Li Songtao, Dou Xiaobing, Ning Hua, Song Qing, Wei Wei, Zhang Ximei, Shen Chen, Li Jiaxin, Sun Changhao, Song Zhenyuan
Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL.
Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin, P. R. China.
Hepatology. 2017 Sep;66(3):936-952. doi: 10.1002/hep.29229. Epub 2017 Jul 20.
Lipotoxicity induced by saturated fatty acids (SFAs) plays a central role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD); however, the exact mechanisms remain to be fully elucidated. Sirtuin 3 (SIRT3) is a nicotinamide adenine dinucleotide-dependent deacetylase located primarily inside mitochondria. In this study, we demonstrated that an SFA-rich high-fat diet (HFD) was more detrimental to the liver than an isocaloric unsaturated HFD rich in fatty acids. Unexpectedly, SIRT3 expression and activity were significantly elevated in the livers of mice exposed to the SFA-rich HFD. Using cultured HepG2 and AML-12 hepatocytes, we demonstrated that unlike monounsaturated fatty acids, SFAs up-regulate SIRT3 expression and activity. SIRT3 overexpression renders both the liver and hepatocytes susceptible to palmitate-induced cell death, which can be alleviated by SIRT3 small interfering RNA (siRNA) transfection. In contrast, SIRT3 suppression protects hepatocytes from palmitate cytotoxicity. Further studies revealed that SIRT3 acts as a negative regulator of autophagy, thereby enhancing the susceptibility of hepatocytes to SFA-induced cytotoxicity. Mechanistic investigations revealed that SIRT3 overexpression causes manganese superoxide dismutase deacetylation and activation, which depleted intracellular superoxide contents, leading to adenosine monophosphate-activated protein kinase (AMPK) inhibition and mammalian target of rapamycin C1 activation, resulting in autophagy suppression. In contrast, SIRT3 siRNA gene silencing enhanced autophagy flux. A similar result was observed in the liver tissue of SIRT3 knockout mice.
Our data indicate that SIRT3 is a negative regulator of autophagy whose activation by SFAs contributes to lipotoxicity in hepatocytes and suggest that restraining SIRT3 overactivation can be a potential therapeutic choice for the treatment of NAFLD as well as other metabolic disorders, with lipotoxicity being the principal pathomechanism. (Hepatology 2017;66:936-952).
饱和脂肪酸（SFA）诱导的脂毒性在非酒精性脂肪性肝病（NAFLD）的发病机制中起核心作用；然而，确切机制仍有待充分阐明。沉默调节蛋白3（SIRT3）是一种主要位于线粒体内的烟酰胺腺嘌呤二核苷酸依赖性脱乙酰酶。在本研究中，我们证明富含SFA的高脂饮食（HFD）比等热量的富含不饱和脂肪酸的HFD对肝脏更有害。出乎意料的是，暴露于富含SFA的HFD的小鼠肝脏中SIRT3的表达和活性显著升高。使用培养的HepG2和AML-12肝细胞，我们证明与单不饱和脂肪酸不同，SFA上调SIRT3的表达和活性。SIRT3过表达使肝脏和肝细胞均易受棕榈酸诱导的细胞死亡影响，而SIRT3小干扰RNA（siRNA）转染可减轻这种影响。相反，SIRT3抑制可保护肝细胞免受棕榈酸细胞毒性作用。进一步研究表明，SIRT3作为自噬的负调节因子，从而增强肝细胞对SFA诱导的细胞毒性的易感性。机制研究表明，SIRT3过表达导致锰超氧化物歧化酶去乙酰化和激活，从而消耗细胞内超氧化物含量，导致腺苷单磷酸激活的蛋白激酶（AMPK）抑制和雷帕霉素靶蛋白C1激活，从而导致自噬抑制。相反，SIRT3 siRNA基因沉默增强了自噬通量。在SIRT3基因敲除小鼠的肝脏组织中也观察到了类似结果。
我们的数据表明，SIRT3是自噬的负调节因子，SFA对其激活导致肝细胞脂毒性，并提示抑制SIRT3过度激活可能是治疗NAFLD以及其他以脂毒性为主要发病机制的代谢紊乱的潜在治疗选择。（《肝脏病学》2017年；66：936 - 952）
