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. Conclusion: 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).

中文翻译：

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Sirtuin 3 作为自噬的负调节因子决定肝细胞对脂毒性的敏感性

饱和脂肪酸 (SFA) 诱导的脂毒性在非酒精性脂肪性肝病 (NAFLD) 的发病机制中起着核心作用；然而，确切的机制仍有待充分阐明。Sirtuin 3 (SIRT3) 是一种烟酰胺腺嘌呤二核苷酸依赖性脱乙酰酶，主要位于线粒体内。在这项研究中，我们证明了富含 SFA 的高脂肪饮食 (HFD) 比富含脂肪酸的等热量不饱和 HFD 对肝脏的危害更大。出乎意料的是，暴露于富含 SFA 的 HFD 的小鼠肝脏中 SIRT3 的表达和活性显着升高。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，SFAs 上调 SIRT3 的表达和活性。SIRT3 过表达使肝脏和肝细胞都容易受到棕榈酸酯诱导的细胞死亡的影响，这可以通过 SIRT3 小干扰 RNA (siRNA) 转染来缓解。相比之下，SIRT3 抑制保护肝细胞免受棕榈酸细胞毒性。进一步的研究表明，SIRT3 作为自噬的负调节因子，从而增强了肝细胞对 SFA 诱导的细胞毒性的敏感性。机制研究表明，SIRT3 过表达导致锰超氧化物歧化酶脱乙酰化和活化，从而耗尽细胞内超氧化物含量，导致腺苷单磷酸活化蛋白激酶 (AMPK) 抑制和哺乳动物雷帕霉素 C1 靶点激活，从而抑制自噬。相比之下，SIRT3 siRNA 基因沉默增强了自噬通量。在 SIRT3 基因敲除小鼠的肝组织中也观察到了类似的结果。结论：我们的数据表明 SIRT3 是自噬的负调节因子，其被 SFA 激活会导致肝细胞的脂毒性，并表明抑制 SIRT3 过度激活可能是治疗 NAFLD 和其他代谢紊乱的潜在治疗选择，脂毒性是主要的病理机制. （肝病学 2017；66：936-952）。