Macrophage TREM2 is a triglyceride-rich lipoprotein receptor that undergoes shedding in prediabetic hepatic steatosis [P524-2]

To investigate if hematopoietic TREM2 regulates apolipoprotein C3 (APOC3) and APOB plasma levels in a mouse model of prediabetes and hepatic steatosis, we analyzed apolipoprotein levels and kinetics in three LDL receptor-deficient (Ldlr -/- ) bone marrow chimeras fed a diabetogenic diet with added cholesterol (36% fat, 36.2% sucrose, 0.15% added cholesterol) for 18 weeks; (i) Trem2 -/- hematopoietic chimeras (TREM2 H-/- mice), (ii) chimeras deficient in ADAM17 in myeloid cells (ADAM17 M-/- mice), and (iii) bone marrow WT chimeras (Lyz2 Cre/Cre ).

Because ADAM17 is the principal TREM2 sheddase, ADAM17 M-/- mice have higher levels of myeloid full-length (non-shed) TREM2. Accordingly, plasma sTREM2 levels were lower in ADAM17 M-/- mice and were much lower in TREM2 H-/- mice. Plasma APOC3 and APOB100 levels and APOC3 and APOB100 secretion rates were higher in TREM2 hematopoietic chimeras than in ADAM17 M-/- mice.