Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Shenzhen University International Cancer Center, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen 518055, China; Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK.
Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Shenzhen University International Cancer Center, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen 518055, China; Shenzhen Bay Laboratory, Shenzhen University School of Medicine, Shenzhen 518055, China.
Mol Cell. 2022 Nov 3;82(21):4099-4115.e9. doi: 10.1016/j.molcel.2022.09.018. Epub 2022 Oct 7.
Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive hepatic lipid accumulation, which can progress to nonalcoholic steatohepatitis (NASH). Histone deacetylase Sirtuin 6 (SIRT6) regulates NAFLD by regulating metabolism-related gene expression, but an extrachromosomal role for SIRT6 in NAFLD development remains elusive. We investigated whether SIRT6 functions on NAFLD in the cytoplasm. We found that SIRT6 binds saturated fatty acids, especially palmitic acid. This binding leads to its nuclear export, where it deacetylates long-chain acyl-CoA synthase 5 (ACSL5), thereby facilitating fatty acid oxidation. High-fat diet-induced NAFLD is suppressed by ACSL5 hepatic overexpression but is exacerbated by its depletion. As confirmation, overexpression of a deacetylated ACSL5 mimic attenuated NAFLD in Sirt6 liver-specific knockout mice. Moreover, NASH-hepatic tissues from both patients and diet-fed mice exhibited significantly reduced cytoplasmic SIRT6 levels and increased ACSL5 acetylation. The SIRT6/ACSL5 signaling pathway has a critical role in NAFLD progression and might constitute an avenue for therapeutic intervention.
非酒精性脂肪性肝病（NAFLD）的特征是肝脏脂质积累过多，可进展为非酒精性脂肪性肝炎（NASH）。组蛋白去乙酰化酶 Sirtuin 6（SIRT6）通过调节代谢相关基因的表达来调节 NAFLD，但 SIRT6 在 NAFLD 发展中的染色体外作用仍不清楚。我们研究了 SIRT6 在细胞质中是否对 NAFLD 起作用。我们发现 SIRT6 与饱和脂肪酸结合，尤其是棕榈酸。这种结合导致其核输出，在核内它去乙酰化长链酰基辅酶 A 合成酶 5（ACSL5），从而促进脂肪酸氧化。高果糖饮食诱导的 NAFLD 通过 ACSL5 肝过表达得到抑制，但通过其耗竭得到加剧。作为证实，去乙酰化 ACSL5 模拟物的过表达可减轻 Sirt6 肝特异性敲除小鼠的 NAFLD。此外，来自患者和饮食喂养小鼠的 NASH 肝组织显示细胞质 SIRT6 水平显著降低和 ACSL5 乙酰化增加。SIRT6/ACSL5 信号通路在 NAFLD 进展中起关键作用，可能构成治疗干预的途径。
