipogenesis, we expressed exogenous HK2 in S100a11-/- mice. Overexpression of Hk2 was sufficient to upregulate steatosis under chow fed basal nutrition conditions in S100a11-/- mouse livers. These studies identify S100A11 and HK2 as potential therapeutic targets for MASH.

ORGANISM(S): Mus musculus

PROVIDER: GSE304356 | GEO | 2025/10/22

REPOSITORIES: GEO

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Raw data for : "Genetic and pharmacological targeting of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis"

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