Hepatocyte-Specific Deletion of Mouse Lamin A/C Leads to Male-Selective Steatohepatitis.
Hepatocyte-Specific Deletion of Mouse Lamin A/C Leads to Male-Selective Steatohepatitis.
复制标题
DOI：
10.1016/j.jcmgh.2017.06.005
复制
发表时间：
2017-11
影响因子：
7.2
通讯作者：
Omary MB
中科院分区：
文献类型：
--
作者：
Kwan R;Brady GF;Brzozowski M;Weerasinghe SV;Martin H;Park MJ;Brunt MJ;Menon RK;Tong X;Yin L;Stewart CL;Omary MB
层粘连蛋白是构成核层的主要成分的核中间丝蛋白。编码层粘连蛋白A/C的LMNA突变可引起层粘连病，包括脂肪营养不良、心肌病和早衰综合征。然而，层粘连蛋白在肝脏中的作用尚不清楚，也不清楚层粘连病相关肝病是由原发性肝细胞缺陷还是全体性改变引起的。为了解决这些问题，我们制造了携带肝细胞特异性缺失Lmna的小鼠（敲除[KO]小鼠），并通过免疫印迹、免疫组织化学、微阵列分析、定量实时聚合酶链反应、油红O和小红染色来表征KO肝脏和原代肝细胞表型。KO肝细胞核形态异常，小鼠体重下降。KO小鼠出现自发性雄性选择性肝骨化，对高脂肪饮食诱导的脂肪性肝炎和纤维化的易感性增加。肝骨化病与编码脂质转运蛋白、脂质生物合成酶、脂滴相关蛋白和干扰素调节基因的基因转录上调有关。肝Lmna缺乏导致信号转导和转录激活因子1 （Stat1）表达增强，抑制生长激素介导的Janus激酶2 （Jak2）、信号转导和转录激活因子5 （Stat5）和细胞外信号调节激酶（Erk）信号转导。Lamin A/C通过正向调节生长激素信号和负向调节Stat1表达，细胞自主地维持肝细胞稳态和核形状，并缓冲雄性选择性脂肪性肝炎。层粘连蛋白是脂肪性肝炎和肝纤维化易感性的潜在基因修饰因子。微阵列数据可以在Gene Expression Omnibus repository （accession number: GSE93643）中找到。
Lamins are nuclear intermediate filament proteins that comprise the major components of the nuclear lamina. Mutations in LMNA, which encodes lamins A/C, cause laminopathies, including lipodystrophy, cardiomyopathy, and premature aging syndromes. However, the role of lamins in the liver is unknown, and it is unclear whether laminopathy-associated liver disease is caused by primary hepatocyte defects or systemic alterations. To address these questions, we generated mice carrying a hepatocyte-specific deletion of Lmna (knockout [KO] mice) and characterized the KO liver and primary hepatocyte phenotypes by immunoblotting, immunohistochemistry, microarray analysis, quantitative real-time polymerase chain reaction, and Oil Red O and Picrosirius red staining. KO hepatocytes manifested abnormal nuclear morphology, and KO mice showed reduced body mass. KO mice developed spontaneous male-selective hepatosteatosis with increased susceptibility to high-fat diet–induced steatohepatitis and fibrosis. The hepatosteatosis was associated with up-regulated transcription of genes encoding lipid transporters, lipid biosynthetic enzymes, lipid droplet-associated proteins, and interferon-regulated genes. Hepatic Lmna deficiency led to enhanced signal transducer and activator of transcription 1 (Stat1) expression and blocked growth hormone–mediated Janus kinase 2 (Jak2), signal transducer and activator of transcription 5 (Stat5), and extracellular signal–regulated kinase (Erk) signaling. Lamin A/C acts cell-autonomously to maintain hepatocyte homeostasis and nuclear shape and buffers against male-selective steatohepatitis by positively regulating growth hormone signaling and negatively regulating Stat1 expression. Lamins are potential genetic modifiers for predisposition to steatohepatitis and liver fibrosis. The microarray data can be found in the Gene Expression Omnibus repository (accession number: GSE93643).
登录
查看更多内容
影响因子：
7.7
作者：
Hall AM;Soufi N;Chambers KT;Chen Z;Schweitzer GG;McCommis KS;Erion DM;Graham MJ;Su X;Finck BN
通讯作者：
Finck BN
影响因子：
6.5
作者：
Agarwal, Anil K.;Tunison, Katie;Garg, Abhimanyu
通讯作者：
Garg, Abhimanyu
DOI：
10.1152/ajpendo.00513.2001
发表时间：
2002-11-01
影响因子：
5.1
作者：
Jaffe, CA;Turgeon, DK;Watkins, PB
通讯作者：
Watkins, PB
影响因子：
13.5
作者：
Browning, JD;Szczepaniak, LS;Hobbs, HH
通讯作者：
Hobbs, HH
影响因子：
11.4
作者：
Butin-Israeli, Veronika;Adam, Stephen A.;Goldman, Anne E.;Goldman, Robert D.
通讯作者：
Goldman, Robert D.