Hepatic Lipid Partitioning and Liver Damage in Nonalcoholic Fatty Liver Disease ROLE OF STEAROYL-CoA DESATURASE
Hepatic Lipid Partitioning and Liver Damage in Nonalcoholic Fatty Liver Disease ROLE OF STEAROYL-CoA DESATURASE
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DOI：
10.1074/jbc.m807616200
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发表时间：
2009-02-27
影响因子：
4.8
通讯作者：
Feldstein, Ariel E.
中科院分区：
文献类型：
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作者：
Li, Zheng Zheng;Berk, Michael;Feldstein, Ariel E.
主要以甘油三酯形式存在的肝脏脂质超载被认为是非酒精性脂肪性肝病（NAFLD）发展的先决条件。然而，响应于脂质溢出的肝脏中甘油三酯蓄积可能代表针对脂毒性的保护机制。我们的目的是通过使用NAFLD的体内饮食模型和脂质过载的体外细胞模型来评估将肝细胞中的脂质区室化与NAFLD中的肝损伤和疾病进展联系起来的基本细胞机制。鼠或人肝细胞暴露于单不饱和脂肪酸（MUFA）导致脂质蓄积，而细胞活力无变化。与此相反，细胞与饱和脂肪酸（SFA）孵育显着降低细胞活力和增加半胱天冬酶的激活和凋亡，只有轻微的脂滴积累。硬脂酰辅酶A去饱和酶-1（SCD 1）（将SFA转化为MUFA的酶）的遗传或药理学抑制使细胞对SFA诱导的细胞凋亡敏感。在高脂肪饮食导致的实验性脂肪变性中，肝脏SCD 1表达增加，而在蛋氨酸胆碱缺乏（MCD）的脂肪性肝炎饮食模型中，肝脏SCD 1表达减少，导致后一种情况下肝脏SFA水平显著增加。与SCD 1（+/+）相比，MCD饲料喂养的SCD 1（-/-）小鼠脂肪变性减少，肝细胞凋亡、肝损伤和纤维化显著增加，而MUFA喂养可预防MCD诱导的损伤。总之，这项研究表明，肝脏SCD 1通过将多余的脂质分配到可以安全储存的MUFA中，在预防脂肪性肝炎中起着关键作用。这一概念对开发针对这种疾病患者的新治疗策略具有重要意义。
Hepatic lipid overloading mainly in the form of triglycerides is considered a prerequisite for the development of nonalcoholic fatty liver disease (NAFLD). However, triglyceride accumulation in the liver in response to lipid overflow may represent a protective mechanism against lipotoxicity. Our aims were to assess the fundamental cellular mechanisms that link lipid compartmentation in hepatocytes to liver damage and disease progression in NAFLD by using both in vivo dietary models of NAFLD and in vitro cell models of lipid overloading. Exposure of murine or human hepatocytes to monounsaturated fatty acids (MUFAs) resulted in lipid accumulation without changes in cell viability. In contrast, cell incubation with saturated fatty acids (SFAs) significantly decreased cell viability and increased caspase activation and apoptosis, with only minor lipid droplet accumulation. Genetic or pharmacological inhibition of stearoyl-CoA desaturase-1 (SCD1), the enzyme that converts SFA to MUFA, sensitized cells to SFA-induced apoptosis. Hepatic SCD1 expression increased in experimental steatosis resulting from high fat diet and decreased in a methionine-choline-deficient (MCD) dietary model of steatohepatitis resulting in the latter situation in significantly increased hepatic SFA levels. SCD1(-/-) mice on the MCD diet had decreased steatosis and markedly increased hepatocellular apoptosis, liver injury, and fibrosis compared with the SCD1(+/+), whereas MUFA feeding prevents the MCD-induced injury. In conclusion, this study suggests hepatic SCD1 plays a key role in prevention of steatohepatitis by partitioning excess lipid into MUFA that can be safely stored. This concept has important implications for the development of novel treatment strategies for patients with this condition.