Hepatocyte MMP14 mediates liver and inter-organ inflammatory responses to diet-induced liver injury
The matrix metalloproteinase MMP14 is a ubiquitously expressed, membrane-bound, secreted endopeptidase that proteolyzes substrates to regulate development, signaling, and metabolism. However, the spatial and contextual events inciting MMP14 activation and its metabolic sequelae are not fully understood. Here, we introduce an inducible, hepatocyte-specific MMP14-deficient model (MMP14<sup>LKO</sup> mice) to elucidate cell-intrinsic and systemic MMP14 function. We show that hepatocyte MMP14 mediates diet-induced body weight gain, peripheral adiposity, and impaired glucose homeostasis and drives diet-induced liver triglyceride accumulation and induction of hepatic inflammatory and fibrotic gene expression. Single-nucleus RNA sequencing revealed that hepatocyte MMP14 mediates Kupffer cell and T-cell accumulation and promotes diet-induced hepatocellular subpopulation shifts toward protection against lipid absorption. MMP14 co-immunoprecipitation and proteomic analyses revealed MMP14 substrate binding across both inflammatory and cytokine signaling, as well as metabolic pathways. Strikingly, hepatocyte MMP14 loss-of-function suppressed skeletal muscle and adipose inflammation in vivo, and in a reductionist adipose-hepatocyte co-culture model. Finally, we reveal that trehalose-type glucose transporter inhibitors decrease hepatocyte MMP14 gene expression and nominate these inhibitors as translatable therapeutic metabolic agents. We conclude that hepatocyte MMP14 drives liver and inter-organ inflammatory and metabolic sequelae of obesogenic dietary insult. Modulating MMP14 activation and blockade thus represents a targetable node in the pathogenesis of hepatic inflammation.
Authors
- Joshua A. Adams (ORCID: https://orcid.org/0009-0006-4589-859X)
- Samuel Ballentine (ORCID: https://orcid.org/0000-0002-6339-548X)
- Xiaoxia Cui (ORCID: https://orcid.org/0000-0002-3073-7332)
- Yiming Zhang (ORCID: https://orcid.org/0000-0002-6020-0237)
- Jiameng Sun (ORCID: https://orcid.org/0000-0002-1176-8010)
- Cassandra B. Higgins (ORCID: https://orcid.org/0000-0003-4751-9611)
- Ilona Wandzik (ORCID: https://orcid.org/0000-0002-6592-4875)
- Brian J. DeBosch (ORCID: https://orcid.org/0000-0002-9924-7921)
- Jun Yoshino (ORCID: https://orcid.org/0000-0001-9833-4356)
- Małgorzata Milewska (ORCID: https://orcid.org/0000-0002-8395-7582)
- Shannon C. Kelly (ORCID: https://orcid.org/0000-0002-9942-9602)
- Benjamin M. Swarts (ORCID: https://orcid.org/0000-0001-8402-359X)
- Shun‐ichi Wada (ORCID: https://orcid.org/0000-0002-6625-7488)
- Yong Miao
Institutions
- James S. McDonnell Foundation (US)
- Silesian University of Technology (PL)
- Central Michigan University (US)
- Keio University (JP)
- Washington University in St. Louis (US)
- Microbial Chemistry Research Foundation (JP)
- McGill Genome Centre (CA)
Publication Details
- Journal
- PNAS Nexus
- Published
- 2024-08-30
- DOI
- https://doi.org/10.1093/pnasnexus/pgae357
- Citations
- 5
- Primary Topic
- Dietary Effects on Health
- Type
- article
- Field-Weighted Citation Impact
- 1.63
Funders
- Doris Duke Charitable Foundation
- Robert Wood Johnson Foundation
- Longer Life Foundation
- American Association for the Study of Liver Diseases
- Gilead Sciences
- Washington University in St. Louis
- Institute of Clinical and Translational Sciences
- Alvin J. Siteman Cancer Center
- Norges Idrettshøgskole
- National Institutes of Health
- Allergan
- Diabetes Research Center, University of Washington
- National Heart, Lung, and Blood Institute
- National Cancer Institute
- National Institute of General Medical Sciences
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Center for Advancing Translational Sciences
- National Center for Complementary and Integrative Health