Jia Yue, Ji Ping, French Samuel W
Harbor-UCLA Medical Center, Torrance, CA 90509, USA.
Biomedicines. 2020 Jul 1;8(7):189. doi: 10.3390/biomedicines8070189.
FAT10 expression is highly up-regulated by pro-inflammatory cytokines IFNγ and TNFα in all cell types and tissues. Increased FAT10 expression may induce increasing mitotic non-disjunction and chromosome instability, leading to tumorigenesis. In this review, we summarized others' and our work on FAT10 expression in liver biopsy samples from patients with alcoholic hepatitis (AH). FAT10 is essential to maintain the function of liver cell protein quality control and Mallory-Denk body (MDB) formation. FAT10 overexpression in AH leads to balloon degeneration and MDB aggregation formation, all of which is prevented in fat10-/- mice. FAT10 causes the proteins' accumulation, overexpression, and forming MDBs through modulating 26s proteasome's proteases. The pathway that increases FAT10 expression includes TNFα/IFNγ and the interferon sequence response element (ISRE), followed by NFκB and STAT3, which were all up-regulated in AH. FAT10 was only reported in human and mouse specimens but plays critical role for the development of alcoholic hepatitis. Flavanone derivatives of milk thistle inhibit TNFα/IFNγ, NFκB, and STAT3, then inhibit the expression of FAT10. NFκB is the key nodal hub of the IFNα/TNFα-response genes. Studies on Silibinin and other milk thistle derivatives to treat AH confirms that overexpressed FAT10 is the major key molecule in these networks.
在所有细胞类型和组织中，促炎细胞因子IFNγ和TNFα可高度上调FAT10的表达。FAT10表达增加可能会导致有丝分裂非整倍性增加和染色体不稳定，从而引发肿瘤发生。在本综述中，我们总结了他人以及我们自己关于酒精性肝炎（AH）患者肝活检样本中FAT10表达的研究工作。FAT10对于维持肝细胞蛋白质质量控制功能和马洛里-登克小体（MDB）形成至关重要。AH中FAT10的过表达会导致气球样变性和MDB聚集形成，而在fat10基因敲除小鼠中这些情况均得到了预防。FAT10通过调节26S蛋白酶体的蛋白酶，导致蛋白质积累、过表达并形成MDB。增加FAT10表达的途径包括TNFα/IFNγ和干扰素序列反应元件（ISRE），随后是NFκB和STAT3，这些在AH中均上调。FAT10仅在人类和小鼠标本中被报道，但对酒精性肝炎的发展起着关键作用。水飞蓟宾的黄酮衍生物可抑制TNFα/IFNγ、NFκB和STAT3，进而抑制FAT10的表达。NFκB是IFNα/TNFα反应基因的关键节点枢纽。对水飞蓟宾和其他水飞蓟衍生物治疗AH的研究证实，过表达的FAT10是这些网络中的主要关键分子。
