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Abstract：
BACKGROUND: The molecular mechanisms underlying nonalcoholic fatty liver disease (NAFLD) remain to be fully elucidated. Ubiquitin specific protease 13 (USP13) is a critical participant in inflammation-related signaling pathways, which are linked to NAFLD. Herein, the roles of USP13 in NAFLD and the underlying mechanisms were investigated.
METHODS: L02 cells and mouse primary hepatocytes were subjected to free fatty acid (FFA) to establish an in vitro model reflective of NAFLD. To prepare in vivo model of NAFLD, mice fed a high-fat diet (HFD) for 16 weeks and leptin-deficient (ob/ob) mice were used. USP13 overexpression and knockout (KO) strategies were employed to study the function of USP13 in NAFLD in mice.
RESULTS: The expression of USP13 was markedly decreased in both in vitro and in vivo models of NAFLD. USP13 overexpression evidently inhibited lipid accumulation and inflammation in FFA-treated L02 cells in vitro. Consistently, the in vivo experiments showed that USP13 overexpression ameliorated hepatic steatosis and metabolic disorders in HFD-fed mice, while its deficiency led to contrary outcomes. Additionally, inflammation was similarly attenuated by USP13 overexpression and aggravated by its deficiency in HFD-fed mice. Notably, overexpressing of USP13 also markedly alleviated hepatic steatosis and inflammation in ob/ob mice. Mechanistically, USP13 bound to transforming growth factor β-activated kinase 1 (TAK1) and inhibited K63 ubiquitination and phosphorylation of TAK1, thereby dampening downstream inflammatory pathways and promoting insulin signaling pathways. Inhibition of TAK1 activation reversed the exacerbation of NAFLD caused by USP13 deficiency in mice.
CONCLUSIONS: Our findings indicate the protective role of USP13 in NAFLD progression through its interaction with TAK1 and inhibition the ubiquitination and phosphorylation of TAK1. Targeting the USP13-TAK1 axis emerges as a promising therapeutic strategy for NAFLD treatment.
METHODS: L02 cells and mouse primary hepatocytes were subjected to free fatty acid (FFA) to establish an in vitro model reflective of NAFLD. To prepare in vivo model of NAFLD, mice fed a high-fat diet (HFD) for 16 weeks and leptin-deficient (ob/ob) mice were used. USP13 overexpression and knockout (KO) strategies were employed to study the function of USP13 in NAFLD in mice.
RESULTS: The expression of USP13 was markedly decreased in both in vitro and in vivo models of NAFLD. USP13 overexpression evidently inhibited lipid accumulation and inflammation in FFA-treated L02 cells in vitro. Consistently, the in vivo experiments showed that USP13 overexpression ameliorated hepatic steatosis and metabolic disorders in HFD-fed mice, while its deficiency led to contrary outcomes. Additionally, inflammation was similarly attenuated by USP13 overexpression and aggravated by its deficiency in HFD-fed mice. Notably, overexpressing of USP13 also markedly alleviated hepatic steatosis and inflammation in ob/ob mice. Mechanistically, USP13 bound to transforming growth factor β-activated kinase 1 (TAK1) and inhibited K63 ubiquitination and phosphorylation of TAK1, thereby dampening downstream inflammatory pathways and promoting insulin signaling pathways. Inhibition of TAK1 activation reversed the exacerbation of NAFLD caused by USP13 deficiency in mice.
CONCLUSIONS: Our findings indicate the protective role of USP13 in NAFLD progression through its interaction with TAK1 and inhibition the ubiquitination and phosphorylation of TAK1. Targeting the USP13-TAK1 axis emerges as a promising therapeutic strategy for NAFLD treatment.
摘要：
背景：非酒精性脂肪性肝病（NAFLD）的分子机制仍有待完全阐明。泛素特异性蛋白酶13（USP13）是炎症相关信号通路的关键参与者，与NAFLD有关。在这里，研究了USP13在NAFLD中的作用和潜在机制.
方法：对L02细胞和小鼠原代肝细胞进行游离脂肪酸（FFA）处理，建立反映NAFLD的体外模型。制备NAFLD体内模型,使用高脂肪饮食(HFD)喂养16周的小鼠和瘦素缺乏(ob/ob)小鼠。采用USP13过表达和敲除(KO)策略来研究USP13在小鼠NAFLD中的功能。
结果:在NAFLD的体外和体内模型中,USP13的表达均显著降低。USP13过表达在体外明显抑制FFA处理的L02细胞中的脂质积累和炎症。始终如一，体内实验表明，USP13过表达改善了HFD喂养小鼠的肝脏脂肪变性和代谢紊乱，而它的不足导致了相反的结果。此外,在HFD喂养的小鼠中,通过USP13过表达类似地减轻炎症,并通过其缺乏而加重炎症。值得注意的是,USP13的过表达也显著减轻ob/ob小鼠的肝脏脂肪变性和炎症。机械上,USP13与转化生长因子β激活激酶1（TAK1）结合，抑制K63泛素化和TAK1的磷酸化，从而抑制下游炎症途径并促进胰岛素信号通路。TAK1激活的抑制逆转了小鼠中由USP13缺乏引起的NAFLD的恶化。
结论：我们的发现表明USP13通过与TAK1的相互作用以及抑制TAK1的泛素化和磷酸化在NAFLD进展中具有保护作用。靶向USP13-TAK1轴成为NAFLD治疗的有希望的治疗策略。
方法：对L02细胞和小鼠原代肝细胞进行游离脂肪酸（FFA）处理，建立反映NAFLD的体外模型。制备NAFLD体内模型,使用高脂肪饮食(HFD)喂养16周的小鼠和瘦素缺乏(ob/ob)小鼠。采用USP13过表达和敲除(KO)策略来研究USP13在小鼠NAFLD中的功能。
结果:在NAFLD的体外和体内模型中,USP13的表达均显著降低。USP13过表达在体外明显抑制FFA处理的L02细胞中的脂质积累和炎症。始终如一，体内实验表明，USP13过表达改善了HFD喂养小鼠的肝脏脂肪变性和代谢紊乱，而它的不足导致了相反的结果。此外,在HFD喂养的小鼠中,通过USP13过表达类似地减轻炎症,并通过其缺乏而加重炎症。值得注意的是,USP13的过表达也显著减轻ob/ob小鼠的肝脏脂肪变性和炎症。机械上,USP13与转化生长因子β激活激酶1（TAK1）结合，抑制K63泛素化和TAK1的磷酸化，从而抑制下游炎症途径并促进胰岛素信号通路。TAK1激活的抑制逆转了小鼠中由USP13缺乏引起的NAFLD的恶化。
结论：我们的发现表明USP13通过与TAK1的相互作用以及抑制TAK1的泛素化和磷酸化在NAFLD进展中具有保护作用。靶向USP13-TAK1轴成为NAFLD治疗的有希望的治疗策略。
