Display options
Cite
Kwan R, Brady GF, Brzozowski M, et al. Hepatocyte-Specific Deletion of Mouse Lamin A/C Leads to Male-Selective Steatohepatitis. Cell Mol Gastroenterol Hepatol. 2017;4(3):365-383doi: 10.1016/j.jcmgh.2017.06.005.
Kwan, R., Brady, G. F., Brzozowski, M., Weerasinghe, S. V., Martin, H., Park, M. J., Brunt, M. J., Menon, R. K., Tong, X., Yin, L., Stewart, C. L., & Omary, M. B. (2017). Hepatocyte-Specific Deletion of Mouse Lamin A/C Leads to Male-Selective Steatohepatitis. Cellular and molecular gastroenterology and hepatology, 4(3), 365-383. https://doi.org/10.1016/j.jcmgh.2017.06.005
Kwan, Raymond, et al. "Hepatocyte-Specific Deletion of Mouse Lamin A/C Leads to Male-Selective Steatohepatitis." Cellular and molecular gastroenterology and hepatology vol. 4,3 (2017): 365-383. doi: https://doi.org/10.1016/j.jcmgh.2017.06.005
Kwan R, Brady GF, Brzozowski M, Weerasinghe SV, Martin H, Park MJ, Brunt MJ, Menon RK, Tong X, Yin L, Stewart CL, Omary MB. Hepatocyte-Specific Deletion of Mouse Lamin A/C Leads to Male-Selective Steatohepatitis. Cell Mol Gastroenterol Hepatol. 2017 Jul 06;4(3):365-383. doi: 10.1016/j.jcmgh.2017.06.005. eCollection 2017 Nov. PMID: 28913408; PMCID: PMC5582719.
Copy Download .nbib Format: NLM
Share it on

Cell Mol Gastroenterol Hepatol. 2017 Jul 06;4(3):365-383. doi: 10.1016/j.jcmgh.2017.06.005. eCollection 2017 Nov.

Hepatocyte-Specific Deletion of Mouse Lamin A/C Leads to Male-Selective Steatohepatitis.

Cellular and molecular gastroenterology and hepatology

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

Affiliations

  1. Department of Molecular and Integrative Physiology.
  2. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
  3. Development and Regenerative Biology Group, Institute of Medical Biology, Immunos, Singapore.

PMID: 28913408 PMCID: PMC5582719 DOI: 10.1016/j.jcmgh.2017.06.005

Abstract

BACKGROUND & AIMS: Lamins are nuclear intermediate filament proteins that comprise the major components of the nuclear lamina. Mutations in

METHODS: To address these questions, we generated mice carrying a hepatocyte-specific deletion of

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

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: % liver weight, liver percentage of body mass; Erk, extracellular signal–regulated kinase; FPLD2, Dunnigan familial partial lipodystrophy; Fibrosis; GH, growth hormone; Growth Hormone Signaling; HFD, high-fat diet; Het, heterozygous; Igf1, insulin-like growth factor 1; Jak2, Janus kinase 2; KO, knockout; Laminopathy; Lipodystrophy; NAFLD, nonalcoholic fatty liver disease; ND, normal diet; Nonalcoholic Fatty Liver Disease; PBS, phosphate-buffered saline; Stat, signal transducer and activator of transcription; WT, wild type; qPCR, quantitative polymerase chain reaction

References

  1. J Biol Chem. 2009 Jul 24;284(30):19937-44 - PubMed
  2. Biochem Biophys Res Commun. 2002 Mar 1;291(3):522-7 - PubMed
  3. Hepatology. 2007 Aug;46(2):504-13 - PubMed
  4. Nat Rev Immunol. 2014 Jan;14(1):36-49 - PubMed
  5. Trends Genet. 2012 Sep;28(9):464-71 - PubMed
  6. J Cell Biol. 2015 Jan 5;208(1):33-52 - PubMed
  7. Clin Endocrinol (Oxf). 2017 May;86(5):698-707 - PubMed
  8. Gut. 2011 Oct;60(10):1394-402 - PubMed
  9. J Cell Sci. 2013 Jul 15;126(Pt 14):3105-12 - PubMed
  10. Development. 1989 Feb;105(2):365-78 - PubMed
  11. Nat Genet. 2000 Feb;24(2):153-6 - PubMed
  12. Ann N Y Acad Sci. 2011 Jul;1229:29-37 - PubMed
  13. J Lipid Res. 2016 Apr;57(4):616-30 - PubMed
  14. Endocrinology. 2007 May;148(5):1977-86 - PubMed
  15. Methods. 2001 Dec;25(4):402-8 - PubMed
  16. Am J Gastroenterol. 2005 Oct;100(10):2218-24 - PubMed
  17. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6868-72 - PubMed
  18. J Clin Invest. 1998 Jul 1;102(1):153-64 - PubMed
  19. Am J Gastroenterol. 2013 Aug;108(8):1299-304 - PubMed
  20. Mol Pharmacol. 1995 Nov;48(5):790-7 - PubMed
  21. Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7239-44 - PubMed
  22. J Biol Chem. 2002 Nov 22;277(47):45592-603 - PubMed
  23. Hepatology. 2005 Jun;41(6):1313-21 - PubMed
  24. Curr Top Dev Biol. 2014;109:1-52 - PubMed
  25. Mol Endocrinol. 2010 Jan;24(1):204-17 - PubMed
  26. Gastroenterology. 2016 Jun;150(8):1728-1744.e7 - PubMed
  27. J Biol Chem. 2006 Jan 13;281(2):982-92 - PubMed
  28. Diabetes. 2000 Nov;49(11):1958-62 - PubMed
  29. J Lipid Res. 2009 Jun;50(6):1068-79 - PubMed
  30. J Cell Biol. 1999 Nov 29;147(5):913-20 - PubMed
  31. J Cell Sci. 1990 Apr;95 ( Pt 4):587-98 - PubMed
  32. J Biol Chem. 2012 Mar 23;287(13):10277-88 - PubMed
  33. J Biol Chem. 1999 Jan 1;274(1):305-15 - PubMed
  34. Hepatology. 2010 Sep;52(3):934-44 - PubMed
  35. Semin Cell Dev Biol. 2014 May;29:148-57 - PubMed
  36. Hepatology. 2012 Jul;56(1):95-107 - PubMed
  37. Hepatology. 2004 Dec;40(6):1387-95 - PubMed
  38. Circulation. 2011 Jan 4;123(1):53-61 - PubMed
  39. Nat Rev Immunol. 2015 Feb;15(2):87-103 - PubMed
  40. Mol Cell Biol. 1992 Aug;12(8):3499-506 - PubMed
  41. Am J Physiol Endocrinol Metab. 2002 Nov;283(5):E1008-15 - PubMed
  42. J Clin Invest. 2007 May;117(5):1282-93 - PubMed
  43. Genomics. 1995 May 20;27(2):230-6 - PubMed
  44. Am J Hum Genet. 2000 Apr;66(4):1192-8 - PubMed
  45. Annu Rev Biochem. 2015;84:131-64 - PubMed
  46. Cell. 2013 Jan 31;152(3):584-98 - PubMed
  47. Trends Cardiovasc Med. 2010 Oct;20(7):217-21 - PubMed
  48. Exp Cell Res. 2007 Jun 10;313(10):2121-33 - PubMed
  49. Gastroenterology. 2016 Jun;150(8):1778-85 - PubMed
  50. J Endocrinol. 1991 Dec;131(3):395-9 - PubMed
  51. Differentiation. 2015 Jan-Feb;89(1-2):11-21 - PubMed
  52. J Clin Invest. 2011 Apr;121(4):1412-23 - PubMed
  53. J Biol Chem. 1993 Aug 5;268(22):16321-6 - PubMed
  54. Diabetes. 2007 Dec;56(12):2863-71 - PubMed
  55. Endocrinology. 2016 Feb;157(2):570-85 - PubMed
  56. Endocr Rev. 2009 Apr;30(2):152-77 - PubMed
  57. Curr Opin Cell Biol. 2015 Feb;32:7-12 - PubMed
  58. Gastroenterology. 2008 Apr;134(4):1169-79 - PubMed
  59. Mol Endocrinol. 2006 Jun;20(6):1333-51 - PubMed
  60. Nat Immunol. 2004 Nov;5(11):1181-9 - PubMed
  61. Cell. 1987 Nov 6;51(3):383-92 - PubMed
  62. N Engl J Med. 2004 Mar 18;350(12):1220-34 - PubMed
  63. J Cell Sci. 2014 Apr 1;127(Pt 7):1464-75 - PubMed
  64. Diabetes. 2014 Jul;63(7):2284-96 - PubMed
  65. Endocrinology. 2011 Jan;152(1):181-92 - PubMed
  66. Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7833-8 - PubMed
  67. Biostatistics. 2003 Apr;4(2):249-64 - PubMed

Publication Types

Grant support