脂质液滴相关激酶STK25调节脂肪肝中的过氧化物酶体活性和代谢应激反应。,Journal of Lipid Research

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脂质液滴相关激酶STK25调节脂肪肝中的过氧化物酶体活性和代谢应激反应。
Journal of Lipid Research ( IF 5.0 ) Pub Date : 2019-12-19 , DOI: 10.1194/jlr.ra119000316
Annika Nerstedt ₁ , Yeshwant Kurhe ₁ , Emmelie Cansby ₁ , Mara Caputo ₁ , Lei Gao ₁ , Egor Vorontsov ₂ , Marcus Ståhlman ₃ , Esther Nuñez-Durán ₁ , Jan Borén ₃ , Hanns-Ulrich Marschall ₃ , Douglas G Mashek ₄ , Darren N Saunders ₅ , Carina Sihlbom ₂ , Andrew J Hoy ₆ , Margit Mahlapuu ₇

Affiliation

非酒精性脂肪肝疾病（NAFLD）和非酒精性脂肪性肝炎（NASH）在全球范围内正在成为导致肝脏疾病的主要原因，并被公认为21世纪未满足的主要医学需求之一。我们最近在小鼠模型，人类细胞系和特征明确的患者队列中进行的转化研究已确定丝氨酸/苏氨酸激酶（STK）25是一种蛋白，可包裹肝细胞内脂质滴（LDs），并严格调节肝脂质稳态和NAFLD / NASH。在这里，我们通过从高脂饮食喂养的Skt25肝LD相关的磷酸化蛋白质组的相对定量研究了STK25在脂肪变性肝脏中的作用机理。基因敲除小鼠与其野生型同窝仔相比。我们观察到总共131种蛋白和60种磷蛋白在STK25缺陷型肝脏中有差异。最值得注意的是，与野生型肝脏相比，Stk25 ^-/-协调调节了涉及过氧化物酶体功能，泛素介导的蛋白水解和抗氧化剂防御的许多蛋白质。我们证实减毒的过氧化物酶体生物合成以及对STK25缺陷型人类肝细胞的氧化和内质网应激的保护作用，证明了STK25作用的肝细胞自主方式。总之，我们的研究结果表明调节过氧化物酶体功能和代谢应激反应可能是STK25控制NAFLD / NASH发育和进程的重要分子机制。

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Lipid droplet-associated kinase STK25 regulates peroxisomal activity and metabolic stress response in steatotic liver.

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are emerging as leading causes of liver disease worldwide and have been recognized as one of the major unmet medical needs of the 21st century. Our recent translational studies in mouse models, human cell lines, and well-characterized patient cohorts have identified serine/threonine kinase (STK)25 as a protein that coats intrahepatocellular lipid droplets (LDs) and critically regulates liver lipid homeostasis and progression of NAFLD/NASH. Here, we studied the mechanism-of-action of STK25 in steatotic liver by relative quantification of the hepatic LD-associated phosphoproteome from high-fat diet-fed Stk25 knockout mice compared with their wild-type littermates. We observed a total of 131 proteins and 60 phosphoproteins that were differentially represented in STK25-deficient livers. Most notably, a number of proteins involved in peroxisomal function, ubiquitination-mediated proteolysis, and antioxidant defense were coordinately regulated in Stk25^-/- versus wild-type livers. We confirmed attenuated peroxisomal biogenesis and protection against oxidative and ER stress in STK25-deficient human liver cells, demonstrating the hepatocyte-autonomous manner of STK25's action. In summary, our results suggest that regulation of peroxisomal function and metabolic stress response may be important molecular mechanisms by which STK25 controls the development and progression of NAFLD/NASH.

更新日期：2020-08-21

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