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Abstract：
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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).
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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).
摘要：
目的：层是核中间丝蛋白，包含核层的主要成分。LMNA突变,编码层板蛋白A/C，导致层板病变，包括脂肪营养不良,心肌病,和早衰综合征。然而,层板在肝脏中的作用是未知的，目前尚不清楚层蛋白病相关肝病是由原发性肝细胞缺陷还是全身性改变引起的。
方法：为了解决这些问题，我们产生了携带肝细胞特异性缺失的小鼠Lmna（敲除[KO]小鼠），并通过免疫印迹表征了KO肝脏和原代肝细胞表型，免疫组织化学，微阵列分析,定量实时聚合酶链反应，和油红O和黄连红染色。
结果：KO肝细胞表现出核形态异常，和KO小鼠显示体重下降。KO小鼠发展为自发性雄性选择性肝骨病，对高脂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的基因转录上调有关，脂质生物合成酶，脂滴相关蛋白，和干扰素调节的基因。肝Lmna缺乏导致信号转导和转录激活因子1（Stat1）表达增强，并阻断生长激素介导的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)信号传导。
结论：LaminA/C通过正向调节生长激素信号和负向调节Stat1表达，以细胞自主作用维持肝细胞稳态和细胞核形状，并缓冲男性选择性脂肪性肝炎。薄片是脂肪性肝炎和肝纤维化倾向的潜在遗传修饰剂。微阵列数据可以在基因表达综合储存库(登录号:GSE93643)中找到。
方法：为了解决这些问题，我们产生了携带肝细胞特异性缺失的小鼠Lmna（敲除[KO]小鼠），并通过免疫印迹表征了KO肝脏和原代肝细胞表型，免疫组织化学，微阵列分析,定量实时聚合酶链反应，和油红O和黄连红染色。
结果：KO肝细胞表现出核形态异常，和KO小鼠显示体重下降。KO小鼠发展为自发性雄性选择性肝骨病，对高脂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的基因转录上调有关，脂质生物合成酶，脂滴相关蛋白，和干扰素调节的基因。肝Lmna缺乏导致信号转导和转录激活因子1（Stat1）表达增强，并阻断生长激素介导的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)信号传导。
结论：LaminA/C通过正向调节生长激素信号和负向调节Stat1表达，以细胞自主作用维持肝细胞稳态和细胞核形状，并缓冲男性选择性脂肪性肝炎。薄片是脂肪性肝炎和肝纤维化倾向的潜在遗传修饰剂。微阵列数据可以在基因表达综合储存库(登录号:GSE93643)中找到。
