纤维连接蛋白／整合素β信号通路在短期高脂饮食诱导的脂肪肝中的作用及其机制

Effects of fibronectin/integrin β signaling on short-term high fat diet induced hepatic steatosis and the underlying mechanism

目的 研究纤维连接蛋白/整合素β信号通路在短期高脂饮食诱导的脂肪肝中的作用及其机制。 方法 用短期高脂饮食诱导小鼠早期脂肪肝模型，并给予整合素β的拮抗剂ATN161处理。检测脂肪肝表型、血脂、血糖及脂代谢相关基因和过氧化物酶体增殖物激活受体γ（PPAR γ）/硬脂酰辅酶A去饱和酶1（SCD1）蛋白的表达。用纤维连接蛋白处理HepG2细胞的同时给予ATN161，检测脂代谢相关基因的表达。 结果 （1）短期高脂饮食喂养显著增加小鼠肝脏脂质沉积和纤维连接蛋白及α平滑肌肌动蛋白（α-SMA）的表达。（2）ATN161显著下调α-SMA的表达，增加短期高脂饮食喂养小鼠肝脏脂质沉积和PPAR γ及其靶基因的表达。PPAR γ和SCD1蛋白表达也明显增加。（3）纤维连接蛋白抑制HepG2细胞脂质合成关键基因的表达，ATN161可以明显减弱其抑制作用。 结论 抑制纤维连接蛋白/整合素β信号通路可阻断短期高脂饮食激活的肝脏纤维化信号通路，同时通过增加PPAR γ的活性和表达进一步增加短期高脂饮食诱导的肝脏脂质沉积。

Objective To investigate the effects of fibronectin/integrin β signaling on short-term high fat diet induced hepatic steatosis and the underlying mechanism. Methods Male C57BL/6 mice were treated with high fat diet or high fat diet combined with ATN161, an inhibitor of integrin β. Serum biochemical parameters and liver histological examinations were observed. The expression of lipid metabolic genes in mice liver were detected with reahime PCR and the protein levels of peroxisome proliferator-activated receptor γ （ PPAR γ） and stearic acyl eoenzyme A desaturase 1 （ SCD1 ） were determined with Western blot. Results （ 1 ） High fat diet increased hepatic lipid accumulation and the expressions of fibronectin and eL-smooth muscle actin （α-SMA）. （2） ATN161 down- regulated the expression of α-SMA while increased hepatic lipid accumulation and the expression of genes involved in lipogenesis and lipid uptake in high fat diet fed mice. The up-regulated genes were target genes of PPARγ, which was also up-regulated. The protein levels of PPAR γ and SCD1 were also increased. （ 3 ） The inhibiting effects of fibronectin on lipogenesis were significantly attenuated by ATN161 in HepG2 cells. Conclusion Inhibition of fibronectin/integrin β signaling with ATN161 may block hepatic fibrotic signaling at the expense of increasing hepatic lipid accumulation through PPAR γin mice fed with high fat diet during a short term.