Glutaredoxin-1 Deficiency Causes Fatty Liver and Dyslipidemia by Inhibiting Sirtuin-1
Glutaredoxin-1 Deficiency Causes Fatty Liver and Dyslipidemia by Inhibiting Sirtuin-1
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DOI：
10.1089/ars.2016.6716
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发表时间：
2017-08-20
影响因子：
6.6
通讯作者：
Bachschmid, Markus M.
中科院分区：
文献类型：
--
作者：
Shao, Di;Han, Jingyan;Bachschmid, Markus M.
目标：非酒精性脂肪肝（NAFL）是一种常见的肝脏疾病，与代谢综合征、肥胖和糖尿病相关，在全球范围内的患病率正在上升。肝脏脂质代谢中关键调节因子和酶的各种分子扰动导致NAFL。然而，通过谷胱甘肽（GSH）加合物在NAFL中的氧化还原调节在很大程度上仍然是难以捉摸的。谷氧还蛋白-1（Glutaredoxin-1，Glutarin）是一种小的巯基转移酶，其去除蛋白质GSH加合物而不具有直接的抗氧化特性。肝脏中含有丰富的Glycosidase，但其代谢功能是unknown.Results：在这里，我们报告说，正常饮食喂养的Glrx缺陷小鼠（Glycosidase（-/-））自发发展肥胖症，高脂血症，肝脂肪变性8个月的年龄。腺病毒Gln在Gln（-/-）小鼠肝脏中的补充纠正了脂质代谢。Glycoprotein（-/-）小鼠表现出sirtuin-1（SirT 1）活性降低，导致SREBP-1的过度乙酰化和激活以及参与脂质合成的关键肝酶的上调。我们发现，GSH加合物抑制SirT 1在Glycoprotein（-/-）小鼠的活性。非氧化半胱氨酸突变体SirT 1的肝脏表达校正了Glycoprotein（-/-）小鼠的肝脏脂质。喂食高脂肪饮食的野生型小鼠在几个月内发展成代谢综合征、糖尿病和NAFL。Glycoprotein缺乏加速了高脂诱导的NAFL和脂肪性肝炎的进展，表现为肝损伤和炎症。创新：这些数据表明肝Glycoprotein在调节SirT 1中起重要作用，SirT 1控制蛋白谷胱甘肽加合物在肝脂肪变性的发病机制中。我们提供了一种新的氧化还原依赖性机制来调节肝脏脂质代谢，并提出肝Glycogen的上调可能是NAFL的有益策略。
Aims: Nonalcoholic fatty liver (NAFL) is a common liver disease associated with metabolic syndrome, obesity, and diabetes that is rising in prevalence worldwide. Various molecular perturbations of key regulators and enzymes in hepatic lipid metabolism cause NAFL. However, redox regulation through glutathione (GSH) adducts in NAFL remains largely elusive. Glutaredoxin-1 (Glrx) is a small thioltransferase that removes protein GSH adducts without having direct antioxidant properties. The liver contains abundant Glrx but its metabolic function is unknown.Results: Here we report that normal diet-fed Glrx-deficient mice (Glrx(-/-)) spontaneously develop obesity, hyperlipidemia, and hepatic steatosis by 8 months of age. Adenoviral Glrx repletion in the liver of Glrx(-/-) mice corrected lipid metabolism. Glrx(-/-) mice exhibited decreased sirtuin-1 (SirT1) activity that leads to hyperacetylation and activation of SREBP-1 and upregulation of key hepatic enzymes involved in lipid synthesis. We found that GSH adducts inhibited SirT1 activity in Glrx(-/-) mice. Hepatic expression of nonoxidizable cysteine mutant SirT1 corrected hepatic lipids in Glrx(-/-) mice. Wild-type mice fed high-fat diet develop metabolic syndrome, diabetes, and NAFL within several months. Glrx deficiency accelerated high-fat-induced NAFL and progression to steatohepatitis, manifested by hepatic damage and inflammation.Innovation: These data suggest an essential role of hepatic Glrx in regulating SirT1, which controls protein glutathione adducts in the pathogenesis of hepatic steatosis.Conclusion: We provide a novel redox-dependent mechanism for regulation of hepatic lipid metabolism, and propose that upregulation of hepatic Glrx may be a beneficial strategy for NAFL.