Plasma membrane phospholipase A2 controls hepatocellular fatty acid uptake and is responsive to pharmacological modulation: implications for nonalcoholic steatohepatitis
Plasma membrane phospholipase A2 controls hepatocellular fatty acid uptake and is responsive to pharmacological modulation: implications for nonalcoholic steatohepatitis
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质膜磷脂酶 A2 控制肝细胞脂肪酸摄取并对药理学调节有反应：对非酒精性脂肪性肝炎的影响
DOI：
10.1096/fj.14-249763
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Chamulitrat W
中科院分区：
文献类型：
--
作者：
Stremmel W;Staffer S;Wannhoff A;Pathil A;Chamulitrat W
过量的肝脏脂肪积累导致非酒精性脂肪性肝炎（NASH），这是对健康的严重威胁，目前尚无有效的治疗方法。然而，肝细胞摄取脂肪酸的机制仍不清楚。使用人肝细胞源性肿瘤细胞系HepG 2，我们发现脂肪酸内流由异四聚体质膜蛋白复合物介导，该复合物由质膜脂肪酸结合蛋白、小窝蛋白-1、CD 36和钙非依赖性膜磷脂酶A2（iPLA 2 β）组成。用胆汁酸-磷脂偶联物熊去氧胆酸盐-溶血磷脂酰乙醇胺（UDCA-LPE）阻断iPLA 2 β可导致复合物解离，从而抑制脂肪酸内流（IC 5047 μM），并通过将溶血磷脂酰胆碱从8.0 μmol/mg蛋白质降低至3.5 μmol/mg蛋白质和相应的磷酸化c-Jun N-末端激酶耗竭来抑制所有亚基的合成。这些发现通过观察到来自iPLA 2 β敲除小鼠的分离肝细胞中脂肪酸内流减少56.5%得到证实。此外，在NASH细胞模型中，UDCA-LPE治疗消除了脂肪变性和炎症。因此，iPLA 2 β作为调节脂肪酸摄取机制的上游检查点，UDCA-LPE对其的抑制使这种无毒化合物有资格作为NASH治疗的候选药物。Stremmel，W.，Staffer，S.，Wannhoff，A.，Pathil，A.，查穆利特拉特湾质膜磷脂酶A2控制肝细胞脂肪酸摄取并对药理学调节有反应：对非酒精性脂肪性肝炎的影响。FASEB J. 28，3159-3170（2014）。www.fasebj.org
Excess hepatic fat accumulation leads to nonalcoholic steatohepatitis (NASH), a serious threat to health for which no effective treatment is available. However, the mechanism responsible for fatty acid uptake by hepatocytes remains unclear. Using the human hepatocyte‐derived tumor cell line HepG2, we found that fatty acid influx is mediated by a heterotetrameric plasma membrane protein complex consisting of plasma membrane fatty acid‐binding protein, caveolin‐1, CD36, and calcium‐independent membrane phospholipase A2(iPLA2β). Blocking iPLA2β with the bile acid‐phospholipid conjugate ursodeoxycholate‐lysophosphatidylethanolamide (UDCA‐LPE) caused the dissociation of the complex, thereby inhibiting fatty acid influx (IC5047 μM), and suppressed the synthesis of all subunits through a reduction in lysophosphatidylcholine from 8.0 to 3.5 μmol/mg of protein and corresponding depletion of phosphorylated c‐Jun N‐terminal kinase. These findings were substantiated by an observed 56.5% decrease in fatty acid influx in isolated hepatocytes derived from iPLA2β‐knockout mice. Moreover, steatosis and inflammation were abrogated by UDCA‐LPE treatment in a cellular model of NASH. Thus, iPLA2β acts as an upstream checkpoint for mechanisms that regulate fatty acid uptake, and its inhibition by UDCA‐LPE qualifies this nontoxic compound as a therapeutic candidate for the treatment of NASH.—Stremmel, W., Staffer, S., Wannhoff, A., Pathil, A., Chamulitrat, W. Plasma membrane phospholipase A2controls hepatocellular fatty acid uptake and is responsive to pharmacological modulation: implications for nonalcoholic steatohepatitis.FASEB J. 28, 3159–3170 (2014). www.fasebj.org
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发表时间：
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影响因子：
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DOI：
--
发表时间：
1978
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影响因子：
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DOI：
10.1073/pnas.95.15.8625
发表时间：
1998-07-21
影响因子：
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影响因子：
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