Smarca4 ablation in myeloid cells attenuates non-alcoholic fatty liver disease in mice

Abstract

Aims

Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation and chronic inflammation. Intercellular crosstalk between hepatocytes and macrophages contributes to NAFLD pathogenesis. We investigated how ablation of Brg1 (encoded by Smarca4), a component of the chromatin remodeling complex, in macrophages might influence NAFLD pathogenesis in mice.

Methods and materials

Brg1^f/f mice were crossed to LyzM-Cre mice to achieve myeloid cell specific Brg1 deletion. NAFLD was induced by feeding the mice with a high-fat high-carbohydrate (HFHC) diet.

Key findings

Brg1 expression was up-regulated in macrophages from the mice fed the HFHC diet compared to the control diet and in peripheral blood monocytic cells from the NAFLD patients compared to the healthy individuals. Co-culture with macrophages promoted lipid accumulation in hepatocytes whereas deletion or pharmaceutical inhibition of Brg1 in macrophages disrupted macrophage-hepatocyte crosstalk. Consistently, Brg1 ablation in myeloid cells attenuated NAFLD pathogenesis in mice. Importantly, administration of a small-molecule Brg1 inhibitor PFI-3 ameliorated NAFLD in mice. RNA-seq identified CC motif chemokine ligand 7 (CCL7) as a downstream target for Brg1 in macrophages.

Significance

Our data suggest that Brg1 might contribute to NAFLD by mediating the macrophage-hepatocyte crosstalk to pivot hepatocytes to a pro-NAFLD phenotype.