Angiopoietin-like protein 4 deficiency augments liver fibrosis in liver diseases such as nonalcoholic steatohepatitis in mice through enhanced free cholesterol accumulation in hepatic stellate cells.
Angiopoietin-like protein 4 deficiency augments liver fibrosis in liver diseases such as nonalcoholic steatohepatitis in mice through enhanced free cholesterol accumulation in hepatic stellate cells.
复制标题
血管生成素样蛋白 4 缺乏会通过增加肝星状细胞中游离胆固醇的积累而加剧小鼠非酒精性脂肪性肝炎等肝脏疾病中的肝纤维化。
作者：
Teratani T.;Tomita K.;Wada A.;Sugihara N.;Higashiyama M.;Inaba K.;Horiuchi K.;Hanawa Y.;Nishii S.;Mizoguchi A.;Tanemoto R.;Ito S.;Okada Y.;Kurihara C.;Akita Y.;Narimatsu K.;Watanabe C.;Komoto S.;Oike Y.;Miura S.;Hokari R.;Kanai T.
目的最近报道脂蛋白脂酶(LPL)介导的肝星状细胞(HSCs)内游离胆固醇(FC)积聚导致非酒精性脂肪性肝炎(NASH)肝纤维化加重。本研究旨在探讨脂蛋白脂酶抑制剂血管生成素样蛋白4(ANGPTL4)在NASH肝纤维化发病机制中的作用。方法采用Ang ptl4基因缺陷小鼠和野生型小鼠，观察ANGPTL4在蛋氨酸和胆碱缺乏饮食诱导的NASH发病机制中的作用。结果在NASH模型中，ANGPTL4缺陷小鼠显著加重肝纤维化，激活HSC，但对肝细胞损伤、肝脏炎症和肝血管生成无促进作用。ANGPTL4缺陷小鼠的HSCs的Fc水平显著高于野生型小鼠。ANGPTL4通过抑制LPL逆转低密度脂蛋白诱导的Fc在HSC中的积聚。ANGPTL4缺乏诱导的HSCFC积聚抑制了HSC转化生长因子-β假受体、骨形态发生蛋白和激活素膜结合抑制物的表达，并使HSC体内外对转化生长因子-β诱导的激活敏感。此外，ANGPTL4对HSC中Fc水平的调节在NASH肝纤维化的发病机制中起重要作用。因此，ANGPTL4可能代表了NASH的一种新的治疗选择。
AimWe recently reported that lipoprotein lipase (LPL)‐mediated free cholesterol (FC) accumulation in hepatic stellate cells (HSCs) augmented liver fibrosis in non‐alcoholic steatohepatitis (NASH). The aim of the present study was to explore the role of angiopoietin‐like protein 4 (Angptl4), an LPL inhibitor, in the pathogenesis of liver fibrosis in NASH.MethodsAngptl4‐deficient or wild‐type mice were used to investigate the role of Angptl4 in the pathogenesis of NASH induced by feeding a methionine‐ and choline‐deficient diet. We also examined the effect of Angptl4 on FC accumulation in HSCs, and the subsequent activation of HSCs, using Angptl4‐deficient HSCs.ResultsIn the NASH model, Angptl4‐deficient mice had significantly aggravated liver fibrosis and activated HSCs without enhancement of hepatocellular injury, liver inflammation, or liver angiogenesis. FC levels were significantly higher in HSCs from Angptl4‐deficient mice than in those from wild‐type mice. Treatment with Angptl4 reversed low‐density lipoprotein‐induced FC accumulation in HSCs through the inhibition of LPL. The Angptl4 deficiency‐induced FC accumulation in HSCs suppressed HSC expression of the transforming growth factor‐β(TGF‐ß) pseudoreceptor, bone morphogenetic protein, and activin membrane‐bound inhibitor, and sensitized HSCs to TGF‐β‐induced activation in vivo and in vitro.ConclusionsAngptl4 plays an important role in the pathogenesis of FC accumulation in HSCs. In addition, regulation of FC levels in HSCs by Angptl4 plays a critical role in the pathogenesis of liver fibrosis in NASH. Thus, Angptl4 could represent a novel therapeutic option for NASH.