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Lakshman MR, Reyes-Gordillo K, Varatharajalu R, et al. Novel modulators of hepatosteatosis, inflammation and fibrogenesis. Hepatol Int. 2014;8:413-20doi: 10.1007/s12072-014-9526-8.
Lakshman, M. R., Reyes-Gordillo, K., Varatharajalu, R., Arellanes-Robledo, J., Leckey, L. C., Garige, M., & Shah, R. (2014). Novel modulators of hepatosteatosis, inflammation and fibrogenesis. Hepatology international, 8413-20. https://doi.org/10.1007/s12072-014-9526-8
Lakshman, M Raj, et al. "Novel modulators of hepatosteatosis, inflammation and fibrogenesis." Hepatology international vol. 8 (2014): 413-20. doi: https://doi.org/10.1007/s12072-014-9526-8
Lakshman MR, Reyes-Gordillo K, Varatharajalu R, Arellanes-Robledo J, Leckey LC, Garige M, Shah R. Novel modulators of hepatosteatosis, inflammation and fibrogenesis. Hepatol Int. 2014 Sep;8:413-20. doi: 10.1007/s12072-014-9526-8. Epub 2014 Mar 26. PMID: 26201319.
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Hepatol Int. 2014 Sep;8:413-20. doi: 10.1007/s12072-014-9526-8. Epub 2014 Mar 26.

Novel modulators of hepatosteatosis, inflammation and fibrogenesis.

Hepatology international

M Raj Lakshman, Karina Reyes-Gordillo, Ravi Varatharajalu, Jaime Arellanes-Robledo, Leslie C Leckey, Mamatha Garige, Ruchi Shah

Affiliations

  1. Lipid Research Laboratory, VA Medical Center, 50 Irving Street, NW, Washington, DC, USA. [email protected].
  2. Department of Biochemistry & Molecular Medicine, The George Washington University, Washington, DC, USA. [email protected].
  3. Lipid Research Laboratory, VA Medical Center, 50 Irving Street, NW, Washington, DC, USA.
  4. Department of Biochemistry & Molecular Medicine, The George Washington University, Washington, DC, USA.

PMID: 26201319 DOI: 10.1007/s12072-014-9526-8

Abstract

Alcoholic steatosis, instead of being innocuous, plays a critical role in liver inflammation and fibrogenesis. The severity of fatty liver is governed by the concerted balance between lipid transport, synthesis, and degradation. Whereas scavenger receptor class B, type I (SR-B1) is critical for reverse cholesterol uptake by the liver, peroxisome proliferator-activated receptor-gamma (PPARγ) coactivator-1α and -β (PGC1α and PGC1β) are critical for lipid degradation and synthesis, respectively. Because betaine is a lipotropic agent, we have evaluated its effects on alcoholic steatosis. Betaine effectively prevented chronic alcohol-mediated (i) impaired SR-B1 glycosylation, plasma membrane localization, and consequent impaired cholesterol transport; and (ii) up regulation of PGC-1β, sterol regulatory element-binding protein 1c and downstream lipogenic genes with concomitant increased liver cholesterol, triglycerides and hepatic lipid score. Similarly, because of its anti-inflammatory and anti-fibrotic effects in other organs, we evaluated the protective effects of thymosin β4 (Tβ4) against carbon tetrachloride (CCl4)-induced hepatotoxicity in rat. Tβ4 prevented CCl4-induced (i) necrosis, inflammatory infiltration and up-regulation of α1(2)collagen, alpha-smooth muscle actin (α-SMA), platelet derived growth factor beta (PDGF-β) receptor and fibronectin mRNA expression; (ii) down-regulation of adipogenic gene, PPARγ and the up-regulation of epigenetic repressor gene, methyl CpG binding protein 2 (MeCP2) mRNA levels, suggesting that the anti-fibrogenic actions of Tβ4 involve the prevention of trans-differentiation of quiescent hepatic stellate cells into myo-fibroblasts largely by up-regulating PPARγ and by down-regulating MeCP2 genes. We therefore conclude that betaine and Tβ4 can effectively protect against alcoholic hepatosteatosis and hepatic fibrogenesis, respectively.

Keywords: Alcoholic liver injury; Betaine; Fatty liver; Fibrogenic genes; Fibrosis; Steatosis; Thymosin beta 4

References

  1. Biochemistry. 1998 Dec 22;37(51):17843-50 - PubMed
  2. Curr Opin Lipidol. 2009 Apr;20(2):98-105 - PubMed
  3. Eur Heart J. 1998 Feb;19 Suppl A:A31-5 - PubMed
  4. Arch Ophthalmol. 2010 May;128(5):636-8 - PubMed
  5. Biochim Biophys Acta. 2007 Jun;1770(6):989-96 - PubMed
  6. Nature. 2007 Jan 11;445(7124):177-82 - PubMed
  7. Cell Death Differ. 2007 Feb;14 (2):275-85 - PubMed
  8. Metabolism. 2007 Jul;56(7):947-53 - PubMed
  9. J Lipid Res. 2004 Nov;45(11):2088-95 - PubMed
  10. Alcohol Clin Exp Res. 1997 Sep;21(6):1100-2 - PubMed
  11. Mech Ageing Dev. 2004 Feb;125(2):113-5 - PubMed
  12. Am J Pathol. 2011 May;178(5):2100-8 - PubMed
  13. Nature. 2004 Nov 25;432(7016):466-72 - PubMed
  14. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2007 Jul-Sep;25(3):185-209 - PubMed
  15. Ann N Y Acad Sci. 2010 Apr;1194:118-24 - PubMed
  16. J Nutr. 2008 Mar;138(3):497-501 - PubMed
  17. Ann N Y Acad Sci. 2007 Sep;1112:458-65 - PubMed
  18. Science. 1996 Jan 26;271(5248):518-20 - PubMed
  19. J Pharmacol Sci. 2010;112(1):105-12 - PubMed
  20. J Clin Invest. 1977 Sep;60(3):546-54 - PubMed
  21. J Lipid Res. 2001 Nov;42(11):1717-26 - PubMed
  22. Arch Toxicol. 2009 Jun;83(6):519-48 - PubMed
  23. Proc Natl Acad Sci U S A. 1983 Sep;80(17):5435-9 - PubMed
  24. Circ Res. 2002 Feb 22;90(3):270-6 - PubMed
  25. Adv Drug Deliv Rev. 2009 Jul 2;61(7-8):497-512 - PubMed
  26. J Biol Chem. 2005 Feb 11;280(6):4959-67 - PubMed
  27. Hum Mutat. 1992;1(6):445-66 - PubMed
  28. MedGenMed. 2002 Jul 15;4(3):27 - PubMed
  29. Ann N Y Acad Sci. 2000 May;902:103-11; discussion 111-2 - PubMed
  30. Pharmacol Ther. 1989;43(1):139-54 - PubMed
  31. J Clin Invest. 2002 May;109(9):1125-31 - PubMed
  32. Ann N Y Acad Sci. 2010 Apr;1194:190-8 - PubMed
  33. Alcohol Clin Exp Res. 1989 Aug;13(4):554-9 - PubMed
  34. J Hepatol. 1999 Jan;30(1):77-87 - PubMed
  35. Ann N Y Acad Sci. 2007 Sep;1112:154-60 - PubMed
  36. Hepatol Res. 2011 Jul;41(7):675-82 - PubMed
  37. J Biol Chem. 2005 Apr 22;280(16):16456-60 - PubMed
  38. Alcohol. 2004 Aug;34(1):45-8 - PubMed
  39. Ann N Y Acad Sci. 2012 Oct;1269:61-8 - PubMed
  40. J Biol Chem. 1999 Jan 22;274(4):2366-71 - PubMed
  41. Biochem Biophys Res Commun. 2008 May 23;370(1):44-8 - PubMed
  42. J Clin Invest. 2005 Oct;115(10):2699-701 - PubMed
  43. Therap Adv Gastroenterol. 2011 Nov;4(6):391-417 - PubMed
  44. Am J Physiol Endocrinol Metab. 2008 Jul;295(1):E10-6 - PubMed
  45. Trends Mol Med. 2005 Sep;11(9):421-9 - PubMed
  46. Annu Rev Pathol. 2011;6:425-56 - PubMed

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