Macrophage TREM2 is a triglyceride-rich lipoprotein receptor that undergoes shedding in prediabetic hepatic steatosis

Prediabetes associates 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, while 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.