Hepatocyte-Specific Deletion of Mouse Lamin A/C Leads to Male-Selective Steatohepatitis
| Autor: | Xin Tong, Lei Yin, Ram K. Menon, Colin L. Stewart, Min-Jung Park, Makayla J. Brunt, M. Bishr Omary, Raymond Kwan, Maria Brzozowski, Graham F. Brady, Sujith V.W. Weerasinghe, Hope Martin |
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| Rok vydání: | 2017 |
| Předmět: |
WT
wild type 0301 basic medicine Premature aging HFD high-fat diet Stat signal transducer and activator of transcription Nonalcoholic Fatty Liver Disease Lipodystrophy Laminopathy Growth Hormone Signaling % liver weight liver percentage of body mass PBS phosphate-buffered saline Igf1 insulin-like growth factor 1 Biology FPLD2 Dunnigan familial partial lipodystrophy Het heterozygous Erk extracellular signal–regulated kinase LMNA 03 medical and health sciences Hepatocyte homeostasis Jak2 Janus kinase 2 medicine lcsh:RC799-869 STAT5 Original Research KO knockout Hepatology ND normal diet Gastroenterology medicine.disease Fibrosis GH growth hormone 3. Good health Cell biology 030104 developmental biology Cancer research biology.protein qPCR quantitative polymerase chain reaction Nuclear lamina lcsh:Diseases of the digestive system. Gastroenterology NAFLD nonalcoholic fatty liver disease Steatohepatitis Lamin |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, Vol 4, Iss 3, Pp 365-383 (2017) |
| ISSN: | 2352-345X |
| Popis: | Background & Aims 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). Graphical abstract |
| Databáze: | OpenAIRE |
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