Interferon regulatory factor 1 contributes to metabolic dysfunction associated steatotic liver disease

Abstract

Aims

Non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction associated steatotic liver disease (MASLD), has reached epidemic levels in multiple regions worldwide and contributes to cirrhosis and hepatocellular carcinoma. We have previously reported that the CC motif chemokine ligand 11 (CCL11) is a key regulator of MASLD. Expression of interferon regulatory factor 1 (IRF1) can be up-regulated by CCL11 treatment in hepatocytes, the relevance of which is not clear. In the present study we investigated the role of IRF1 in NAFLD pathogenesis.

Methods and materials

MASLD was investigated in mice fed a high-fat high carbohydrate (HFHC) diet or in the genetically predisposed obese mice (db/db).

Key findings

Hepatocytes from CCL11 knockout mice displayed a less severe MASLD phenotype, when treated with palmitic acid (PA), compared to wild type hepatocytes, which could be normalized by IRF1 over-expression. On the contrary, IRF1 knockdown in hepatocytes significantly down-regulated expression of pro-inflammatory mediators and dampened lipid accumulation induced by PA treatment. More importantly, IRF1 knockdown in hepatocytes led to amelioration of MASLD in mice. RNA-seq and CUT&Tag-seq identified pro-MASLD genes, including Osbpl3, Ddit4, and Ccl2, as potential targets for IRF1 in hepatocytes.

Significance

Our data reveal a novel regulatory role of IRF1 in MASLD pathogenesis. Targeting IRF1 can be considered as a reasonable approach for MASLD intervention.