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Eicosapentaenoic Acid-Enriched Phosphatidylcholine Attenuated Hepatic Steatosis Through Regulation of Cholesterol Metabolism in Rats with Nonalcoholic Fatty Liver Disease

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Lipids

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Disturbed cholesterol metabolism plays a crucial role in the development of NAFLD. The present study was conducted to evaluate the effects of EPA-PC extracted from sea cucumber on liver steatosis and cholesterol metabolism in NAFLD. Male Wistar rats were randomly divided into seven groups (normal control group, model group, lovastatin group, low- and high-dose EPA groups, and low- and high-dose EPA-PC groups). Model rats were established by administering a diet containing 1% orotic acid. To determine the possible cholesterol metabolism promoting mechanism of EPA-PC, we analyzed the transcription of key genes and transcriptional factors involved in hepatic cholesterol metabolism. EPA-PC dramatically alleviated hepatic lipid accumulation, reduced the serum TC concentration, and elevated HDLC levels in NAFLD rats. Fecal neutral cholesterol excretion was also promoted by EPA-PC administration. Additionally, EPA-PC decreased the mRNA expression of hydroxymethyl glutaric acid acyl (HMGR) and cholesterol 7α-hydroxylase (CYP7A), and increased the transcription of sterol carrying protein 2 (SCP2). Moreover, EPA-PC stimulated the transcription of peroxisome proliferators-activated receptor α (PPARα) and adenosine monophosphate activated protein kinase (AMPK) as well as its modulators, liver kinase B1 (LKB1) and Ca2+/calmodulin-dependent kinase kinase (CAMKK). Based on the results, the promoting effects of EPA-PC on NAFLD may be partly associated with the suppression of cholesterol synthesis via HMGR inhibition and the enhancement of fecal cholesterol excretion through increased SCP2 transcription. The underlying mechanism may involve stimulation of PPARα and AMPK.

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Abbreviations

AMPK:

Adenosine monophosphate activated protein kinase

CAMKK:

Ca2+/calmodulin-dependent kinase kinase

CYP7A:

Cholesterol 7α-hydroxylase

HMGR:

Hydroxymethyl glutaric acid acyl CoA reductase,

LKB1:

Liver kinase B1

NAFLD:

Nonalcoholic fatty liver disease

PPARα:

Peroxisome proliferators-activated receptor α

SCP2:

Sterol carrying protein 2

TC:

Total cholesterol

HDLC:

High-density lipoprotein cholesterol

TG:

Triacylglycerol

PC:

Phosphatidylcholine

EPA-PC:

Eicosapentaenoic acid-enriched phosphatidylcholine

EPA:

Eicosapentaenoic acid

NASH:

Nonalcoholic steatohepatitis

OA:

Orotic acid

References

  1. Nomura K, Yamanouchi T (2012) The role of fructose-enriched diets in mechanisms of nonalcoholic fatty liver disease. J Nutr Biochem 23:203–208

    Article  CAS  PubMed  Google Scholar 

  2. Krawczyk M, Bonfrate L, Portincasa P (2010) Nonalcoholic fatty liver disease. Best Pract Res Clin Gastroenterol 24:695–708

    Article  CAS  PubMed  Google Scholar 

  3. Musso G, Gambino R, Cassader M (2013) Cholesterol metabolism and the pathogenesis of non-alcoholic steatohepatitis. Prog Lipid Res 52:175–191

    Article  CAS  PubMed  Google Scholar 

  4. DeFilippis AP, Blaha MJ, Martin SS (2013) Nonalcoholic fatty liver disease and serum lipoproteins: the multi-ethnic study of atherosclerosis. Atherosclerosis 227:429–436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Targher G, Day CP, Bonora E (2010) Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 363:1341–1350

    Article  CAS  PubMed  Google Scholar 

  6. Hamaguchi M, Kojima T, Takeda N, Nagata C, Takeda J, Sarui H, Yoshikawa T (2007) Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease. World J Gastroenterol 13:1579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Targher G, Bertolini L, Rodella S, Tessari R, Zenari L, Lippi G, Arcaro G (2007) Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients. Diabetes Care 30:2119–2121

    Article  CAS  PubMed  Google Scholar 

  8. Xu J, Wang YM, Feng TY, Zhang B, Sugawara T, Xue CH (2010) Isolation and anti-fatty liver activity of a novel cerebroside from the sea cucumber Acaudina molpadioides. Biosci Biotech Biochem 75:1466–1471

    Article  Google Scholar 

  9. Liu YJ, Xu H, Xu J, Guo YL, Xue Y, Wang JF, Xue CH (2015) Vanadium-binding protein from vanadium-enriched sea cucumber Apostichopus japonicus inhibits adipocyte differentiation through activating wnt/β-catenin pathway. J Funct Foods 17:504–513

    Article  Google Scholar 

  10. Yu L, Ge L, Xue C, Chang Y, Zhang C, Xu X, Wang Y (2014) Structural study of fucoidan from sea cucumber Acaudina molpadioides: a fucoidan containing novel tetrafucose repeating unit. Food Chem 142:197–200

    Article  CAS  PubMed  Google Scholar 

  11. Lou QM, Wang YM, Liu XF, Xue CH (2012) Lipid profile and fatty acid compositions in body wall of Apostichopus japonicus (Selenka). J Food Biochem 36:317–321

    Article  CAS  Google Scholar 

  12. Du ZY, Ma T, Liaset B, Keenan AH, Araujo P, Lock EJ, Madsen L (2013) Dietary eicosapentaenoic acid supplementation accentuates hepatic triglyceride accumulation in mice with impaired fatty acid oxidation capacity. BBA-Mol Cell Biol L 1831:291–299

    CAS  Google Scholar 

  13. Jung UJ, Millman PN, Tall AR, Deckelbaum RJ (2011) n-3 Fatty acids ameliorate hepatic steatosis and dysfunction after LXR agonist ingestion in mice. BBA-Mol Cell Biol L 1811:491–497

    CAS  Google Scholar 

  14. Loguercio C, Andreone P, Brisc C, Brisc MC, Bugianesi E, Chiaramonte M, Federico A (2012) Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: a randomized controlled trial. Free Radic Bio Med 52:1658–1665

    Article  CAS  Google Scholar 

  15. Liu X, Xue Y, Liu C, Lou Q, Wang J, Yanagita T, Wang Y (2013) Eicosapentaenoic acid-enriched phospholipid ameliorates insulin resistance and lipid metabolism in diet-induced-obese mice. Lipids Health Dis 12:109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hu S, Xu L, Shi D, Wang J, Wang Y, Lou Q, Xue C (2013) Eicosapentaenoic acid-enriched phosphatidylcholine isolated from Cucumaria frondosa exhibits anti-hyperglycemic effects via activating phosphoinositide 3-kinase/protein kinase B signal pathway. J Biosci Bioeng 117:457–463

    Article  PubMed  Google Scholar 

  17. Folch J, Lees M, Sloane-Stanley GH (1957) A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 226:497–509

    CAS  PubMed  Google Scholar 

  18. Hossain Z, Kurihara H, Hosokawa M, Takahashi K (2006) Docosahexaenoic acid and eicosapentaenoic acid-enriched phosphatidylcholine liposomes enhance the permeability, transportation and uptake of phospholipids in Caco-2 cells. Mol Cell Biochem 285:155–163

    Article  CAS  PubMed  Google Scholar 

  19. Wang YM, Hu XQ, Xue Y, Li ZJ, Yanagita T, Xue CH (2011) Study on possible mechanism of orotic acid–induced fatty liver in rats. Nutr 27:571–575

    Article  Google Scholar 

  20. Lorbek G, Rozman D (2012) Cholesterol and inflammation at the crossroads of non-alcoholic fatty liver disease (NAFLD) and atherogenesis. Atherogenesis 13:281–304

    Google Scholar 

  21. Lorbek G, Lewinska M, Rozman D (2012) Cytochrome P450 s in the synthesis of cholesterol and bile acids–from mouse models to human diseases. FEBS J 279:1516–1533

    Article  CAS  PubMed  Google Scholar 

  22. Christians U, Jacobsen W, Floren LC (1998) Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in transplant patients: are the statins mechanistically similar? Pharmacol Ther 80:1–34

    Article  CAS  PubMed  Google Scholar 

  23. Caballero F, Fernández A, De Lacy AM, Fernández-Checa JC, Caballería J, García-Ruiz C (2009) Enhanced free cholesterol, SREBP-2 and StAR expression in human NASH. J Hepatol 50:789–796

    Article  CAS  PubMed  Google Scholar 

  24. Min HK, Kapoor A, Fuchs M, Mirshahi F, Zhou H, Maher J, Kellum J, Warnick R, Contos MJ, Sanyal AJ (2012) Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease. Cell Metab 15:665–674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sun F, Xie ML, Xue J, Wang HB (2010) Osthol regulates hepatic PPARα-mediated lipogenic gene expression in alcoholic fatty liver murine. Phytomedicine 17:669–673

    Article  CAS  PubMed  Google Scholar 

  26. Wang ZQ, Zhang XH, Yu Y, Tipton RC, Raskin I, Ribnicky D, Johnson W, Cefalu WT (2013) Artemisia scoparia extract attenuates non-alcoholic fatty liver disease in diet-induced obesity mice by enhancing hepatic insulin and AMPK signaling independently of FGF21 pathway. Metabol 62:1239–1249

    Article  CAS  Google Scholar 

  27. Xu Q, Xue C, Zhang Y, Liu Y, Wang J, Yu X, Zhang X, Zhang R, Yang X, Guo C (2013) Medium-chain fatty acids enhanced the excretion of fecal cholesterol and cholic acid in C57BL/6J mice fed a cholesterol-rich diet. Biosci Biotechnol Biochem 77:1390–1396

    Article  CAS  PubMed  Google Scholar 

  28. Hunt MC, Yang YZ, Eggertsen G, Carneheim CM, Gåfvels M, Einarsson C, Alexson SE (2000) The peroxisome proliferator-activated receptor α (PPARα) regulates bile acid biosynthesis. J Biol Chem 275:28947–28953

    Article  CAS  PubMed  Google Scholar 

  29. Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B (2009) Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 89:147–191

    Article  CAS  PubMed  Google Scholar 

  30. Gilardi F, Mitro N, Godio C, Scotti E, Caruso D, Crestani M, De Fabiani E (2007) The pharmacological exploitation of cholesterol 7α-hydroxylase, the key enzyme in bile acid synthesis: from binding resins to chromatin remodelling to reduce plasma cholesterol. Pharmacol Ther 116:449–472

    Article  CAS  PubMed  Google Scholar 

  31. Baker DM, Wang SL, Bell DJ, Drevon CA, Davis RA (2000) One or more labile proteins regulate the stability of chimeric mRNAs containing the 3′-untranslated region of cholesterol-7α-hydroxylase mRNA. J Biol Chem 275:19985–19991

    Article  CAS  PubMed  Google Scholar 

  32. Agellon L, Cheema S (1997) The 3′-untranslated region of the mouse cholesterol 7α-hydroxylase mRNA contains elements responsive to post-transcriptional regulation by bile acids. Biochem J 328:393–399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Seedorf U, Ellinghaus P, Roch NJ (2000) Sterol carrier protein-2. BBA-Mol Cell Biol L 1486:45–54

    CAS  Google Scholar 

  34. Moncecchi D, Murphy EJ, Schroeder DRP (1996) Sterol carrier protein-2 expression in mouse l-cell fibroblasts alters cholesterol uptake. Biochim Biophys Acta 1302:110–116

    Article  PubMed  Google Scholar 

  35. Murphy EJ, Schroeder F (1997) Sterol carrier protein-2 mediated cholesterol esterification in transfected l-cell fibroblasts. Biochim Biophys Acta 1345:283–292

    Article  CAS  PubMed  Google Scholar 

  36. Schroeder F, Atshaves BP, McIntosh AL, Gallegos AM, Storey SM, Parr RD, Jefferson JR, Ball JM, Kier AB (2007) Sterol carrier protein-2: new roles in regulating lipid rafts and signaling. BBA Mol Cell Biol L 1771:700–718

    CAS  Google Scholar 

  37. Fullerton MD, Steinberg GR, Schertzer JD (2013) Immunometabolism of AMPK in insulin resistance and atherosclerosis. Mol Cell Endocrinol 366:224–234

    Article  CAS  PubMed  Google Scholar 

  38. Witczak CA, Sharoff CG, Goodyear LJ (2008) AMP-activated protein kinase in skeletal muscle: from structure and localization to its role as a master regulator of cellular metabolism. Cell Mol Life Sci 65:3737–3755

    Article  CAS  PubMed  Google Scholar 

  39. Oakhill JS, Scott JW, Kemp BE (2012) AMPK functions as an adenylate charge-regulated protein kinase. Trends Endocrinol Metab 23:125–132

    Article  CAS  PubMed  Google Scholar 

  40. Burg JS, Espenshade PJ (2011) Regulation of HMG-CoA reductase in mammals and yeast. Prog Lipid Res 50:403–410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hsu WH, Chen TH, Lee BH, Hsu YW, Pan TM (2014) Monascin and ankaflavin act as natural AMPK activators with PPARα agonist activity to down-regulate nonalcoholic steatohepatitis in high-fat diet-fed C57BL/6 mice. Food Chem Toxicol 64:94–103

    Article  CAS  PubMed  Google Scholar 

  42. Chen WL, Chen YL, Chiang YM, Wang SG, Lee HM (2012) Fenofibrate lowers lipid accumulation in myotubes by modulating the PPARα/AMPK/Foxo1/ATGL pathway. Biochem Pharmacol 84:522–531

    Article  CAS  PubMed  Google Scholar 

  43. West AL, Burdge GC, Calder PC (2016) Lipid structure does not modify incorporation of EPA and DHA into blood lipids in healthy adults: a randomised-controlled trial. Br J Nutr 116(5):1–10

    Article  Google Scholar 

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Acknowledgements

We acknowledged support from the National Natural Science Foundation of China (No. 31330060), Science and Technology Development Plan of Shandong Province (No. 2012CX80201), National Science & Technology Pillar Program during the 12th Five-year Plan Period (No. 2012BAD33B07). We gratefully acknowledge the College of Food Science and Engineering, Ocean University of China for financial support. We greatly appreciate suggestions from the anonymous referees for the improvement of this article.

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Authors and Affiliations

  1. College of Food Science and Engineering, Ocean University of China, 5 Yushan Road, Qingdao, 266003, Shandong Province, China

    Yanjun Liu, Di Shi, Yingying Tian, Qiping Zhan, Jie Xu, Jingfeng Wang & Changhu Xue

  2. Shandong Oriental Ocean Sci-tech Co., Ltd., Yantai, 264003, Shandong Province, China

    Yuntao Liu

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  1. Yanjun Liu
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Liu, Y., Shi, D., Tian, Y. et al. Eicosapentaenoic Acid-Enriched Phosphatidylcholine Attenuated Hepatic Steatosis Through Regulation of Cholesterol Metabolism in Rats with Nonalcoholic Fatty Liver Disease. Lipids 52, 119–127 (2017). https://doi.org/10.1007/s11745-016-4222-1

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