Abstract
Nonalcoholic steatohepatitis (NASH) is emerging as a leading cause of chronic liver disease. However, therapeutic options are limited by incomplete understanding of the mechanisms of NASH fibrosis, which is mediated by activation of hepatic stellate cells (HSCs). In humans, human genetic studies have shown that hypomorphic variations in MERTK, encoding the macrophage c-mer tyrosine kinase (MerTK) receptor, provide protection against liver fibrosis, but the mechanisms remain unknown. We now show that holo- or myeloid-specific Mertk targeting in NASH mice decreases liver fibrosis, congruent with the human genetic data. Furthermore, ADAM metallopeptidase domain 17 (ADAM17)-mediated MerTK cleavage in liver macrophages decreases during steatosis to NASH transition, and mice with a cleavage-resistant MerTK mutant have increased NASH fibrosis. Macrophage MerTK promotes an ERK-TGFβ1 pathway that activates HSCs and induces liver fibrosis. These data provide insights into the role of liver macrophages in NASH fibrosis and provide a plausible mechanism underlying MERTK as a genetic risk factor for NASH fibrosis.
[Display omitted]
•MerTK signaling in liver macrophages promotes liver fibrosis in NASH•Macrophage MerTK activates hepatic stellate cells in NASH by inducing TGF-β1•ATRA-induced MerTK cleavage blocks the TGF-b1-fibrosis pathway in steatosis•ATRA-induced MerTK cleavage becomes defective in NASH
Genome-wide association studies have indicated that MerTK is a risk factor for liver fibrosis in NASH with an unknown mechanism. Cai et al. discovered that MerTK signaling in liver macrophages, which is enhanced in NASH owing to suppression of its cleavage by ADAM17, promotes TGF-β1 production, HSC activation, and liver fibrosis in NASH.