PM2.5通过抑制FGF21/AMPKα2通路促发非酒精性脂肪肝

PM 2.5 Promotes the Incidence of Nonalcoholic Fatty Liver Disease Via Inhibiting FGF21/AMPKα2 Pathway

目的:探讨PM2.5对非酒精性脂肪肝(NAFLD)的影响及与FGF21/AMPKα2通路的关系。方法:根据气管滴注的PM2.5浓度随机将40只6周龄雄性小鼠分为4组:对照组(生理盐水,10只)和低毒组(6.25μg/mL)、中毒组(12.5μg/mL)、高毒组(25.0μg/mL),10只/组,持续染毒19天。10周龄起给予高脂饲料喂养6周,构建NAFLD小鼠模型。分别于染毒前、染毒后、高脂喂养6周测定循环TG、TC及FGF21水平。处死小鼠,取肝细胞培养后随机分两组,分别转染Ad-FGF21与对照病毒Ad-GFP 16 h,后加入PM2.5混悬液进行染毒共培养36 h,测定两组细胞存活率,肝细胞内TC及TG、FGF21、AMPKα2含量。结果:染毒后及高脂喂养6周后,各组血清TG、TC较染毒前明显升高,血清FGF21水平降低,且随着染毒浓度的增加,血清TG、TC亦相应升高,FGF21随之降低(P<0.05)。与染毒后比较,高脂喂养6周后各组血清TG、TC均显著升高,血清FGF21显著降低(P<0.05)。与Ad-GFP组比较,Ad-FGF21组PM2.5染毒后肝细胞存活率显著升高,TG、TC水平明显降低,而肝细胞FGF21、AMPKα2表达含量则显著升高(P<0.05)。结论:幼年期PM2.5暴露可加速成年后NAFLD发生,且与暴露浓度密切相关,PM2.5可能通过抑制肝脏FGF21/AMPKα2信号通路促进肝细胞脂质沉积和NAFLD的发生发展。

Objective:To explore the influence of PM 2.5 on the nonalcoholic fatty liver disease(NAFLD)and its correlation with FGF21/AMPKα2 pathway.Methods:406-week-old male mice were randomly divided into 4 groups according to the concentration of PM2.5 in trachea drip:control group(10 mice with normal saline),low toxicity group(6.25μg/mL),medium toxic group(12.5μg/mL),high toxicity group(25.0μg/mL),10 mice/group,continued exposure for 19 days.A NAFLD mouse model was established by feeding high-fat diet for 6 weeks from 10 weeks of age.Levels of circulating TG,TC and FGF21 were measured before,after contamination and after high fat feeding for 6 weeks.Mice were sacrificed,and liver cells were cultured and randomly divided into two groups,respectively transfected with Ad-FGF21 and control virus Ad-GFP for 16h.After that,PM2.5 suspension was added for a total culture of 36 h,and the survival rate of the two groups was measured,and the contents of TC,TG,FGF21 and AMPK alpha 2 in liver cells were measured.Results:After the contamination and 6 weeks of high-fat feeding,serum TG and TC in each group were significantly increased compared with those before the contamination,and serum FGF21 levels were decreased.With the increase of the concentration of the contamination,serum TG and TC were also increased,and serum FGF21 was decreased(P<0.05).After 6 weeks of high-fat feeding,serum TG and TC in each group were significantly increased and serum FGF21 significantly decreased(P<0.05).Compared with the Ad-GFP group,the survival rate of hepatocytes in the Ad-FGF21 group was significantly increased after PM2.5 exposure,TG and TC levels were significantly reduced,and the FGF21 and AMPKα2 hepatic expression levels were significantly increased(P<0.05).Conclusions:Childhood PM2.5 exposure can accelerate the development of NAFLD in adulthood and is closely related to the exposure concentration.PM2.5 may promote hepatic lipid deposition and the development of NAFLD by inhibiting the liver FGF21/AMPKα2 signaling pathway.