Human centenarian-associated SIRT6 mutants modulate hepatocyte metabolism and collagen deposition in multilineage hepatic 3D spheroids
Human centenarian-associated SIRT6 mutants modulate hepatocyte metabolism and collagen deposition in multilineage hepatic 3D spheroids
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DOI：
10.1007/s11357-022-00713-1
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发表时间：
2022-12-19
期刊：
影响因子：
5.6
通讯作者：
Vinciguerra, Manlio
中科院分区：
文献类型：
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作者：
Frohlich, Jan;Raffaele, Marco;Vinciguerra, Manlio
非酒精性脂肪肝病 (NAFLD) 包括脂肪肝及其进展为非酒精性脂肪性肝炎 (NASH)、纤维化、肝硬化和肝细胞癌 (HCC)，是全球范围内迅速上升的健康问题之一。 SIRT6 是一种重要的核去乙酰化酶，可调节包括胰岛素抵抗和炎症在内的多种病理过程，最近它与改善 NAFLD 进展有关。 SIRT6 过度表达可防止纤维化病变的形成。然而，潜在的分子机制尚未完全阐明。此外，SIRT6 (N308K/A313S) 的新等位基因变体最近通过改善基因组维护和 DNA 修复、抑制转座子和杀死癌细胞而与德系犹太人的长寿相关。这些新的 SIRT6 变体在肝脏疾病中是否发挥不同或增强的作用目前尚不清楚。在这项研究中，我们旨在阐明这些与百岁老人相关的新 SIRT6 基因变异如何影响肝脏代谢和相关疾病。我们提供的证据表明，百岁老人相关的 SIRT6 变体的过度表达显着改变了未受挑战的永生化人类肝细胞 (IHH) 的代谢组学和分泌组学特征。与用 SIRT6 野生型序列转染的 IHH 相比，过表达 IHH 的 SIRT6 N308K/A313S 中的大多数氨基酸增加。 SIRT6 N308K/A313S 过表达后，多种不饱和脂肪酸和甘油磷脂增加，神经酰胺趋于减少。此外，我们发现，在人永生化肝细胞（IHH）和肝星状细胞（LX2）共培养形成的3D肝球体模型中，SIRT6 N308K/A313S的过度表达在没有代谢或饮食挑战的情况下抑制胶原蛋白沉积和纤维化基因表达。因此，我们的研究结果表明，与长寿相关的新型 SIRT6 N308K/A313S 变体可以通过改变肝细胞蛋白质组和脂质组来预防 NASH。
Non-alcoholic fatty liver disease (NAFLD), encompassing fatty liver and its progression into nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), is one of the rapidly rising health concerns worldwide. SIRT6 is an essential nuclear sirtuin that regulates numerous pathological processes including insulin resistance and inflammation, and recently it has been implicated in the amelioration of NAFLD progression. SIRT6 overexpression protects from formation of fibrotic lesions. However, the underlying molecular mechanisms are not fully delineated. Moreover, new allelic variants of SIRT6 (N308K/A313S) were recently associated with the longevity in Ashkenazi Jews by improving genome maintenance and DNA repair, suppressing transposons and killing cancer cells. Whether these new SIRT6 variants play different or enhanced roles in liver diseases is currently unknown. In this study, we aimed to clarify how these new centenarian-associated SIRT6 genetic variants affect liver metabolism and associated diseases. We present evidence that overexpression of centenarian-associated SIRT6 variants dramatically altered the metabolomic and secretomic profiles of unchallenged immortalized human hepatocytes (IHH). Most amino acids were increased in the SIRT6 N308K/A313S overexpressing IHH when compared to IHH transfected with the SIRT6 wild-type sequence. Several unsaturated fatty acids and glycerophospholipids were increased, and ceramide tended to be decreased upon SIRT6 N308K/A313S overexpression. Furthermore, we found that overexpression of SIRT6 N308K/A313S in a 3D hepatic spheroid model formed by the co-culture of human immortalized hepatocytes (IHH) and hepatic stellate cells (LX2) inhibited collagen deposition and fibrotic gene expression in absence of metabolic or dietary challenges. Hence, our findings suggest that novel longevity associated SIRT6 N308K/A313S variants could favor the prevention of NASH by altering hepatocyte proteome and lipidome.