SIRT3促进脂质吞噬和分子伴侣介导的自噬，以保护肝细胞免受脂质毒性。,Cell Death and Differentiation

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SIRT3促进脂质吞噬和分子伴侣介导的自噬，以保护肝细胞免受脂质毒性。
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2019-06-03 , DOI: 10.1038/s41418-019-0356-z
Tian Zhang ₁ , Jingxin Liu ₁ , Shengnan Shen ₁ , Qiang Tong ₂ , Xiaojun Ma ₃ , Ligen Lin ₁

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脂肪吞噬是一种溶酶体脂解途径，可补充细胞溶质中性脂肪酶的作用。伴侣介导的自噬（CMA）触发脂质滴（LDs）分解，通过细胞溶脂酶或大自噬引发脂解作用。SIRT3是线粒体NAD +依赖性脱乙酰基酶，可调节许多参与能量代谢的底物的乙酰化状态和活性。但是，SIRT3在调节脂肪吞噬中的作用是有争议的。当前的研究表明，高脂饮食喂养的小鼠和经P / O（棕榈酸和油酸混合物）处理的AML12小鼠肝细胞中的SIRT3表达降低，并且巨噬细胞通量受阻，与相应的对照组相比。SIRT3过表达通过激活AMP激活的蛋白激酶（AMPK）和unc-51-like激酶1促进了P / O处理的肝细胞中LD的巨噬细胞自噬，从而增强了LDs的消化。SIRT3表达的增加刺激了溶酶体相关膜蛋白2A（LAMP-2A）-热休克同源71 kDa蛋白（HSC70）-perilipin-2（PLN2）复合物的形成，促进了CMA进程并降低了肝细胞中LDs的稳定性。此外，SIRT3减少了硬脂酰辅酶A去饱和酶1的表达，从而抑制了脂肪形成。此外，SIRT3的过表达促进了LDs在脱酪氨酸微管上的分散，并直接使长链酰基辅酶A脱氢酶直接脱乙酰化，从而增强了线粒体的能量。综上所述，SIRT3改善了肝细胞的脂毒性，

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SIRT3 promotes lipophagy and chaperon-mediated autophagy to protect hepatocytes against lipotoxicity.

Lipophagy is a lysosomal lipolytic pathway that complements the actions of cytosolic neutral lipases. Chaperon-mediated autophagy (CMA) triggers lipid droplets (LDs) breakdown, to initiate lipolysis via either cytosolic lipases or macroautophagy. SIRT3, a mitochondrial NAD+-dependent deacetylase, regulates the acetylation status and activity of many substrates involving in energy metabolism. However, the role of SIRT3 in regulating lipophagy is controversial. The current study showed that SIRT3 expression was decreased and the macroautophagy flux was blocked in the primary hepatocytes from high-fat diet fed mice and P/O (palmitic acid and oleic acid mixture) treated AML12 mouse hepatocytes, compared with the corresponding controls. SIRT3 overexpression promoted macroautophagy in LDs from P/O-treated hepatocytes through activating AMP-activated protein kinase (AMPK) and unc-51-like kinase 1, to boost LDs digestion. Gain of SIRT3 expression stimulated the formation of lysosome-associated membrane protein 2A (LAMP-2A)-heat shock cognate 71 kDa protein (HSC70)-perilipin-2 (PLN2) complex, to promote CMA process and reduce the stability of LDs in hepatocytes. Moreover, SIRT3 reduced the expression of stearoyl-CoA desaturase 1, to suppress lipogenesis. In addition, SIRT3 overexpression promoted LDs dispersion on detyrosinated microtubules, and directly deacetylated long-chain acyl-CoA dehydrogenase to enhance mitochondrial energetics. Taken together, SIRT3 ameliorates lipotoxicity in hepatocytes, which might be a potential target for the treatment of nonalcoholic fatty liver disease.

更新日期：2019-06-03

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