Compound K modulates fatty acid-induced lipid droplet formation and expression of proteins involved in lipid metabolism in hepatocytes

Liver International

Volumn 33, Issue 10, 2013, Pages 1583-1593

  Kim, Moon Sun ^a   Lee, Kyoung Tae ^b   Iseli, Tristan J ^a   Hoy, Andrew J ^a   George, Jacob ^a   Grewal, Thomas ^a   Roufogalis, Basil D ^a  

^a UNIVERSITY OF SYDNEY   (Australia)

^b Korea Forest Research Institute   (South Korea)

Author keywords

5' AMP activated protein kinase; Acyl CoA oxidase 1; Compound K; Ginsenoside metabolite; Hepatic steatosis; Lipid droplets; Non alcoholic fatty liver disease; Peroxisome proliferator activated receptor

Indexed keywords

3 [3 TERT BUTYLTHIO 1 (4 CHLOROBENZYL) 5 ISOPROPYL 2 INDOLYL] 2,2 DIMETHYLPROPIONIC ACID; ACYL COENZYME A OXIDASE; COMPOUND K; FAT DROPLET; FATTY ACID; GINSENOSIDE; MITOGEN ACTIVATED PROTEIN KINASE; PERILIPIN; PERILIPIN 2; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; TRIACYLGLYCEROL; UNCLASSIFIED DRUG;

ARTICLE; CONTROLLED STUDY; DRUG EFFICACY; ENZYME ACTIVITY; FATTY LIVER; HUMAN; HUMAN CELL; IMMUNOHISTOCHEMISTRY; LIPID METABOLISM; LIVER CELL; PROMOTER REGION; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; WESTERN BLOTTING;

5′-AMP-ACTIVATED PROTEIN KINASE; ACYL-COA OXIDASE 1; COMPOUND K; GINSENOSIDE METABOLITE; HEPATIC STEATOSIS; LIPID DROPLETS; NON-ALCOHOLIC FATTY LIVER DISEASE; PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-Α;

AMP-ACTIVATED PROTEIN KINASES; ANALYSIS OF VARIANCE; AZO COMPOUNDS; BLOTTING, WESTERN; CELL LINE; FATTY ACIDS; FATTY LIVER; GENE EXPRESSION REGULATION; GINSENOSIDES; HEPATOCYTES; HUMANS; IMMUNOHISTOCHEMISTRY; INDOLES; LIPID METABOLISM; PHOSPHORYLATION; PPAR ALPHA; TRIGLYCERIDES;

EID: 84885190330     PISSN: 14783223     EISSN: 14783231     Source Type: Journal    
DOI: 10.1111/liv.12287     Document Type: Article

References (68)

1. Xie JT, Mehendale SR, Li X, et al. Anti-diabetic effect of ginsenoside Re in ob/ob mice. Biochim Biophys Acta 2005; 1740: 319-25.
2. Zhou YJ, Zheng SZ, Lin JG, Zhang QJ, Chen AP. The interruption of the PDGF and EGF signaling pathways by curcumin stimulates gene expression of PPAR gamma in rat activated hepatic stellate cell in vitro. Lab Invest 2007; 87: 488-98.
3. Bradbury MW, Berk PD. Lipid metabolism in hepatic steatosis. Clin Liver Dis 2004; 8: 639-71, xi.
4. Reddy JK, Rao MS. Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. Am J Physiol Gastrointest Liver Physiol 2006; 290: G852-8.
5. Beller M, Thiel K, Thul PJ, Jackle H. Lipid droplets: a dynamic organelle moves into focus. FEBS Lett 2010; 584: 2176-82.
6. Kusminski C, Shetty S, Orci L, Unger R, Scherer P. Diabetes and apoptosis: lipotoxicity. Apoptosis 2009; 14: 1484-95.
7. Gasbarrini G, Vero V, Miele L, et al. Nonalcoholic fatty liver disease: defining a common problem. Eur Rev Med Pharmacol Sci 2005; 9: 253-9.
8. Bradbury MW. Lipid metabolism and liver inflammation. I. Hepatic fatty acid uptake: possible role in steatosis. Am J Physiol Gastrointest Liver Physiol 2006; 290: G194-8.
9. Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 1999; 20: 649-88.
10. Wahli W. Peroxisome proliferator-activated receptors (PPARs): from metabolic control to epidermal wound healing. Swiss Med Wkly 2002; 132: 83-91.
11. Akbiyik F, Cinar K, Demirpence E, et al. Ligand-induced expression of peroxisome proliferator-activated receptor alpha and activation of fatty acid oxidation enzymes in fatty liver. Eur J Clin Invest 2004; 34: 429-35.
12. Reddy JK, Hashimoto T. Peroxisomal beta-oxidation and peroxisome proliferator-activated receptor alpha: an adaptive metabolic system. Annu Rev Nutr 2001; 21: 193-230.
13. Harano Y, Yasui K, Toyama T, et al. Fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, reduces hepatic steatosis and lipid peroxidation in fatty liver Shionogi mice with hereditary fatty liver. Liver Int 2006; 26: 613-20.
14. Svegliati-Baroni G, Candelaresi C, Saccomanno S, et al. A model of insulin resistance and nonalcoholic steatohepatitis in rats: role of peroxisome proliferator-activated receptor-alpha and n-3 polyunsaturated fatty acid treatment on liver injury. Am J Pathol 2006; 169: 846-60.
15. Sapiro JM, Mashek MT, Greenberg AS, Mashek DG. Hepatic triacylglycerol hydrolysis regulates peroxisome proliferator-activated receptor alpha activity. J Lipid Res 2009; 50: 1621-9.
16. Chawla A, Lee CH, Barak Y, et al. PPARdelta is a very low-density lipoprotein sensor in macrophages. Proc Natl Acad Sci USA 2003; 100: 1268-73.
17. Corsini E, Viviani B, Zancanella O, et al. Induction of adipose differentiation related protein and neutral lipid droplet accumulation in keratinocytes by skin irritants. J Invest Dermatol 2003; 121: 337-44.
18. Steinberg GR, Kemp BE. AMPK in health and disease. Physiol Rev 2009; 89: 1025-78.
19. Hawley SA, Boudeau J, Reid JL, et al. Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol 2003; 2: 28.
20. Shaw RJ, Kosmatka M, Bardeesy N, et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci USA 2004; 101: 3329-35.
21. Woods A, Johnstone S, Dickerson K, et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr Biol 2003; 13: 2004-8.
22. Tan MJ, Ye JM, Turner N, et al. Antidiabetic activities of triterpenoids isolated from bitter melon associated with activation of the AMPK pathway. Chem Biol 2008; 15: 263-73.
23. Turner N, Li JY, Gosby A, et al. Berberine and its more biologically available derivative, dihydroberberine, inhibit mitochondrial respiratory complex I: a mechanism for the action of berberine to activate AMP-activated protein kinase and improve insulin action. Diabetes 2008; 57: 1414-8.
24. Iseli TJ, Turner N, Zeng XY, et al. Activation of AMPK by bitter melon triterpenoids involves CaMKKbeta. PLoS ONE 2013; 8: e62309.
25. Corton JM, Gillespie JG, Hawley SA, Hardie DG. 5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? Eur J Biochem 1995; 229: 558-65.
26. Tomita K, Tamiya G, Ando S, et al. AICAR, an AMPK activator, has protective effects on alcohol-induced fatty liver in rats. Alcohol Clin Exp Res 2005; 29: 240S-5S.
27. Zang M, Zuccollo A, Hou X, et al. AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells. J Biol Chem 2004; 279: 47898-905.
28. Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006; 355: 2297-307.
29. Aithal GP, Thomas JA, Kaye PV, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 2008; 135: 1176-84.
30. Sakamoto J, Kimura H, Moriyama S, et al. Activation of human peroxisome proliferator-activated receptor (PPAR) subtypes by pioglitazone. Biochem Biophys Res Commun 2000; 278: 704-11.
31. Azoulay L, Yin H, Filion KB, et al. The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study. BMJ 2012; 344: e3645.
32. Liu CX, Xiao PG. Recent advances on ginseng research in China. J Ethnopharmacol 1992; 36: 27-38.
33. Attele AS, Zhou YP, Xie JT, et al. Antidiabetic effects of Panax ginseng berry extract and the identification of an effective component. Diabetes 2002; 51: 1851-8.
34. Xu TM, Xin Y, Cui MH, Jiang X, Gu LP. Inhibitory effect of ginsenoside Rg3 combined with cyclophosphamide on growth and angiogenesis of ovarian cancer. Chin Med J 2007; 120: 584-8.
35. Yang ZG, Sun HX, Ye YP. Ginsenoside Rd from Panax notoginseng is cytotoxic towards HeLa cancer cells and induces apoptosis. Chem Biodivers 2006; 3: 187-97.
36. Gillis CN. Panax ginseng pharmacology: a nitric oxide link? Biochem Pharmacol 1997; 54: 1-8.
37. Cho WC, Chung WS, Lee SK, et al. Ginsenoside Re of Panax ginseng possesses significant antioxidant and antihyperlipidemic efficacies in streptozotocin-induced diabetic rats. Eur J Pharmacol 2006; 550: 173-9.
38. Yokozawa T, Kobayashi T, Kawai A, Oura H, Kawashima Y. Hyperlipemia-improving effects of ginsenoside-Rb2 in cholesterol-fed rats. Chem Pharm Bull 1985; 33: 722-9.
39. Zhang XM, Qu SC, Sui DY, Yu XF, Lv ZZ. [Effects of ginsenoside-Rb on blood lipid metabolism and anti-oxidation in hyperlipidemia rats]. Zhongguo Zhong Yao Za Zhi 2004; 29: 1085-8.
40. Trinh HT, Han SJ, Kim SW, Lee YC, Kim DH. Bifidus fermentation increases hypolipidemic and hypoglycemic effects of red ginseng. J Microbiol Biotechnol 2007; 17: 1127-33.
41. Hasegawa H, Benno Y. Anticarcinogenesis in mice by ginseng hydrolyzing colonic bacteria. Microb Ecol Health Dis 2000; 12: 85-91.
42. Hasegawa H, Sung JH, Matsumiya S, Uchiyama M. Main ginseng saponin metabolites formed by intestinal bacteria. Planta Med 1996; 62: 453-7.
43. Bae EA, Choo MK, Park EK, et al. Metabolism of ginsenoside R(c) by human intestinal bacteria and its related antiallergic activity. Biol Pharm Bull 2002; 25: 743-7.
44. Kim A, Kang K, Zhang R, et al. Ginseng saponin metabolite induces apoptosis in MCF-7 breast cancer cells through the modulation of AMP-activated protein kinase. Environ Toxicol Pharmacol 2010; 30: 134-40.
45. Wakabayashi C, Murakami K, Hasegawa H, Murata J, Saiki I. An intestinal bacterial metabolite of ginseng protopanaxadiol saponins has the ability to induce apoptosis in tumor cells. Biochem Biophys Res Commun 1998; 246: 725-30.
46. Lee SJ, Sung JH, Lee S, Moon CK, Lee BH. Antitumor activity of a novel ginseng saponin metabolite in human pulmonary adenocarcinoma cells resistant to cisplatin. Cancer Lett 1999; 144: 39-43.
47. Lee SJ, Ko WG, Kim JH, et al. Induction of apoptosis by a novel intestinal metabolite of ginseng saponin via cytochrome c-mediated activation of caspase-3 protease. Biochem Pharmacol 2000; 60: 677-85.
48. Choi Y, Han G, Han E, et al. Effects of compound K on insulin secretion and carbohydrate metabolism. J Ginseng Res 2007; 31: 79-85.
49. Lee ES, Choi JS, Kim MS, et al. Ginsenoside metabolite compound K differentially antagonizing tumor necrosis factor-alpha-induced monocyte-endothelial trafficking. Chem Biol Interact 2011; 194: 13-22.
50. Li W, Zhang M, Gu J, et al. Hypoglycemic effect of protopanaxadiol-type ginsenosides and compound K on Type 2 diabetes mice induced by high-fat diet combining with streptozotocin via suppression of hepatic gluconeogenesis. Fitoterapia 2012; 83: 192-8.
51. Han GC, Ko SK, Sung JH, Chung SH. Compound K enhances insulin secretion with beneficial metabolic effects in db/db mice. J Agric Food Chem 2007; 55: 10641-8.
52. Park D, Yoon M. Compound K, a novel ginsenoside metabolite, inhibits adipocyte differentiation in 3T3-L1 cells: involvement of angiogenesis and MMPs. Biochem Biophys Res Commun 2012; 422: 263-7.
53. Hasegawa H. Proof of the mysterious efficacy of ginseng: basic and clinical trials: metabolic activation of ginsenoside: deglycosylation by intestinal bacteria and esterification with fatty acid. J Pharmacol Sci 2004; 95: 153-7.
54. Green H, Kehinde O. An established preadipose cell line and its differentiation in culture. II. Factors affecting the adipose conversion. Cell 1975; 5: 19-27.
55. Listenberger LL, Brown DA. Fluorescent detection of lipid droplets and associated proteins. Curr Protoc Cell Biol 2007; 24: 24.2.
56. Fujimoto Y, Onoduka J, Homma KJ, et al. Long-chain fatty acids induce lipid droplet formation in a cultured human hepatocyte in a manner dependent of Acyl-CoA synthetase. Biol Pharm Bull 2006; 29: 2174-80.
57. Liangpunsakul S, Wou SE, Wineinger KD, et al. Effects of WY-14, 643 on the phosphorylation and activation of AMP-dependent protein kinase. Arch Biochem Biophys 2009; 485: 10-5.
58. Hardie DG. AMP-activated protein kinase: a master switch in glucose and lipid metabolism. Rev Endocr Metab Disord 2004; 5: 119-25.
59. Woodyatt NJ, Lambe KG, Myers KA, Tugwood JD, Roberts RA. The peroxisome proliferator (PP) response element upstream of the human acyl CoA oxidase gene is inactive among a sample human population: significance for species differences in response to PPs. Carcinogenesis 1999; 20: 369-72.
60. Au AY, Mcbride C, Wilhelm KG Jr, et al. PAX8-peroxisome proliferator-activated receptor gamma (PPARgamma) disrupts normal PAX8 or PPARgamma transcriptional function and stimulates follicular thyroid cell growth. Endocrinology 2006; 147: 367-76.
61. Kehrer JP, Biswal SS, La E, et al. Inhibition of peroxisome-proliferator-activated receptor (PPAR)alpha by MK886. Biochem J 2001; 356(Pt. 3): 899-906.
62. Kim DY, Yuan HD, Chung IK, Chung SH. Compound K, intestinal metabolite of ginsenoside, attenuates hepatic lipid accumulation via AMPK activation in human hepatoma cells. J Agric Food Che 2009; 57: 1532-7.
63. Chanda D, Lee CH, Kim YH, et al. Fenofibrate differentially regulates plasminogen activator inhibitor-1 gene expression via adenosine monophosphate-activated protein kinase-dependent induction of orphan nuclear receptor small heterodimer partner. Hepatology 2009; 50: 880-92.
64. Lee SK, Lee JO, Kim JH, et al. Coenzyme Q10 increases the fatty acid oxidation through AMPK-mediated PPARalpha induction in 3T3-L1 preadipocytes. Cell Signal 2012; 24: 2329-36.
65. Bumpus NN, Johnson EF. 5-Aminoimidazole-4-carboxyamide-ribonucleoside (AICAR)-stimulated hepatic expression of Cyp4a10, Cyp4a14, Cyp4a31, and other peroxisome proliferator-activated receptor alpha-responsive mouse genes is AICAR 5'-monophosphate-dependent and AMP-activated protein kinase-independent. J Pharmacol Exp Ther 2011; 339: 886-95.
66. Listenberger LL, Ostermeyer-Fay AG, Goldberg EB, Brown WJ, Brown DA. Adipocyte differentiation-related protein reduces the lipid droplet association of adipose triglyceride lipase and slows triacylglycerol turnover. J Lipid Res 2007; 48: 2751-61.
67. Lee HU, Bae EA, Han MJ, Kim NJ, Kim DH. Hepatoprotective effect of ginsenoside Rb1 and compound K on tert-butyl hydroperoxide-induced liver injury. Liver Int 2005; 25: 1069-73.
68. Yang C, Ko S, Cho B, et al. Compound K (CK) rich fractions from Korean Red Ginseng inhibit toll-like receptor (TLR) 4 or TLR9-mediated mitogen-activated protein kinase activation and pro-inflammatory responses in murine macrophages. J Ginseng Res 2007; 31: 181-90.