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Curcumin Recovers Intracellular Lipid Droplet Formation Through Increasing Perilipin 5 Gene Expression in Activated Hepatic Stellate Cells In Vitro

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Summary

The activation of hepatic stellate cells (HSCs) is a major event during hepatic fibrogenesis. Restoration of intracellular lipid droplet (LD) formation turns the activated HSC back to a quiescent state. Our previous studies have shown that curcumin suppresses HSC activation through increasing peroxisome proliferator-activated receptor, gamma (PPARγ) and 5′ adenosine monophosphate-activated protein kinase (AMPK) activities. This study aims at evaluating the effect of curcumin on lipid accumulation in HSCs and hepatocytes, and further elucidating the underlying mechanisms. Now we showed that curcumin increased LD formation in activated HSCs and stimulated the expression of sterol regulatory element-binding protein and fatty acid synthase, and reduced the expression of adipose triglyceride lipase. Exogenous perilin5 expression in primary HSCs promoted LD formation. Perilipin 5 siRNA eliminated curcumin-induced LD formation in HSCs. These results suggest that curcumin recovers LD formation and lipid accumulation in activated HSCs by increasing perilipin 5 gene expression. Furthermore, inhibition of AMPK or PPARγ activity blocked curcumin’s effect on Plin5 gene expression and LD formation. Our results provide a novel evidence in vitro for curcumin as a safe, effective candidate to treat liver fibrosis.

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References

  1. Dobie R, Henderson NC. Homing in on the hepatic scar: recent advances in cell-specific targeting of liver fibrosis. F1000Res, 2016,5(1):F1000 Faculty Rev-1749

    PubMed  PubMed Central  Google Scholar 

  2. Iwaisako K, Brenner DA, Kisseleva T. What’s new in liver fibrosis? The origin of myofibroblasts in liver fibrosis. J Gastroenterol Hepatol, 2012,27(Suppl 2):65–68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Joshi K, Kohli A, Manch R, et al. Alcoholic Liver Disease: High Risk or Low Risk for Developing Hepatocellular Carcinoma? Clin Liver Dis, 2016,20(3):563–580

    Article  PubMed  Google Scholar 

  4. Trautwein C, Friedman SL, Schuppan D, et al. Hepatic fibrosis: concept to treatment. J Hepatol, 2015,62(1 Suppl):S15–24

    Article  CAS  PubMed  Google Scholar 

  5. Pinzani M. Pathophysiology of non-alcoholic steatohepatitis and basis for treatment. Dig Dis, 2015,29(2):243–248

    Article  Google Scholar 

  6. Wells RG. Liver fibrosis: challenges of the new era. Gastroenterology, 2009,136(2):387–388

    Article  PubMed  Google Scholar 

  7. Lee YA, Wallace MC, Friedman SL. Pathobiology of liver fibrosis: a translational success story. Gut, 2015,64(5):830–841

    Article  CAS  PubMed  Google Scholar 

  8. Friedman SL, Sheppard D, Duffield JS, et al. Therapy for fibrotic diseases: nearing the starting line. Sci Transl Med, 2013,5(167):167sr1

    Article  PubMed  CAS  Google Scholar 

  9. Puche JE, Saiman Y, Friedman SL. Hepatic stellate cells and liver fibrosis. Compr Physiol, 2013,3(4):1473–1492

    Article  PubMed  Google Scholar 

  10. Sauvant P, Cansell M, Atgié C. Vitamin A and lipid metabolism: relationship between hepatic stellate cells (HSCs) and adipocytes. J Physiol Biochem, 2011,67(3):487–496

    Article  CAS  PubMed  Google Scholar 

  11. Friedman SL, Rockey DC, McGuire RF, et al. Isolated hepatic lipocytes and Kupffer cells from normal human liver: morphological and functional characteristics in primary culture. Hepatology, 1992,15(2):234–243

    Article  CAS  PubMed  Google Scholar 

  12. El Taghdouini A, Najimi M, Sancho-Bru P, et al. In vitro reversion of activated primary human hepatic stellate cells. Fibrogenesis Tissue Repair, 2015,8(8):14

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Chen A, Tang Y, Davis V, et al. Liver fatty acid binding protein (L-Fabp) modulates murine stellate cell activation and diet-induced nonalcoholic fatty liver disease. Hepatology, 2013,57(6):2202–2212

    Article  CAS  PubMed  Google Scholar 

  14. Park S, Choi S, Lee MG, et al. Retinol binding proteinalbumin domain III fusion protein deactivates hepatic stellate cells. Mol Cells, 2012,34(6):517–522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chang WJ, Song LJ, Yi T, et al. Early activated hepatic stellate cell-derived molecules reverse acute hepatic injury. World J Gastroenterol, 2015,21(14):4184–4194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lin J, Zheng S, Chen A. Curcumin attenuates the effects of insulin on stimulating hepatic stellate cell activation by interrupting insulin signaling and attenuating oxidative stress. Lab Invest, 2009,89(12):1397–1409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bartneck M, Warzecha KT, Tag CG, et al. Isolation and time lapse microscopy of highly pure hepatic stellate cells. Anal Cell Pathol (Amst), 2015,2015(6):417023

    Google Scholar 

  18. Gao Q, Goodman JM. The lipid droplet-a well-connected organelle. Front Cell Dev Biol, 2015,3(8):49

    PubMed  PubMed Central  Google Scholar 

  19. Hashemi HF, Goodman JM. The life cycle of lipid droplets. Curr Opin Cell Biol, 2015,33(4):119–124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lu X, Gruia-Gray J, Copeland NG, et al. The murine perilipin gene: the lipid droplet-associated perilipins derive from tissue-specific, mRNA splice variants and define a gene family of ancient origin. Mamm Genome, 2001,12(9):741–749

    Article  CAS  PubMed  Google Scholar 

  21. Miura S, Gan JW, Brzostowski J, et al. Functional conservation for lipid storage droplet association among Perilipin, ADRP, and TIP47 (PAT)-related proteins in mammals, Drosophila, and, Dictyostelium. J Biol Chem, 2002,277(35):32253–32257

    Article  CAS  PubMed  Google Scholar 

  22. Sztalryd C, Kimmel AR. Perilipins: lipid droplet coat proteins adapted for tissue-specific energy storage and utilization, and lipid cytoprotection. Biochimie, 2014,96(1):96–101

    Article  CAS  PubMed  Google Scholar 

  23. Wang H, Sztalryd C. Oxidative tissue: perilipin 5 links storage with the furnace. Trends Endocrinol Metab, 2011,22(6):197–203

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Li Z, Thiel K, Thul PJ, et al. Lipid droplets control the maternal histone supply of Drosophila embryos. Curr Biol, 2012,22(22):2104–2113

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Anand P, Cermelli S, Li Z, et al. A novel role for lipid droplets in the organismal antibacterial response. Elife, 2012,1(11):e00003

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Saka HA, Valdivia R. Emerging roles for lipid droplets in immunity and host-pathogen interactions. Annu Rev Cell Dev Biol, 2012,28(5):411–437

    Article  CAS  PubMed  Google Scholar 

  27. Ikura Y, Caldwell SH. Lipid droplet-associated proteins in alcoholic liver disease: a potential linkage with hepatocellular damage. Int J Clin Exp Pathol, 2015,8(8):8699–8708

    PubMed  PubMed Central  Google Scholar 

  28. Langhi C, Marquart TJ, Allen RM, et al. Perilipin-5 is regulated by statins and controls triglyceride contents in the hepatocyte. J Hepatol, 2014,61(2):358–365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mason RR, Mokhtar R, Matzaris M, et al. PLIN5 deletion remodels intracellular lipid composition and causes insulin resistance in muscle. Mol Metab, 2014,3(6):652–663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lin J, Chen A. Perilipin 5 restores the formation of lipid droplets in activated hepatic stellate cells and inhibits their activation. Lab Invest, 2016,96(7):791–806

    Article  CAS  PubMed  Google Scholar 

  31. Pulido-Moran M, Moreno-Fernandez J, Ramirez-Tortosa C, et al. Curcumin and health. Molecules, 2016,21(3):264

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Fu Y, Zheng S, Lin J, et al. Curcumin protects the rat liver from CCl4-caused injury and fibrogenesis by attenuating oxidative stress and suppressing inflammation. Mol Pharmacol, 2008,73(2):399–409

    Article  CAS  PubMed  Google Scholar 

  33. El Swefy S, Hasan RA, Ibrahim A, et al. Curcumin and hemopressin treatment attenuates cholestasis-induced liver fibrosis in rats: role of CB1 receptors. Naunyn Schmiedebergs Arch Pharmacol, 2016,389(1):103–116

    Article  CAS  PubMed  Google Scholar 

  34. Kim J, Jeong SW, Quan H, et al. Effect of curcumin (Curcuma longa extract) on LPS-induced acute lung injury is mediated by the activation of AMPK. J Anesth, 2016,30(1):100–108

    Article  PubMed  Google Scholar 

  35. Shehzad A, Lee YS. Molecular mechanisms of curcumin action: signal transduction. Biofactors, 2013,39(1):27–36

    Article  CAS  PubMed  Google Scholar 

  36. Bengmark S. Curcumin, an atoxic antioxidant and natural NFkappaB, cyclooxygenase-2, lipooxygenase, and inducible nitric oxide synthase inhibitor: a shield against acute and chronic diseases. JPEN J Parenter Enteral Nutr, 2006,30(1):45–51

    Article  CAS  PubMed  Google Scholar 

  37. Kawanishi S, Oikawa S, Murata M. Evaluation for safety of antioxidant chemopreventive agents. Antioxid Redox Signal, 2005,7(11–12):1728–1739

    Article  CAS  PubMed  Google Scholar 

  38. Tang Y, Chen A. Curcumin prevents leptin raising glucose levels in hepatic stellate cells by blocking translocation of glucose transporter-4 and increasing glucokinase. Br J Pharmacol, 2010,161(50):1137–1149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Nguyen P, Leray V, Diez M, et al. Liver lipid metabolism. J Anim Physiol Anim Nutr (Berl), 2008,92(3):272–283

    Article  CAS  Google Scholar 

  40. Ress C, Kaser S. Mechanisms of intrahepatic triglyceride accumulation. World J Gastroenterol, 2016,22(4):1664–1673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shirakami Y, Lee SA, Clugston RD, et al. Hepatic metabolism of retinoids and disease associations. Biochim Biophys Acta, 2012,1821(1):124–136

    Article  CAS  PubMed  Google Scholar 

  42. Povero D, Feldstein AE. Novel Molecular Mechanisms in the Development of Non-Alcoholic Steatohepatitis. Diabetes Metab J, 2016,40(1):1–11

    Article  PubMed  PubMed Central  Google Scholar 

  43. Rangwala SM, Lazar MA. Transcriptional control of adipogenesis. Annu Rev Nutr, 2000,20(1):535–559

    Article  CAS  PubMed  Google Scholar 

  44. Wang Y, Viscarra J, Kim SJ, et al. Transcriptional Regulation of Hepatic Lipogenesis. Nat Rev Mol Cell Biol, 2015,16(11):678–689

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. She H, Xiong S, Hazra S, et al. Adipogenic transcriptional regulation of hepatic stellate cells. J Biol Chem, 2005,280(6):4959–4967

    Article  CAS  PubMed  Google Scholar 

  46. Walther TC, Farese RV Jr. Lipid droplets and cellular lipid metabolism. Annu Rev Biochem, 2012,81(4):687–714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wang H, Sreenevasan U, Hu H, et al. Perilipin 5, a lipid droplet-associated protein, provides physical and metabolic linkage to mitochondria. J Lipid Res, 2011,52(12):2159–2168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Granneman JG, Moore HP, Mottillo EP, et al. Interactions of perilipin-5 (Plin5) with adipose triglyceride lipase. J Biol Chem, 2011,286(7):5126–5135

    Article  CAS  PubMed  Google Scholar 

  49. Boeszoermenyi A, Nagy HM, Arthanari H, et al. Structure of a CGI-58 motif provides the molecular basis of lipid droplet anchoring. J Biol Chem, 2015,290(44):26361–26372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Mason RR, Watt MJ. Unraveling the roles of PLIN5: linking cell biology to physiology. Trends Endocrinol Metab, 2015,26(3):144–152

    Article  CAS  PubMed  Google Scholar 

  51. Jeon SM. Regulation and function of AMPK in physiology and diseases. Exp Mol Med, 2016,48(7):e245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lee HS, Shin HS, Choi J, et al. AMP-activated protein kinase activator, HL156A reduces thioacetamide-induced liver fibrosis in mice and inhibits the activation of cultured hepatic stellate cells and macrophages. Int J Oncol, 2016,49(4):1407–1414

    Article  CAS  PubMed  Google Scholar 

  53. Corton JM, Gillespie JG, Hawley SA, et al. 5-Aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? Eur J Biochem, 1995,229(2):558–565

    Article  CAS  PubMed  Google Scholar 

  54. Joo MS, Kim WD, Lee KY, et al. AMPK Facilitates Nuclear Accumulation of Nrf2 by Phosphorylating at Serine 550. Mol Cell Biol, 2016,36(14):1931–1942

    Article  PubMed  PubMed Central  Google Scholar 

  55. Mazidi M, Karimi E, Meydani M, et al. Potential effects of curcumin on peroxisome proliferator-activated receptor-γ in vitro and in vivo. World J Methodol, 2016,6(1):112–117

    Article  PubMed  PubMed Central  Google Scholar 

  56. Zhai X, Qiao H, Guan W, et al. Curcumin regulates peroxisome proliferator-activated receptor-γ coactivator-1α expression by AMPK pathway in hepatic stellate cells in vitro. Eur J Pharmacol, 2015,746(1):56–62

    Article  CAS  PubMed  Google Scholar 

  57. Mölzer C, Wallner M, Kern C, et al. Features of an altered AMPK metabolic pathway in Gilbert’s Syndrome, and its role in metabolic health. Sci Rep, 2016,6(7):30051

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Guven C, Taskin E, Akcakaya H. Melatonin Prevents Mitochondrial Damage Induced by Doxorubicin in Mouse Fibroblasts Through Ampk-Ppar Gamma-Dependent Mechanisms. Med Sci Monit, 2016,22(2):438–446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Santha S, Viswakarma N, Das S, et al. Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-Troglitazone-induced Apoptosis in Prostate Cancer Cells InvolveAMP-activated Protein Kinase. J Biol Chem, 2015,290(36):21865–21875

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kim JC. The effect of exercise training combined with PPARα agonist on skeletal muscle glucose uptake and insulin sensitivity in induced diabetic obese Zucker rats. J Exerc Nutrition Biochem, 2016,20(2):42–50

    Article  PubMed  PubMed Central  Google Scholar 

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Correspondence to Jian-guo Lin.

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Conflict of Interest Statement

The authors declare that there is no conflict of interest with any financial organization or corporation or individual that can inappropriately influence this work.

This study was supported by the National Natural Science Foundation of China (No. 81760356) to Dr. Xiao-qun HAN and Talent Initial Funding (No. YY2017-002) sponsored by Guangdong Second Provincial General Hospital to Jian-guo LIN, and sponsored by Medical Scientific and Technological Research Program of Guangdong Province (No. C2019056) to Jian-guo LIN.

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Han, Xq., Xu, Sq. & Lin, Jg. Curcumin Recovers Intracellular Lipid Droplet Formation Through Increasing Perilipin 5 Gene Expression in Activated Hepatic Stellate Cells In Vitro. CURR MED SCI 39, 766–777 (2019). https://doi.org/10.1007/s11596-019-2104-5

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