Soluble TREM2 is a biomarker but not a mediator of fibrosing steatohepatitis.

Background: Triggering receptor expressed on myeloid cells 2 (TREM2), a transmembrane, lipid-sensing protein expressed by Kupffer cells, is thought to play a role in metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Plasma levels of the TREM2 cleavage product, soluble TREM2 (sTREM2), are strongly associated with MASLD severity. We investigated the role of TREM2 in MASH pathogenesis and whether sTREM2 acts both as biomarker and mediator of MASH. Methods: Adult C57BL/6J mice were assigned to normal, high-fat (HF), or high-fat and high-cholesterol (HFHC) diets for 15, 30, 90, and 180 days. Plasma sTrem2 levels, liver pathology, and hepatic RNA expression were assessed. To test whether sTrem2 is a mediator of MASH, C57BL/6J mice were injected retro-orbitally with a liver-targeted adeno-associated virus, TBG-AAV8-sTrem2, resulting in secretion of sTrem2 by hepatocytes, or empty TBG-AAV8-control, and subsequently fed HFHC diet for 15, 90, or 180 days. Results: HFHC-fed mice developed fibrosing steatohepatitis at 180 days together with a 15-fold increase in plasma sTrem2 levels. In the livers of HFHC-fed mice, crown-like structures (CLSs) consisting of TREM2 Conclusion: TREM2