PPARα信号通路激活抵抗高脂和Leptin缺失诱导的肥胖和脂肪肝

脂肪酰基辅酶A氧化酶1(acyl-coenzyme A oxidase 1,Acox1)缺失可通过内源性配体激活过氧化物酶体增殖物激活受体α(peroxisome proliferator-activated receptor-α,PPARα)及其调控的信号通路,从而减轻肥胖基因leptin突变型(ob/ob)小鼠的肥胖和脂肪肝症状,但提高了其肝癌发生率.为进一步研究PPARα信号通路在高脂日粮和leptin缺失诱导的脂肪肝形成过程中的作用,本研究以野生型、Acox1-/-、ob/ob和Acox1Δob/ob小鼠为模型,用正常日粮或60%高脂日粮饲喂10个月.结果显示,正常日粮或高脂日粮饲喂情况下,Acox1-/-和Acox1Δob/ob小鼠的体重、白色脂肪细胞体积、棕色脂肪组织含量及肝脏脂肪含量均分别显著低于WT和ob/ob小鼠.溴化脱氧尿嘧啶核苷(Brdurd)及烯酰辅酶A水合酶(L-PBE)免疫组化染色结果显示Acox1-/-和Acox1Δob/ob小鼠肝脏内肝细胞增殖及L-PBE活性、肝脏重量及其占体重的百分比均显著高于WT和ob/ob小鼠.正常日粮饲喂的WT、Acox1-/-、ob/ob和Acox1Δob/ob小鼠肝癌发生率分别为0%、100%、0%和4%,高脂日粮饲喂后,其肝癌发生率分别为0%、100%、2.9%和100%.Q-PCR结果显示Acox1-/-和Acox1Δob/ob小鼠肝脏内L-PBE、Cyp4a3、Akr1b10、ap2等基因的表达水平显著高于WT和ob/ob小鼠.综上所述,PPARα信号通路激活可以抵抗高脂日粮和leptin缺失诱导的肥胖和脂肪肝,但脂质过氧化反应可能通过Nrf2-Akr1b10信号通路促进了肝癌发生.

Activation of PPARα Pathway is Resistant to Obesity and Fatty Liver Induced by High Fat Diet and Leptin Deficiency

Acyl-coenzyme A oxidase 1(Acox1) deficiency induces peroxisome proliferator-activated receptor-α (PPARα) and PPARα-regulated pathways by endogenous ligands, which contributes to attenuation of obesity and fatty liver in leptin-deficient (ob/ob) mice, but increases liver cancer risk. To further evaluate the role of PPARα pathway in the process of fatty liver disease induced by leptin deficiency and high fat diet, wild type(WT), Acox1-/-, ob/ob and Acox1Δob/ob mice were fed with normal or 60% high fat diet(HFD)for 10 months. In Acox1-/- and Acox1Δob/ob mice fed with normal or HFD, the body weight, white adipocyte size, brown adipose tissue mass and hepatic fat content were significantly lower than that in WT and ob/ob mice separately. Immunohistochemical staining of Brdurd and L-PBE showed that hepatocyte proliferation and L-PBE activity, liver weight and liver/ body weight ratio were significantly higher than that in WT and ob/ob mice. Under normal diet, the liver tumor incidence of WT, Acox1-/-, ob/ob and Acox1Δob/ob mice was 0%, 100%,0% and 4%,respectively,after HFD,the liver tumor incidence was 0%,100%,2.9% and 100%, respectively. Real-time PCR results showed that the expression levels of L-PBE, Cyp4a3, Akr1b10, ap2 in Acox1-/- and Acox1 Δob/ob mouse liver were much higher than that in WT and ob/ob mouse liver. In conclusion, sustained activation of PPARα pathway by Acox1 deficiency is resistant to leptin deficiency and HFD induced obesity and hepatic steatosis, but lipid peroxidation may increase liver tumor risk through Nrf2-Akr1b10 pathway.