Deletion of hepatic small heterodimer partner ameliorates development of nonalcoholic steatohepatitis in mice.
Deletion of hepatic small heterodimer partner ameliorates development of nonalcoholic steatohepatitis in mice.
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DOI：
10.1016/j.jlr.2023.100454
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发表时间：
2023-11
影响因子：
6.5
通讯作者：
Hardwick, James P.
中科院分区：
文献类型：
--
作者：
Lee, Yoon-Kwang;Park, Jung Eun;Lee, Mikang;Mifflin, Ryan;Xu, Yang;Novak, Robert;Zhang, Yanqiao;Hardwick, James P.
小异源二聚体伴侣（SHP，Nr 0 b2）是一种孤儿核受体，调节胆汁酸，脂质和葡萄糖代谢。Shp−/−小鼠对饮食诱导的肥胖和肝脂肪变性有抵抗力。在这项研究中，我们探讨了SHP在非酒精性脂肪性肝炎（NASH）发展中的潜在作用。使用6个月的西方饮食（WD）方案来诱导NASH。Shp缺失通过抑制炎症和纤维化基因、氧化应激和巨噬细胞浸润保护小鼠免于NASH进展。WD喂养破坏了WT小鼠肝线粒体的超微结构，但在Shp−/−小鼠中没有。在ApoE−/−小鼠中，Shp缺失也有效地改善了1周WD方案后的肝脏炎症，但没有明显的抗脂肪变性作用。此外，Shp−/−小鼠抵抗由蛋氨酸和胆碱缺乏饮食诱导的纤维化。值得注意的是，在喂食WD或蛋氨酸和胆碱缺乏饮食的肝脏特异性Shp−/−小鼠中重现了观察到的针对NASH的保护作用。在所研究的Shp缺失小鼠模型中，肝脏胆固醇持续降低。我们的数据表明，Shp缺乏可能通过调节肝脏胆固醇代谢和炎症来改善NASH的发展。
Small heterodimer partner (SHP, Nr0b2) is an orphan nuclear receptor that regulates bile acid, lipid, and glucose metabolism. Shp−/− mice are resistant to diet-induced obesity and hepatic steatosis. In this study, we explored the potential role of SHP in the development of nonalcoholic steatohepatitis (NASH). A 6-month Western diet (WD) regimen was used to induce NASH. Shp deletion protected mice from NASH progression by inhibiting inflammatory and fibrotic genes, oxidative stress, and macrophage infiltration. WD feeding disrupted the ultrastructure of hepatic mitochondria in WT mice but not in Shp−/− mice. In ApoE−/− mice, Shp deletion also effectively ameliorated hepatic inflammation after a 1 week WD regimen without an apparent antisteatotic effect. Moreover, Shp−/− mice resisted fibrogenesis induced by a methionine- and choline-deficient diet. Notably, the observed protection against NASH was recapitulated in liver-specific Shp−/− mice fed either the WD or methionine- and choline-deficient diet. Hepatic cholesterol was consistently reduced in the studied mouse models with Shp deletion. Our data suggest that Shp deficiency ameliorates NASH development likely by modulating hepatic cholesterol metabolism and inflammation.
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影响因子：
6.9
作者：
Myronovych, Andriy;Salazar-Gonzalez, Rosa-Maria;Ryan, Karen K.;Miles, Lili;Zhang, Wujuan;Jha, Pinky;Wang, Li;Setchell, Kenneth D. R.;Seeley, Randy J.;Kohli, Rohit
通讯作者：
Kohli, Rohit
影响因子：
5.3
作者：
Lee, YK;Dell, H;Moore, DD
通讯作者：
Moore, DD
影响因子：
29
作者：
Mari, Montserrat;Caballero, Francisco;Garcia-Ruiz, Carmen
通讯作者：
Garcia-Ruiz, Carmen
影响因子：
29.4
作者：
De Minicis, Samuele;Bataller, Ramon;Brenner, David A.
通讯作者：
Brenner, David A.
DOI：
10.1073/pnas.021544398
发表时间：
2001-01-16
影响因子：
11.1
作者：
Nishigori, H;Tomura, H;Takeda, J
通讯作者：
Takeda, J