Effect of triggering receptor expressed on myeloid cells 2-associated alterations on lipid metabolism in macrophages in the development of non-alcoholic fatty liver disease.

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) plays crucial roles in metabolic homeostasis and inflammatory response. Altered metabolic function in macrophages could modulate their activation and immune phenotype. The present study aimed to investigate the expression of TREM2 in non-alcoholic fatty liver disease (NAFLD) and to clarify the underlying mechanism of TREM2 on macrophages lipid metabolism and oxidative stress. Hepatic TREM2 expression and its relationship with NAFLD progression were analyzed in patients with NAFLD and mice fed a high-fat diet. Lipid metabolism and oxidative stress were investigated in macrophages from NAFLD mice or stimulated with saturated fatty acids. Knockdown and overexpression of TREM2 were further explored. Triggering receptor expressed on myeloid cells 2+ macrophages were increased along with NAFLD development, characterized by aggravated steatosis and liver damage in humans and mice. TREM2 expression was upregulated and lipid metabolism was changed in macrophages from NAFLD mice or metabolically activated by saturated fatty acid in vitro, as demonstrated by increased lipid uptake and catabolism, but reduced de novo synthesis of fatty acids (FAs). Regulation of TREM2 expression in lipid-laden macrophages reprogrammed lipid metabolism, especially the fatty acid oxidation capacity of mitochondria. TREM2 knockdown promoted oxidative stress by aggravating FAs deposition in mitochondria. Intervention of mitochondrial FAs transport in lipid-laden macrophages alleviated FA deposition and reactive oxygen species production induced by TREM2 knockdown. Triggering receptor expressed on myeloid cells 2 expression was associated with the lipid metabolic profile and reactive oxygen species production in macrophages. High expression of TREM2 in macrophages may protect the liver from oxidative stress in NAFLD.