Protein kinase STK25 controls lipid partitioning in hepatocytes and correlates with liver fat content in humans
Protein kinase STK25 controls lipid partitioning in hepatocytes and correlates with liver fat content in humans
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DOI：
10.1007/s00125-015-3801-7
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发表时间：
2016-02-01
期刊：
影响因子：
8.2
通讯作者：
Mahlapuu, Margit
中科院分区：
文献类型：
--
作者：
Amrutkar, Manoj;Kern, Matthias;Mahlapuu, Margit
目的/假设2型糖尿病与肝脏病理性脂质蓄积密切相关，这被认为是积极促进胰岛素抵抗的发展。我们最近在小鼠模型系统中鉴定了丝氨酸/苏氨酸蛋白激酶25（STK 25）作为肝脏脂肪变性、全身葡萄糖耐量和胰岛素敏感性的调节剂。本研究的目的是评估STK 25在人肝脏脂质代谢控制中的作用。方法在永生化人肝细胞（IHH）和HepG 2肝癌细胞中研究STK 25过表达或小干扰RNA敲低STK 25对细胞内脂肪沉积、脂质代谢和胰岛素敏感性的影响。结果STK 25在IHH和HepG 2细胞中的过表达通过抑制β-氧化和三酰甘油（TAG）的分泌而增强脂质沉积，同时增加脂质合成。相反，STK 25的敲低通过刺激β-氧化和TAG分泌而减弱脂质积累，同时抑制脂质合成。此外，TAG水解酶活性在过表达STK 25的肝细胞中被抑制，而在STK 25敲低的细胞中TAG水解酶活性增加。胰岛素敏感性在STK 25过表达的细胞中降低，在STK 25缺陷的肝细胞中增强。我们还发现了一个统计学上显着的正相关性STK 25 mRNA表达在人类肝活检和肝脂肪container.Conclusions/interpretation我们的数据表明，STK 25调节脂质分配在人类肝细胞通过控制TAG合成以及脂解活性，从而NEFA释放脂滴β-氧化和TAG分泌。我们的研究结果突出了STK 25作为预防和治疗2型糖尿病的潜在药物靶点。
Aims/hypothesis Type 2 diabetes is closely associated with pathological lipid accumulation in the liver, which is suggested to actively contribute to the development of insulin resistance. We recently identified serine/threonine protein kinase 25 (STK25) as a regulator of liver steatosis, whole-body glucose tolerance and insulin sensitivity in a mouse model system. The aim of this study was to assess the role of STK25 in the control of lipid metabolism in human liver.Methods Intracellular fat deposition, lipid metabolism and insulin sensitivity were studied in immortalised human hepatocytes (IHHs) and HepG2 hepatocellular carcinoma cells in which STK25 was overexpressed or knocked down by small interfering RNA. The association between STK25 mRNA expression in human liver biopsies and hepatic fat content was analysed.Results Overexpression of STK25 in IHH and HepG2 cells enhanced lipid deposition by suppressing beta-oxidation and triacylglycerol (TAG) secretion, while increasing lipid synthesis. Conversely, knockdown of STK25 attenuated lipid accumulation by stimulating beta-oxidation and TAG secretion, while inhibiting lipid synthesis. Furthermore, TAG hydrolase activity was repressed in hepatocytes overexpressing STK25 and reciprocally increased in cells with STK25 knockdown. Insulin sensitivity was reduced in STK25-overexpressing cells and enhanced in STK25-deficient hepatocytes. We also found a statistically significant positive correlation between STK25 mRNA expression in human liver biopsies and hepatic fat content.Conclusions/interpretation Our data suggest that STK25 regulates lipid partitioning in human liver cells by controlling TAG synthesis as well as lipolytic activity and thereby NEFA release from lipid droplets for beta-oxidation and TAG secretion. Our findings highlight STK25 as a potential drug target for the prevention and treatment of type 2 diabetes.