Macrophage MerTK Promotes Liver Fibrosis in Nonalcoholic Steatohepatitis

Cell Metab. 2020 Feb 4;31(2):406-421.e7. doi: 10.1016/j.cmet.2019.11.013. Epub 2019 Dec 12.


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.

Keywords: ADAM17; MerTK; MerTK cleavage; NASH; TGFβ;; hepatic stellate cells; liver fibrosis; macrophage; nonalcoholic steatohepatitis; retinoic acid.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM17 Protein / metabolism
  • Animals
  • Cell Line
  • Chronic Disease
  • Humans
  • Liver / cytology
  • Liver / metabolism*
  • Liver Cirrhosis / metabolism*
  • Macrophages / cytology
  • Macrophages / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Rats
  • c-Mer Tyrosine Kinase / physiology*


  • MERTK protein, human
  • Mertk protein, mouse
  • c-Mer Tyrosine Kinase
  • ADAM17 Protein
  • ADAM17 protein, human