2. Academic Validation
  3. Macrophage MerTK Promotes Liver Fibrosis in Nonalcoholic Steatohepatitis

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.
Bishuang Cai 1,  Paola Dongiovanni 2,  Kathleen E Corey 3,  Xiaobo Wang 4,  Igor O Shmarakov 4,  Ze Zheng 4,  Canan Kasikara 4,  Viralkumar Davra 5,  Marica Meroni 2,  Raymond T Chung 3,  Carla V Rothlin 6,  Robert F Schwabe 7,  William S Blaner 4,  Raymond B Birge 5,  Luca Valenti 8,  Ira Tabas 9
Affiliations

Affiliations

  • 1 Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: [email protected].
  • 2 General Medicine and Metabolic Diseases, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano 20122, Italy.
  • 3 Liver Center, Gastrointestinal Division, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA, USA.
  • 4 Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 5 Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers University, New Jersey Medical School Cancer Center, Newark, NJ 07103, USA.
  • 6 Department of Immunobiology, Yale University School of Medicine and Department of Pharmacology, Yale University, New Haven, CT, USA.
  • 7 Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA; Institute of Human Nutrition, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 8 Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano 20122, Italy; Translational Medicine - Transfusion Medicine and Hematology, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano 20122, Italy.
  • 9 Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA; Departments of Pathology & Cell Biology and Physiology & Cellular Biophysics, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: [email protected].
PMID: 31839486 DOI: 10.1016/j.cmet.2019.11.013
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.

Keywords

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

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