Augmenter of liver regeneration protein deficiency promotes hepatic steatosis by inducing oxidative stress and microRNA-540 expression
Augmenter of liver regeneration protein deficiency promotes hepatic steatosis by inducing oxidative stress and microRNA-540 expression
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DOI：
10.1096/fj.201802015r
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发表时间：
2019-03-01
期刊：
影响因子：
4.8
通讯作者：
Gandhi, Chandrashekhar R.
中科院分区：
文献类型：
--
作者：
Kumar, Sudhir;Rani, Richa;Gandhi, Chandrashekhar R.
肝再生增强剂（ALR），一种多功能蛋白的水平在脂肪性肝炎中降低。ALR(flox/flox)/Alb-Cre [ALR- l敲除（KO）]小鼠的ALR缺失导致肝细胞脂肪变性和凋亡，以及出生后1至2周的细胞周围纤维化。表达alr的肝细胞出现后，脂肪变性在4周后消退。我们研究了ALR消耗诱导脂肪变性的机制。采用ALR- l - ko小鼠（1、2和4周龄）和转染了adeno - cre的ALR（flox/flox）肝细胞进行体内和体外研究。体内肝细胞ALR的消耗下调了过氧化物酶体增殖物激活受体(PPAR)-，肉碱棕榈酰转移酶I (CPT1)a，过氧化物酶体膜蛋白70 (PMP70)（适度下调）和酰基辅酶a氧化酶1 （ACOX1）。发现了显著上调（20X）的新型microRNA-540 （miR-540）靶向PPAR、PMP70、ACOX1和CPT1a。原代肝细胞ALR的缺失增加了氧化应激、miR-540表达和脂肪变性，并下调了PPAR、ACOX1、PMP70和CPT1a的表达。Anti-miR-540减轻了ALR消耗诱导的脂肪变性，并阻止PPAR、ACOX1、PMP70和CPT1a表达的丧失。抗氧化剂n-乙酰半胱氨酸和重组ALR （rALR）均抑制ALR消耗诱导的miR-540表达和肝细胞脂质积累。最后，在1 - 2周期间用rALR治疗ALR-L-KO小鼠可以阻止miR-540的表达，并阻止脂肪变性和纤维化。我们得出结论，ALR缺陷介导的氧化应激诱导miR-540的产生，miR-540通过过氧化物酶体和线粒体脂质稳态失调促进脂肪变性。Kumar， S., Rani， R., Karns， R., Gandhi， C. R.。肝再生蛋白缺乏通过诱导氧化应激和microRNA-540表达促进肝脏脂肪变性。
Levels of augmenter of liver regeneration (ALR), a multifunctional protein, are reduced in steatohepatitis. ALR depletion from ALR(flox/flox)/Alb-Cre [ALR-L-knockout (KO)] mouse causes robust steatosis and apoptosis of hepatocytes, and pericellular fibrosis between 1 and 2 wk postbirth. Steatosis regresses by 4 wk upon reappearance of ALR-expressing hepatocytes. We investigated mechanisms of ALR depletion-induced steatosis. ALR-L-KO mice (1-, 2-, and 4 wk old) and Adeno-Cre-transfected ALR(flox/flox) hepatocytes were used for in vivo and in vitro studies. ALR depletion from hepatocytes in vivo downregulated peroxisome proliferator-activated receptor (PPAR)-, carnitine palmitoyl transferase I (CPT1)a, peroxisomal membrane protein 70 (PMP70) (modest down-regulation), and acyl-CoA oxidase 1 (ACOX1). The markedly up-regulated (20X) novel microRNA-540 (miR-540) was identified to target PPAR, PMP70, ACOX1, and CPT1a. ALR depletion from primary hepatocytes increased oxidative stress, miR-540 expression, and steatosis and down-regulated PPAR, ACOX1, PMP70, and CPT1a expression. Anti-miR-540 mitigated ALR depletion-induced steatosis and prevented loss of PPAR, ACOX1, PMP70, and CPT1a expression. Antioxidant N-acetylcysteine and recombinant ALR (rALR) both inhibited ALR depletion-induced miR-540 expression and lipid accumulation in hepatocytes. Finally, treatment of ALR-L-KO mice with rALR between 1 and 2 wk prevented miR-540 expression, and arrested steatosis and fibrosis. We conclude that ALR deficiency-mediated oxidative stress induces generation of miR-540, which promotes steatosis by dysregulating peroxisomal and mitochondrial lipid homeostasis.Kumar, S., Rani, R., Karns, R., Gandhi, C. R. Augmenter of liver regeneration protein deficiency promotes hepatic steatosis by inducing oxidative stress and microRNA-540 expression.