Hepatic Huwe1 loss protects mice from non-alcoholic fatty liver disease through lipid metabolic rewiring.
Hepatic Huwe1 loss protects mice from non-alcoholic fatty liver disease through lipid metabolic rewiring.
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肝脏中Huwe1的缺失通过脂质代谢重编程保护小鼠免受非酒精性脂肪性肝病的影响。
DOI：
10.1016/j.isci.2023.108405
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发表时间：
2023-12-15
期刊：
影响因子：
5.8
通讯作者：
Kurokawa, Manabu
中科院分区：
文献类型：
--
作者：
Feng, William W.;Bang, Scott;Takacs, Eric M.;Day, Cora;Crawford, Katherine J.;Al-Sheyab, Ruba;Almufarrej, Dara B.;Wells, Wendy;Ilchenko, Serguei;Kasumov, Takhar;Kon, Ning;Novak, Colleen M.;Gu, Wei;Kurokawa, Manabu
非酒精性脂肪性肝病（NAFLD）是全球最普遍的肝脏疾病。在此，我们证明泛素E3连接酶Huwe1在NAFLD发病机制中至关重要。通过质谱分析和RNA测序，我们发现1岁小鼠（约相当于人类中年）肝脏特异性缺失Huwe1（Huwe1LKO）会引发广泛的脂质代谢重编程，包括新生脂肪生成和脂肪酸摄取下调、脂肪酸β -氧化上调以及氧化磷酸化增加。ChEA转录因子预测分析推断这些变化是由于Huwe1LKO肝脏中过氧化物酶体增殖物激活受体α（PPARɑ）、肝X受体（LXR）和视黄醇X受体（RXR）活性减弱所致。因此，与野生型小鼠相比，喂食普通饲料的Huwe1LKO小鼠肝脏脂肪变性显著减轻，葡萄糖耐量更佳。到6个月大时，Huwe1LKO还能保护小鼠免受高脂肪饮食诱导的肝脏脂肪变性，并且随着小鼠达到中年，观察到的差异愈发显著。总之，我们提供的证据表明Huwe1在年龄和饮食诱导的NAFLD发展中起关键作用。
肝脏特异性缺失Huwe1可防止小鼠因衰老而诱发的NAFLD
肝脏特异性缺失Huwe1还可保护小鼠免受饮食诱导的NAFLD
质谱分析和RNA测序分析确定了Huwe1基因敲除小鼠的代谢重塑
ChEA分析显示Huwe1基因敲除小鼠中PPARα、LXR和RXR活性下调
生物化学；病理生理学
Non-alcoholic fatty liver disease (NAFLD) is the most pervasive liver pathology worldwide. Here, we demonstrate that the ubiquitin E3 ligase Huwe1 is vital in NAFLD pathogenesis. Using mass spectrometry and RNA sequencing, we reveal that liver-specific deletion of Huwe1 (Huwe1LKO) in 1-year-old mice (approximately middle age in humans) elicits extensive lipid metabolic reprogramming that involves downregulation of de novo lipogenesis and fatty acid uptake, upregulation of fatty acid β-oxidation, and increased oxidative phosphorylation. ChEA transcription factor prediction analysis inferred these changes result from attenuated PPARɑ, LXR, and RXR activity in Huwe1LKO livers. Consequently, Huwe1LKO mice fed chow diet exhibited significantly reduced hepatic steatosis and superior glucose tolerance compared to wild-type mice. Huwe1LKO also conferred protection from high-fat diet-induced hepatic steatosis by 6-months of age, with increasingly robust differences observed as mice reached middle age. Together, we present evidence that Huwe1 plays a critical role in the development of age- and diet-induced NAFLD. Liver-specific deletion of Huwe1 prevents NAFLD induced by aging in mice Liver-specific deletion of Huwe1 also protects mice from diet-induced NAFLD Mass spectrometry and RNA-seq analyses identified metabolic remodeling in Huwe1 KO ChEA analysis revealed downregulation of PPARα, LXR, and RXR activity in Huwe1 KO Biochemistry; Pathophysiology
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泛素连接酶 Huwe1 调节造血干细胞的维持和淋巴定向。
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
影响因子：
8.8
作者：
Feng, William W.;Wilkins, Owen;Kurokawa, Manabu
通讯作者：
Kurokawa, Manabu
影响因子：
5.8
作者：
Lachmann, Alexander;Xu, Huilei;Ma'ayan, Avi
通讯作者：
Ma'ayan, Avi
影响因子：
5.3
作者：
Liu, ZQ;Oughtred, R;Wing, SS
通讯作者：
Wing, SS