Hepatocyte-Specific Deletion of Mouse Lamin A/C Leads to Male-Selective SteatohepatitisSummary
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...
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Elsevier
2017-11-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X17301030 |
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doaj-6460db21f5444d62a8af8a332bfa76d62020-11-24T21:07:35ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2017-11-0143365383Hepatocyte-Specific Deletion of Mouse Lamin A/C Leads to Male-Selective SteatohepatitisSummaryRaymond Kwan0Graham F. Brady1Maria Brzozowski2Sujith V. Weerasinghe3Hope Martin4Min-Jung Park5Makayla J. Brunt6Ram K. Menon7Xin Tong8Lei Yin9Colin L. Stewart10M. Bishr Omary11Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan; Correspondence Address correspondence to: Raymond Kwan, Department of Molecular and Integrative Physiology, University of Michigan, 7720 Med Sci II, Ann Arbor, Michigan 48109.Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan, Ann Arbor, MichiganDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MichiganDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MichiganDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MichiganDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MichiganDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MichiganDepartment of Internal Medicine, University of Michigan, Ann Arbor, MichiganDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MichiganDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan, Ann Arbor, MichiganDevelopment and Regenerative Biology Group, Institute of Medical Biology, Immunos, SingaporeDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan, Ann Arbor, MichiganBackground & 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 dietâinduced 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 hormoneâmediated Janus kinase 2 (Jak2), signal transducer and activator of transcription 5 (Stat5), and extracellular signalâregulated 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). Keywords: Nonalcoholic Fatty Liver Disease, Laminopathy, Growth Hormone Signaling, Lipodystrophy, Fibrosishttp://www.sciencedirect.com/science/article/pii/S2352345X17301030 |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Raymond Kwan Graham F. Brady Maria Brzozowski Sujith V. Weerasinghe Hope Martin Min-Jung Park Makayla J. Brunt Ram K. Menon Xin Tong Lei Yin Colin L. Stewart M. Bishr Omary |
| spellingShingle |
Raymond Kwan Graham F. Brady Maria Brzozowski Sujith V. Weerasinghe Hope Martin Min-Jung Park Makayla J. Brunt Ram K. Menon Xin Tong Lei Yin Colin L. Stewart M. Bishr Omary Hepatocyte-Specific Deletion of Mouse Lamin A/C Leads to Male-Selective SteatohepatitisSummary Cellular and Molecular Gastroenterology and Hepatology |
| author_facet |
Raymond Kwan Graham F. Brady Maria Brzozowski Sujith V. Weerasinghe Hope Martin Min-Jung Park Makayla J. Brunt Ram K. Menon Xin Tong Lei Yin Colin L. Stewart M. Bishr Omary |
| author_sort |
Raymond Kwan |
| title |
Hepatocyte-Specific Deletion of Mouse Lamin A/C Leads to Male-Selective SteatohepatitisSummary |
| title_short |
Hepatocyte-Specific Deletion of Mouse Lamin A/C Leads to Male-Selective SteatohepatitisSummary |
| title_full |
Hepatocyte-Specific Deletion of Mouse Lamin A/C Leads to Male-Selective SteatohepatitisSummary |
| title_fullStr |
Hepatocyte-Specific Deletion of Mouse Lamin A/C Leads to Male-Selective SteatohepatitisSummary |
| title_full_unstemmed |
Hepatocyte-Specific Deletion of Mouse Lamin A/C Leads to Male-Selective SteatohepatitisSummary |
| title_sort |
hepatocyte-specific deletion of mouse lamin a/c leads to male-selective steatohepatitissummary |
| publisher |
Elsevier |
| series |
Cellular and Molecular Gastroenterology and Hepatology |
| issn |
2352-345X |
| publishDate |
2017-11-01 |
| description |
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 dietâinduced 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 hormoneâmediated Janus kinase 2 (Jak2), signal transducer and activator of transcription 5 (Stat5), and extracellular signalâregulated 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). Keywords: Nonalcoholic Fatty Liver Disease, Laminopathy, Growth Hormone Signaling, Lipodystrophy, Fibrosis |
| url |
http://www.sciencedirect.com/science/article/pii/S2352345X17301030 |
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