Macrophage TREM2 is a triglyceride-rich lipoprotein receptor that undergoes shedding in prediabetic hepatic steatosis
9 affiliations
- 1Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington Medicine Diabetes Institute, University of Washington, Seattle, Washington, USA.
- 2Department of Biochemistry and Molecular Biology, and
- 3Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, USA.
- 4Ionis Pharmaceuticals, Carlsbad, California, USA.
- 5Research and Development and Division of Gastroenterology, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.
- 6Division of Gastroenterology, University of Washington, Seattle, Washington, USA.
- 7Department of Medicine, Division of Nutritional Science & Obesity Medicine, and
- 8Division of Gastroenterology, Washington University School of Medicine, Saint Louis, Missouri, USA.
- 9Department of Laboratory Medicine and Pathology, University of Washington Medicine Diabetes Institute, University of Washington, Seattle, Washington, USA.
Abstract
Prediabetes is associated with increased production of triglyceride-rich lipoproteins (TRLs), cardiovascular disease (CVD), and hepatic steatosis, which is linked to increased plasma levels of soluble TREM2 (sTREM2), the shed domain of TREM2 (triggering receptor expressed on myeloid cells 2). Whether and how TREM2 shedding contributes to elevated TRLs is unknown. By complementary analyses of individuals with prediabetes and hepatic steatosis and preclinical models, we show that plasma sTREM2 levels correlate positively with plasma apolipoprotein C3 (APOC3), an apolipoprotein that slows TRL catabolism and predicts CVD risk. Individuals with prediabetes and hepatic steatosis had higher plasma concentrations of APOC3-rich TRLs 35 to 60 nm in diameter than healthy controls. Mouse models of prediabetes with hepatic steatosis revealed that the increased plasma concentrations of sTREM2, APOC3, and TRLs were due to activation of macrophage ADAM17, a TREM2 sheddase. Preserving macrophage full-length TREM2 protected against the elevated plasma APOC3, sTREM2, dyslipidemia, and atherosclerosis, whereas TREM2 deficiency increased APOC3, TRLs, and atherosclerosis. Mechanistically, full-length TREM2 mediates macrophage TRL uptake, preventing excessive hepatic APOC3-rich TRL release and atherosclerosis. Our findings identify macrophage TREM2 shedding as an upstream contributor to the elevated TRLs in hepatic steatosis, providing a mechanistic link between hepatic steatosis and CVD risk in prediabetes.
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BibTeX
@article{tang2026macrophage,
title = {{Macrophage TREM2 is a triglyceride-rich lipoprotein receptor that undergoes shedding in prediabetic hepatic steatosis}},
author = {Jingjing Tang and Jenny E. Kanter and Baohai Shao and Masami Shimizu-Albergine and Farah Kramer and Ah Reum Khang and Jason Luo and Huaqing Zheng and Alan Tran and Jocelyn Cervantes and Jeremy M. Frey and Mauricio D. Dorfman and Cheng-Chieh Hsu and Laura J. den Hartigh and Tomas Vaisar and Brandon S.J. Davies and Adam E. Mullick and George N. Ioannou and Gordon I. Smith and Samuel Klein and Nicholas O. Davidson and Karin E. Bornfeldt},
journal = {JCI Insight},
year = {2026},
month = aug,
doi = {10.1172/jci.insight.202675},
url = {https://doi.org/10.1172/jci.insight.202675},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Macrophage TREM2 is a triglyceride-rich lipoprotein receptor that undergoes shedding in prediabetic hepatic steatosis
AU - Jingjing Tang
AU - Jenny E. Kanter
AU - Baohai Shao
AU - Masami Shimizu-Albergine
AU - Farah Kramer
AU - Ah Reum Khang
AU - Jason Luo
AU - Huaqing Zheng
AU - Alan Tran
AU - Jocelyn Cervantes
AU - Jeremy M. Frey
AU - Mauricio D. Dorfman
AU - Cheng-Chieh Hsu
AU - Laura J. den Hartigh
AU - Tomas Vaisar
AU - Brandon S.J. Davies
AU - Adam E. Mullick
AU - George N. Ioannou
AU - Gordon I. Smith
AU - Samuel Klein
AU - Nicholas O. Davidson
AU - Karin E. Bornfeldt
PY - 2026
DA - 2026/08/27
JO - JCI Insight
DO - 10.1172/jci.insight.202675
UR - https://doi.org/10.1172/jci.insight.202675
AB - Prediabetes is associated with increased production of triglyceride-rich lipoproteins (TRLs), cardiovascular disease (CVD), and hepatic steatosis, which is linked to increased plasma levels of soluble TREM2 (sTREM2), the shed domain of TREM2 (triggering receptor expressed on myeloid cells 2). Whether and how TREM2 shedding contributes to elevated TRLs is unknown. By complementary analyses of individuals with prediabetes and hepatic steatosis and preclinical models, we show that plasma sTREM2 levels correlate positively with plasma apolipoprotein C3 (APOC3), an apolipoprotein that slows TRL catabolism and predicts CVD risk. Individuals with prediabetes and hepatic steatosis had higher plasma concentrations of APOC3-rich TRLs 35 to 60 nm in diameter than healthy controls. Mouse models of prediabetes with hepatic steatosis revealed that the increased plasma concentrations of sTREM2, APOC3, and TRLs were due to activation of macrophage ADAM17, a TREM2 sheddase. Preserving macrophage full-length TREM2 protected against the elevated plasma APOC3, sTREM2, dyslipidemia, and atherosclerosis, whereas TREM2 deficiency increased APOC3, TRLs, and atherosclerosis. Mechanistically, full-length TREM2 mediates macrophage TRL uptake, preventing excessive hepatic APOC3-rich TRL release and atherosclerosis. Our findings identify macrophage TREM2 shedding as an upstream contributor to the elevated TRLs in hepatic steatosis, providing a mechanistic link between hepatic steatosis and CVD risk in prediabetes.
SN - 2379-3708
ER -