Abstract
BACKGROUND AND AIMS: 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, 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 consisting of TREM2(+) macrophages surrounded necrotic, steatotic hepatocytes and their remnant lipid droplets, which contained prominent crystals containing cholesterol. TBG-AAV8-sTrem2-injected mice had higher levels of plasma sTREM2 than TBG-AAV8-control-injected mice, but there were no differences in liver weight, body weight, hepatic fibrosis, hepatic inflammation, hepatic cholesterol crystals, or plasma cholesterol levels. CONCLUSION: TREM2(+) macrophages characterize the crown-like structures that surround necrotic hepatocytes and their remnant lipid droplets and cholesterol crystals in fibrosing steatohepatitis-MASH. Plasma sTREM2 is a biomarker, but not a causal mediator, of MASH.