TREM2 sustains macrophage-hepatocyte metabolic coordination in nonalcoholic fatty liver disease and sepsis
Jinchao Hou, … , Marco Colonna, Xiangming Fang
Jinchao Hou, … , Marco Colonna, Xiangming Fang
Published February 15, 2021
Citation Information: J Clin Invest. 2021;131(4):e135197. https://doi.org/10.1172/JCI135197.
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Research Article Hepatology Metabolism

TREM2 sustains macrophage-hepatocyte metabolic coordination in nonalcoholic fatty liver disease and sepsis

Abstract

Sepsis is a leading cause of death in critical illness, and its pathophysiology varies depending on preexisting medical conditions. Here we identified nonalcoholic fatty liver disease (NAFLD) as an independent risk factor for sepsis in a large clinical cohort and showed a link between mortality in NAFLD-associated sepsis and hepatic mitochondrial and energetic metabolism dysfunction. Using in vivo and in vitro models of liver lipid overload, we discovered a metabolic coordination between hepatocyte mitochondria and liver macrophages that express triggering receptor expressed on myeloid cells-2 (TREM2). Trem2-deficient macrophages released exosomes that impaired hepatocytic mitochondrial structure and energy supply because of their high content of miR-106b-5p, which blocks Mitofusin 2 (Mfn2). In a mouse model of NAFLD-associated sepsis, TREM2 deficiency accelerated the initial progression of NAFLD and subsequent susceptibility to sepsis. Conversely, overexpression of TREM2 in liver macrophages improved hepatic energy supply and sepsis outcome. This study demonstrates that NAFLD is a risk factor for sepsis, providing a basis for precision treatment, and identifies hepatocyte-macrophage metabolic coordination and TREM2 as potential targets for future clinical trials.

Authors

Jinchao Hou, Jue Zhang, Ping Cui, Yingyue Zhou, Can Liu, Xiaoliang Wu, Yun Ji, Sicong Wang, Baoli Cheng, Hui Ye, Liqi Shu, Kai Zhang, Di Wang, Jielin Xu, Qiang Shu, Marco Colonna, Xiangming Fang

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Figure 4

Trem2 deficiency exacerbates hepatocyte mitochondrial dysfunction and accelerates NAFLD progression in a mouse model.

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Trem2 deficiency exacerbates hepatocyte mitochondrial dysfunction and a...
(A) Experimental design used to evaluate the role of Trem2 in NAFLD progression. Liver weights (B) and liver weight/body weight ratios (C) of WT and Trem2–/– mice after being fed HFD for 8 weeks. n = 10 in WT group; n = 13 in Trem2–/– group. Levels of TG (D) and cholesterol (E) in serum and livers from mice after being fed HFD for 8 weeks. n = 6 in WT group; n = 9 in Trem2–/– group. (F) Representative images of H&E- and ORO-stained liver sections. n = 4 in WT group; n = 4-5 in Trem2–/– group. Solid and dashed black arrows indicate hepatocytes with macrovesicular fat (Macroves. fat) or hepatocyte ballooning (Hep. balloon.), respectively. Number of hepatocytes with Macroves. fat or Hep. balloon. and percentage of ORO-positive area per high magnification field (HMF) was determined by ImageJ from 6 fields per section. Scale bar: 100 μm. (G) GO analysis of the identified DEGs between WT and Trem2–/– groups (n = 3 per group). (H) Heatmap showing the expression pattern of the identified DEGs (n = 3 per group). The color key indicates the expression levels. (I) Heatmap displays the upregulated and downregulated lipid species in livers (n = 9 mice per group), P < 0.05. The color key indicates the lipid levels. (J) Representative TEM images of mouse hepatocytes (upper) and hepatocellular mitochondria (bottom). n = 4 in WT group; n = 5 in Trem2–/– group. Solid and dashed white arrows refer to complete and fragmented mitochondria, respectively. Scale bars: 10 μm and 1 μm, respectively. (K) ATP levels in WT and Trem2–/– livers. n = 7 per group. All data are shown as the mean ± SD. The data were analyzed by an unpaired, 2-tailed Student’s t test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.