Macrophage proinflammatory hyperactivation drives the pathogenesis of acute liver injury, a common complication of sepsis. The role of the nuclear receptor constitutive androstane receptor (CAR) in endotoxin-induced liver injury remains unclear. Here, this study reports that CAR is highly expressed in human and murine macrophages. CAR activation markedly attenuated endotoxin-induced liver damage, alleviating hepatocyte death and hepatic inflammation. Macrophage-hepatocyte coculture confirmed that CAR inhibited inflammation through macrophage crosstalk. CAR-mediated hepatoprotection and anti-inflammatory effects are absent in AAV8- F4/80- sh Car -treated mice, confirming the essential role of CAR in macrophages. Mechanistically, CAR is found to interact with Tlr4 , and the suppressive effects of CAR on TLR4 are proven in Tlr4 −/− mice. Furthermore, CAR activation reduced LPS-induced inflammation in hMDMs, BMDMs, RAW264.7, and THP-1 cells, and Car or Tlr4 knockdown abolished CAR-mediated immunosuppression. Overall, these findings showed that macrophage CAR activation attenuated endotoxin-induced liver injury and hepatic inflammation through the TLR4 signaling pathway, providing insights for treating inflammatory liver diseases.
Objective Di(2-ethylhexyl) phthalate (DEHP) is reported to cause obesity and hypothyroidism in both humans and rodents, but the underlying mechanisms were largely unknown. This study was designed to clarify the effects and the mechanisms of DEHP on the pathogenesis of obesity and hypothyroidism and to discover the relationship between them. Methods Male C3H/He mice were treated with DEHP for 5 weeks, and the body weight, food intake, and body temperature were recorded during the exposure. After exposure, key organs and serum were analyzed by Q-PCR, Western blot, and ELISA. Results DEHP induced significant body weight gain and adipogenesis in all exposure groups except for 0.05 mg/kg. Marked hyperphagia and daytime hypothermia were also observed, which were accompanied by disturbed hypothalamic neuropeptide expression and reduced BAT UCP1 expression. In addition, WAT lipid metabolism was significantly deceased at low dose (0.5 mg/kg) and increased at high dose (50 and 200 mg/kg). DEHP also induced hypothyroidism, which was probably attributed to the combined effects of hepatic CAR activation and hypothalamic TRH inhibition induced by hypothalamic leptin resistance. Conclusions Chronic DEHP exposure could induce obesity by interrupting energy homeostasis, which is probably due to the synergistic effects of hypothyroidism and hypothalamic leptin resistance.
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