CC Motif Chemokine Ligand 7 Promotes HSC ‐Myofibroblast Transition and Liver Fibrosis by Enabling SREBP2 ‐Dependent Cholesterologenesis

Liver fibrosis is both a pathological feature and an instigator/promoter of chronic liver disease. Hepatic stellate cells (HSCs), by trans-differentiating into myofibroblasts, are the principal mediator of liver fibrosis. In the present study we investigated the involvement of macrophage-derived C-C motif chemokine ligand 7 (CCL7) in this process. We report that mice harboring macrophage conditional knockout (CKO) of BRG1, a chromatin remodeling protein, displayed diminished liver fibrosis compared to wild type littermates. Co-culture with macrophages from WT, but not CKO, mice enhanced HSC-myofibroblast transition. RNA-seq identified CCL7 as a target for BRG1. Depletion of CCL7 disrupted the crosstalk between macrophages and HSCs. On the contrary, recombinant CCL7 stimulated HSC-myofibroblast transition. Importantly, CCL7 blockade with a neutralizing antibody attenuated liver fibrosis in mice. Transcriptomic analysis indicated that CCL7 activated sterol response element binding protein 2 (SREBP2) to modulate intracellular cholesterol levels during HSC-myofibroblast transition. Consistently, cholesterol depletion with methyl-beta-cyclodextrin (MβCD) blocked HSC-myofibroblast transition and mitigated liver fibrosis. Finally, a positive correlation between CCL7 levels in peripheral blood monocytic cells (PBMCs) and myofibroblast markers in liver tissues was identified in patients with cirrhosis. In conclusion, our data uncover an uncanonical role for CCL7 in liver fibrosis by directly promoting HSC-myofibroblast transition.