AMPK agonist AICAR ameliorates maternal hepatic lipid metabolism disorder, inflammation, and fibrosis caused by PM2.5 exposure during pregnancy
摘要
Liver is an important target organ of ambient fine particulate matter (PM2.5). Numerous studies have shown that PM2.5 exposure can cause liver lipid metabolism disorders and other liver damage in mammals. However, the impact of PM2.5 on liver health during pregnancy, a sensitive life stage, remains understudied, and the underlying mechanisms are also unknown. Given the critical role of adenosine 5’-monophosphate activated protein kinase (AMPK) in regulating lipid metabolism and inflammation, we hypothesize that AMPK activation may mitigate maternal hepatic lipid metabolism disorders, reduce inflammation, and attenuate fibrosis induced by PM2.5 exposure during pregnancy. To test this hypothesis, pregnant C57BL/6 mice were randomly assigned to 4 groups: filtered air (FA) + NS (normal saline), PM2.5+NS, FA + AICAR (acadesine, an AMPK activator), and PM2.5+AICAR. PM2.5+NS and PM2.5+AICAR groups were continuously exposed to PM2.5 with a whole-body PM2.5 exposure chamber, while the other two groups were exposed to filtered air in the FA chamber. Simultaneously, the FA + AICAR and PM2.5+AICAR groups received intraperitoneal injections of the AMPK agonist AICAR (200 mg/kg∙bw per day) from gestational day 13 (GD13) to GD17, while mice in the FA + NS and PM2.5+NS groups were administered normal saline injection. We found that gestational PM2.5 exposure induced dyslipidemia in pregnant mice, which was alleviated by AICAR treatment. Histopathological analysis showed that the exposure to PM2.5 during pregnancy induced hepatic lipid deposition and fibrosis in pregnant mice, and biochemical assays revealed that hepatic triglyceride and cholesterol levels were also significantly increased in pregnant mice after exposure to PM2.5, whereas the AICAR treatment ameliorated hepatic lipid deposition and fibrosis induced by the exposure to PM2.5 during pregnancy. Furthermore, PM2.5 exposure during pregnancy disrupted the expression of key genes and proteins associated with hepatic lipid synthesis, cholesterol synthesis, inflammation, and fibrosis, while treatment with AICAR mitigated these effects. These findings demonstrated that AMPK activation ameliorates hepatic lipid metabolism disorders, reduces inflammation, and attenuates fibrosis caused by PM2.5 exposure in mice during pregnancy. AMPK may be a target of action for maternal liver injury induced by PM2.5 exposure during pregnancy.