Deletion of SIRT1 from hepatocytes in mice disrupts lipin-1 signaling and aggravates alcoholic fatty liver.
Deletion of SIRT1 from hepatocytes in mice disrupts lipin-1 signaling and aggravates alcoholic fatty liver.
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DOI：
10.1053/j.gastro.2013.11.008
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发表时间：
2014-03
期刊：
影响因子：
29.4
通讯作者：
You M
中科院分区：
文献类型：
--
作者：
Yin H;Hu M;Liang X;Ajmo JM;Li X;Bataller R;Odena G;Stevens SM Jr;You M
Sirtuin（SIRT 1）是一种NAD+依赖性蛋白脱乙酰酶，通过修饰组蛋白和转录因子来调节肝脏脂质代谢。酒精暴露破坏SIRT 1活性，导致啮齿动物酒精性肝病（ALD），但确切的致病机制尚不清楚。我们比较了肝脏特异性缺失Sirt 1（Sirt 1 LKO）小鼠与LOX同窝出生的小鼠（对照）。我们在雄性Sirt 1 LKO和对照小鼠中诱导酒精性肝损伤，将其置于含Lieber-DeCarli乙醇的饮食中10天，然后通过管饲法给予单剂量乙醇（5 g/kg体重）。采集肝脏和血清样本。我们还测量了酒精性肝炎（AH）患者和非AH患者（对照组）肝脏样本中SIRT 1、SFRS 10、lipin-1β和lipin-1α的mRNA水平。在含乙醇的饮食中，Sirt 1 LKO小鼠的肝脏积累了大量的肝脂质，并表达了比对照小鼠更高水平的炎性细胞因子; Sirt 1 LKO小鼠的血清丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平升高。肝脏SIRT 1的缺失加剧了乙醇介导的脂质代谢缺陷，主要是通过改变脂质代谢转录调节因子lipin-1的功能。在培养的小鼠AML-12肝细胞中，SIRT 1的转基因表达阻止了乙醇暴露引起的脂肪积累，主要是通过逆转乙醇诱导的lipin-1信号传导的畸变。与对照组相比，AH患者的肝脏样本中SIRT 1水平降低，Lpin 1 β：α mRNA的比例较高。在小鼠中，肝脏Sirt 1的缺失会促进酒精刺激后的脂肪变性、炎症和纤维化。乙醇介导的肝脏SIRT 1信号通过lipin-1的损害有助于酒精性脂肪变性和炎症的发展。可能会开发旨在增加SIRT 1对lipin-1调节的试剂来治疗酒精性脂肪肝患者。
Sirtuin (SIRT1) is a NAD+-dependent protein deacetylase that regulates hepatic lipid metabolism by modifying histones and transcription factors. Ethanol exposure disrupts SIRT1 activity and contributes to alcoholic liver disease (ALD) in rodents, but the exact pathogenic mechanism is not clear. We compared mice with liver-specific deletion of Sirt1 (Sirt1LKO) mice with their LOX littermates (controls). We induced alcoholic liver injury in male Sirt1LKO and control mice, placing them on Lieber-DeCarli ethanol-containing diets for 10 days and then administering a single dose of ethanol (5 g/kg body weight) via gavage. Liver and serum samples were collected. We also measured mRNA levels of SIRT1, SFRS10, and lipin-1β and lipin-1α in liver samples from patients with alcoholic hepatitis (AH) and individuals without AH (controls). On the ethanol-containing diet, livers of Sirt1LKO mice accumulated larger amounts of hepatic lipid and expressed higher levels of inflammatory cytokines than control mice; serum of Sirt1LKO mice had increased levels of alanine aminotransferase and aspartate aminotransferase. Hepatic deletion of SIRT1 exacerbated ethanol-mediated defects in lipid metabolism, mainly by altering the function of lipin-1, a transcriptional regulator of lipid metabolism. In cultured mouse AML-12 hepatocytes, transgenic expression of SIRT1 prevented fat accumulation in response to ethanol exposure, largely by reversing the aberrations in lipin-1 signaling induced by ethanol. Liver samples from patients with AH had reduced levels of SIRT1 and a higher ratio of Lpin1β:α mRNAs than controls. In mice, hepatic deletion of Sirt1 promotes steatosis, inflammation, and fibrosis in response to ethanol challenge. Ethanol-mediated impairment of hepatic SIRT1 signaling via lipin-1 contributes to development of alcoholic steatosis and inflammation. Reagents designed to increase SIRT1 regulation of lipin-1 might be developed to treat patients with alcoholic fatty liver disease.
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