Protein kinase MST3 modulates lipid homeostasis in hepatocytes and correlates with nonalcoholic steatohepatitis in humans
Protein kinase MST3 modulates lipid homeostasis in hepatocytes and correlates with nonalcoholic steatohepatitis in humans
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DOI：
10.1096/fj.201900356rr
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发表时间：
2019-09-01
期刊：
影响因子：
4.8
通讯作者：
Mahlapuu, Margit
中科院分区：
文献类型：
--
作者：
Cansby, Emmelie;Kulkarni, Nagaraj M.;Mahlapuu, Margit
肝脏中的异位脂质储存被认为是非酒精性脂肪性肝炎（NASH）的主要危险因素。因此，了解控制肝细胞脂质沉积的分子网络对于开发有效预防和治疗这种复杂疾病的新策略至关重要。在这里，我们描述了一种新的调节人肝细胞中的脂质分配：哺乳动物无菌20样（MST）3。我们发现MST 3蛋白包被小鼠和人类肝细胞中的脂滴。MST 3的敲除通过刺激β-氧化和三酰甘油分泌同时抑制脂肪酸内流和脂质合成来减弱人肝细胞中的脂质积聚。我们还观察到，脂肪生成基因表达和乙酰辅酶A羧化酶蛋白丰度在MST 3缺陷肝细胞中减少，从而深入了解脂质储存减少的分子机制。此外，MST 3表达与NASH的关键特征（即，肝脂质含量、小叶炎症和肝细胞气球样变）。总之，我们的结果揭示了MST 3在控制肝脏脂质催化剂与脂质拮抗剂的动态代谢平衡中的作用。我们的研究结果强调MST 3是预防和治疗NASH和相关复杂代谢疾病的潜在药物靶标。坎斯比，E.，Kulkarni，N. M.，Magnusson，E.，Kurhe，Y.，Amrutkar，M.，Nerstedt，A.，Stahlman，M.，锡尔博姆角Marschall，H.美国、Boren，J.，Bluher，M.，Mahlapuu，M.蛋白激酶MST 3调节肝细胞中的脂质稳态，并与人类非酒精性脂肪性肝炎相关。
Ectopic lipid storage in the liver is considered the main risk factor for nonalcoholic steatohepatitis (NASH). Understanding the molecular networks controlling hepatocellular lipid deposition is therefore essential for developing new strategies to effectively prevent and treat this complex disease. Here, we describe a new regulator of lipid partitioning in human hepatocytes: mammalian sterile 20-like (MST) 3. We found that MST3 protein coats lipid droplets in mouse and human liver cells. Knockdown of MST3 attenuated lipid accumulation in human hepatocytes by stimulating beta-oxidation and triacylglycerol secretion while inhibiting fatty acid influx and lipid synthesis. We also observed that lipogenic gene expression and acetyl-coenzyme A carboxylase protein abundance were reduced in MST3-deficient hepatocytes, providing insight into the molecular mechanisms underlying the decreased lipid storage. Furthermore, MST3 expression was positively correlated with key features of NASH (i.e., hepatic lipid content, lobular inflammation, and hepatocellular ballooning) in human liver biopsies. In summary, our results reveal a role of MST3 in controlling the dynamic metabolic balance of liver lipid catabolism vs. lipid anabolism. Our findings highlight MST3 as a potential drug target for the prevention and treatment of NASH and related complex metabolic diseases.-Cansby, E., Kulkarni, N. M., Magnusson, E., Kurhe, Y., Amrutkar, M., Nerstedt, A., Stahlman, M., Sihlbom, C., Marschall, H.-U., Boren, J., Bluher, M., Mahlapuu, M. Protein kinase MST3 modulates lipid homeostasis in hepatocytes and correlates with nonalcoholic steatohepatitis in humans.