nach oben

European Journal of Nutrition

Erschienen in:

01.10.2015 | Original Contribution

Understanding the cholesterol metabolism-perturbing effects of docosahexaenoic acid by gas chromatography–mass spectrometry targeted metabonomic profiling

verfasst von: Priti Bahety, Thi Hai Van Nguyen, Yanjun Hong, Luqi Zhang, Eric Chun Yong Chan, Pui Lai Rachel Ee

Erschienen in: European Journal of Nutrition | Ausgabe 1/2017

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Over the past few decades, docosahexaenoic acid (DHA) has gained special attention for management of cholesterol-associated metabolic disorders and neurodegenerative diseases such as Alzheimer’s disease (AD) owing to its neuroprotective, anti-inflammatory and hypolipidemic properties. Several epidemiological studies have reported the effect of DHA in reducing the risk of developing AD by lowering cholesterol. Hypercholesterolemia is a pro-amyloidogenic factor influencing the enzymatic processing of amyloid-β precursor protein (AβPP) to toxic β-amyloid. However, the mechanism by which DHA modulates the cholesterol pathway has not been established. Thus, the objective of this study was to investigate the mechanism of regulation of cholesterol metabolism by DHA in an AβPP₆₉₅ overexpressing AD cell model.

Methods

A gas chromatography/mass spectrometry method was developed and validated for the targeted profiling of 11 cholesterol metabolites in DHA-treated Chinese hamster ovary wild-type (CHO-wt) and AβPP₆₉₅ overexpressing (CHO-AβPP₆₉₅) cells. The differential metabolite profiles between DHA- and vehicle-treated groups were further analyzed using fold change values of the ratio of concentration of metabolites in CHO-AβPP₆₉₅ to CHO-wt cells. Effect of DHA on key rate-limiting enzymatic activities within the cholesterol pathway was established using biochemical assays.

Results

Our results showed that DHA reduced the levels of key cholesterol anabolites and catabolites in CHO-AβPP₆₉₅ cells as compared to CHO-wt cells. Further enzymatic studies revealed that the cholesterol-lowering effect of DHA was mediated by regulating HMG-CoA reductase and squalene epoxidase enzyme activities.

Conclusion

We demonstrate for the first time the dual effects of DHA in inhibiting HMG-CoA reductase and squalene epoxidase and modulating the sterol biosynthesis axis of the cholesterol pathway in AβPP₆₉₅ overexpressing AD. Our novel findings underscore the potential of DHA as a multi-target hypocholesterolemic agent for the prophylaxis of AD and other cholesterol-associated diseases.

Nur mit Berechtigung zugänglich

Muskiet FAJ, van Goor SA, Kuipers RS, Velzing-Aarts FV, Smit EN, Bouwstra H, Janneke Dijck-Brouwer DA, Rudy Boersma E, Hadders-Algra M (2006) Long-chain polyunsaturated fatty acids in maternal and infant nutrition. Prostaglandins Leukot Essent Fatty Acids 75(3):135–144CrossRef

Bazan NG, Molina MF, Gordon WC (2011) Docosahexaenoic acid signalolipidomics in nutrition: significance in aging, neuroinflammation, macular degeneration, Alzheimer’s, and other neurodegenerative diseases. Annu Rev Nutr 31:321–351CrossRef

Jacobson TA, Glickstein SB, Rowe JD, Soni PN (2012) Effects of eicosapentaenoic acid and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids: a review. J Clin Lipidol 6(1):5–18CrossRef

Holub BJ (2009) Docosahexaenoic acid (DHA) and cardiovascular disease risk factors. Prostaglandins Leukot Essent Fatty Acids 81(2–3):199–204CrossRef

Morris M, Evans DA, Bienias JL et al (2003) Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol 60(7):940–946CrossRef

Farooqui AA, Ong WY, Horrocks LA, Chen P, Farooqui T (2007) Comparison of biochemical effects of statins and fish oil in brain: the battle of the titans. Brain Res Rev 56(2):443–471CrossRef

Sparks DL, Scheff SW, Hunsaker JC III, Liu H, Landers T, Gross DR (1994) Induction of Alzheimer-like β-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol. Exp Neurol 126(1):88–94CrossRef

Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261(5123):921–923CrossRef

Notkola IL, Sulkava R, Pekkanen J, Erkinjuntti T, Ehnholm C, Kivinen P, Tuomilehto J, Nissinen A (1998) Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer’s disease. Neuroepidemiology 17(1):14–20CrossRef

10.

Kivipelto M, Helkala E-L, Laakso MP, Hänninen T, Hallikainen M, Alhainen K, Soininen H, Tuomilehto J, Nissinen A (2001) Midlife vascular risk factors and Alzheimer’s disease in later life: longitudinal, population based study. Br Med J 322(7300):1447–1451. doi:10.1136/bmj.322.7300.1447 CrossRef

11.

Barrett PJ, Song Y, Horn WDV, Hustedt EJ, Schafer JM, Hadziselimovic A, Beel AJ, Sanders CR (2012) The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol. Science 336(6085):1168–1171CrossRef

12.

Silva T, Teixeira J, Remiao F, Borges F (2013) Alzheimer’s disease, cholesterol, and statins: the junctions of important metabolic pathways. Angew Chem Int Ed Engl 52(4):1110–1121CrossRef

13.

Lutjohann D, Papassotiropoulos A, Bjorkhem I, Locatelli S, Bagli M, Oehring RD, Schlegel U, Jessen F, Rao ML, von Bergmann K, Heun R (2000) Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients. J Lipid Res 41(2):195–198

14.

Schonknecht P, Lutjohann D, Pantel J, Bardenheuer H, Hartmann T, von Bergmann K, Beyreuther K, Schroder J (2002) Cerebrospinal fluid 24S-hydroxycholesterol is increased in patients with Alzheimer’s disease compared to healthy controls. Neurosci Lett 324(1):83–85CrossRef

15.

Grimm MO, Kuchenbecker J, Grosgen S, Burg VK, Hundsdorfer B, Rothhaar TL, Friess P, de Wilde MC, Broersen LM, Penke B, Peter M, Vigh L, Grimm HS, Hartmann T (2011) Docosahexaenoic acid reduces amyloid β production via multiple pleiotropic mechanisms. J Biol Chem 286(16):14028–14039CrossRef

16.

Nicholson JK, Lindon JC, Holmes E (1999) ‘Metabonomics’: understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica 29(11):1181–1189CrossRef

17.

Greenberg N, Grassano A, Thambisetty M, Lovestone S, Legido-Quigley C (2009) A proposed metabolic strategy for monitoring disease progression in Alzheimer’s disease. Electrophoresis 30(7):1235–1239CrossRef

18.

Motsinger-Reif A, Zhu H, Kling M, Matson W, Sharma S, Fiehn O, Reif D, Appleby D, Doraiswamy PM, Trojanowski J, Kaddurah-Daouk R, Arnold S (2013) Comparing metabolomic and pathologic biomarkers alone and in combination for discriminating Alzheimer’s disease from normal cognitive aging. Acta Neuropathol Commun 1(1):28CrossRef

19.

Oresic M, Hyotylainen T, Herukka SK, Sysi-Aho M, Mattila I, Seppanan-Laakso T, Julkunen V, Gopalacharyulu PV, Hallikainen M, Koikkalainen J, Kivipelto M, Helisalmi S, Lotjonen J, Soininen H (2011) Metabolome in progression to Alzheimer’s disease. Trans Psychiatry 1:e57CrossRef

20.

Li NJ, Liu WT, Li W, Li SQ, Chen XH, Bi KS, He P (2010) Plasma metabolic profiling of Alzheimer’s disease by liquid chromatography/mass spectrometry. Clin Biochem 43(12):992–997CrossRef

21.

Bahety P, Tan YM, Hong Y, Zhang L, Chan ECY, Ee P-LR (2014) Metabotyping of docosahexaenoic acid-treated Alzheimer’s disease cell model. PLoS One 9(2):e90123CrossRef

22.

Chang TY, Hasan MT, Chin J, Chang CC, Spillane DM, Chen J (1997) Chinese hamster ovary cell mutants affecting cholesterol metabolism. Curr Opin Lipidol 8(2):65–71CrossRef

23.

Christian AE, Haynes MP, Phillips MC, Rothblat GH (1997) Use of cyclodextrins for manipulating cellular cholesterol content. J Lipid Res 38(11):2264–2272

24.

Lagace TA, Byers DM, Cook HW, Ridgway ND (1997) Altered regulation of cholesterol and cholesteryl ester synthesis in Chinese-hamster ovary cells overexpressing the oxysterol-binding protein is dependent on the pleckstrin homology domain. Biochem J 326(Pt 1):205–213CrossRef

25.

Leonard S, Sinensky M (1988) Somatic cell genetics and the study of cholesterol metabolism. Biochim Biophys Acta 947(1):101–112CrossRef

26.

Cadigan KM, Spillane DM, Chang TY (1990) Isolation and characterization of Chinese hamster ovary cell mutants defective in intracellular low density lipoprotein–cholesterol trafficking. J Cell Biol 110(2):295–308. doi:10.1083/jcb.110.2.295 CrossRef

27.

Li S, Deng J, Hou H, Tian J, Giunta B, Wang Y, Sawmiller D, Smith A, Sanberg PR, Obregon D, Mori T, Tan J (2014) Specific antibody binding to the APP672-699 region shifts APP processing from [α]- to [β]-cleavage. Cell Death Dis 5:e1374CrossRef

28.

Ma QH, Futagawa T, Yang WL, Jiang XD, Zeng L, Takeda Y, Xu RX, Bagnard D, Schachner M, Furley AJ, Karagogeos D, Watanabe K, Dawe GS, Xiao ZC (2008) A TAG1-APP signalling pathway through Fe65 negatively modulates neurogenesis. Nat Cell Biol 10(3):283–294CrossRef

29.

Urano Y, Ochiai S, Noguchi N (2013) Suppression of amyloid-β production by 24S-hydroxycholesterol via inhibition of intracellular amyloid precursor protein trafficking. FASEB J 27(10):4305–4315CrossRef

30.

Huttunen HJ, Peach C, Bhattacharyya R, Barren C, Pettingell W, Hutter-Paier B, Windisch M, Berezovska O, Kovacs DM (2009) Inhibition of acyl-coenzyme A: cholesterol acyl transferase modulates amyloid precursor protein trafficking in the early secretory pathway. FASEB J 23(11):3819–3828CrossRef

31.

Acimovic J, Lovgren-Sandblom A, Monostory K, Rozman D, Golicnik M, Lutjohann D, Bjorkhem I (2009) Combined gas chromatographic/mass spectrometric analysis of cholesterol precursors and plant sterols in cultured cells. J Chromatogr B Anal Technol Biomed Life Sci 877(22):2081–2086CrossRef

32.

Axelson M, Larsson O (1996) 27-hydroxylated low density lipoprotein (LDL) cholesterol can be converted to 7α,27-dihydroxy-4-cholesten-3-one (cytosterone) before suppressing cholesterol production in normal human fibroblasts. Evidence that an altered metabolism of LDL cholesterol can underlie a defective feedback control in malignant cells. J Biol Chem 271(22):12724–12736CrossRef

33.

Le Fur Y, Maume G, Feuillat M, Maume BF (1999) Characterization by gas chromatography/mass spectrometry of sterols in Saccharomyces cerevisiae during autolysis. J Agric Food Chem 47(7):2860–2864CrossRef

34.

Wolf C, Chevy F, Pham J, Kolf-Clauw M, Citadelle D, Mulliez N, Roux C (1996) Changes in serum sterols of rats treated with 7-dehydrocholesterol-delta 7-reductase inhibitors: comparison to levels in humans with Smith–Lemli–Opitz syndrome. J Lipid Res 37(6):1325–1333

35.

Grimm MOW, Zimmer VC, Lehmann J, Grimm HS, Hartmann T (2013) The impact of cholesterol, DHA, and sphingolipids on Alzheimer’s disease. BioMed Res Int 2013:814390CrossRef

36.

Hooff GP, Wood WG, Müller WE, Eckert GP (2010) Isoprenoids, small GTPases and Alzheimer’s disease. Biochim Biophys Acta 1801(8):896–905. doi:10.1016/j.bbalip.2010.03.014 CrossRef

37.

Zhou Y, Su Y, Li B, Liu F, Ryder JW, Wu X, Gonzalez-DeWhitt PA, Gelfanova V, Hale JE, May PC, Paul SM, Ni B (2003) Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Aβ42 by inhibiting Rho. Science 302(5648):1215–1217CrossRef

38.

Wood WG, Schroeder F, Igbavboa U, Avdulov NA, Chochina SV (2002) Brain membrane cholesterol domains, aging and amyloid β-peptides. Neurobiol Aging 23(5):685–694CrossRef

39.

Serrano-Pozo A, Vega GL, Lütjohann D, Locascio JJ, Tennis MK, Deng A, Atri A, Hyman BT, Irizarry MC, Growdon JH (2010) Effects of simvastatin on cholesterol metabolism and Alzheimer disease biomarkers. Alzheimer Dis Assoc Disord 24(3):220–226

40.

Lindenthal B, Bertsch T, Fassbender K, Stroick M, Khl S, Ltjohann D, von Bergmann K (2002) Influence of simvastatin, pravastatin, and BM 15.766 on neutral sterols in liver and testis of guinea pigs. Metabolism 51(4):492–499CrossRef

41.

Kempen HJ, Glatz JF, Gevers Leuven JA, van der Voort HA, Katan MB (1988) Serum lathosterol concentration is an indicator of whole-body cholesterol synthesis in humans. J Lipid Res 29(9):1149–1155

42.

Xu L, Korade Z, Rosado DA Jr, Mirnics K, Porter NA (2013) Metabolism of oxysterols derived from nonenzymatic oxidation of 7-dehydrocholesterol in cells. J Lipid Res 54(4):1135–1143CrossRef

43.

Herman GE (2003) Disorders of cholesterol biosynthesis: prototypic metabolic malformation syndromes. Hum Mol Genet 12(suppl 1):R75–R88. doi:10.1093/hmg/ddg072 CrossRef

44.

Shafaati M, Marutle A, Pettersson H, Lovgren-Sandblom A, Olin M, Pikuleva I, Winblad B, Nordberg A, Bjorkhem I (2011) Marked accumulation of 27-hydroxycholesterol in the brains of Alzheimer’s patients with the Swedish APP 670/671 mutation. J Lipid Res 52(5):1004–1010CrossRef

45.

Prasanthi J, Huls A, Thomasson S, Thompson A, Schommer E, Ghribi O (2009) Differential effects of 24-hydroxycholesterol and 27-hydroxycholesterol on β-amyloid precursor protein levels and processing in human neuroblastoma SH-SY5Y cells. Mol Neurodegener 4(1):1CrossRef

46.

Karanth S, Tran VM, Kuberan B, Schlegel A (2013) Polyunsaturated fatty acyl-coenzyme As are inhibitors of cholesterol biosynthesis in zebrafish and mice. Dis Model Mech 6(6):1365–1377CrossRef

47.

Gelsomino G, Corsetto PA, Campia I, Montorfano G, Kopecka J, Castella B, Gazzano E, Ghigo D, Rizzo AM, Riganti C (2013) Omega 3 fatty acids chemosensitize multidrug resistant colon cancer cells by down-regulating cholesterol synthesis and altering detergent resistant membranes composition. Mol Cancer 12:137. doi:10.1186/1476-4598-12-137 CrossRef

48.

Schwenk RW, Holloway GP, Luiken JJFP, Bonen A, Glatz JFC (2010) Fatty acid transport across the cell membrane: regulation by fatty acid transporters. Prostaglandins Leukot Essent Fatty Acids (PLEFA) 82(4–6):149–154. doi:10.1016/j.plefa.2010.02.029 CrossRef

49.

Dutta-Roy AK (2000) Cellular uptake of long-chain fatty acids: role of membrane-associated fatty-acid-binding/transport proteins. CMLS Cell Mol Life Sci 57(10):1360–1372. doi:10.1007/pl00000621 CrossRef

Titel: Understanding the cholesterol metabolism-perturbing effects of docosahexaenoic acid by gas chromatography–mass spectrometry targeted metabonomic profiling
verfasst von: Priti Bahety
Thi Hai Van Nguyen
Yanjun Hong
Luqi Zhang
Eric Chun Yong Chan
Pui Lai Rachel Ee
Publikationsdatum: 01.10.2015
Verlag: Springer Berlin Heidelberg
Erschienen in: European Journal of Nutrition / Ausgabe 1/2017
Print ISSN: 1436-6207
Elektronische ISSN: 1436-6215
DOI: https://doi.org/10.1007/s00394-015-1053-4

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

24.04.2024 | DGIM 2024 | Kongressbericht | Nachrichten

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Understanding the cholesterol metabolism-perturbing effects of docosahexaenoic acid by gas chromatography–mass spectrometry targeted metabonomic profiling

Abstract

Purpose

Methods

Results

Conclusion

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Metformin rückt in den Hintergrund

Myokarditis nach Infekt – richtig schwierig wird es bei Profisportlern

Thrombophiliescreening – Wenn, dann richtig und nur bei therapeutischer Konsequenz

Bei Senioren mit Prostatakarzinom auf Anämie achten!

Update Innere Medizin

Springer Medizin

Abstract

Purpose

Methods

Results

Conclusion

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 1/2017

Higher plasma quercetin levels following oral administration of an onion skin extract compared with pure quercetin dihydrate in humans

Inhibition of pancreatic cancer cell migration by plasma anthocyanins isolated from healthy volunteers receiving an anthocyanin-rich berry juice

Quantitative analysis of absorption, metabolism, and excretion of benzoxazinoids in humans after the consumption of high- and low-benzoxazinoid diets with similar contents of cereal dietary fibres: a crossover study

Urine color as an indicator of urine concentration in pregnant and lactating women

Adherence to the DASH diet in relation to psychological profile of Iranian adults

Gender differences in plasma and urine metabolites from Sprague–Dawley rats after oral administration of normal and high doses of hydroxytyrosol, hydroxytyrosol acetate, and DOPAC

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Metformin rückt in den Hintergrund

Myokarditis nach Infekt – richtig schwierig wird es bei Profisportlern

Thrombophiliescreening – Wenn, dann richtig und nur bei therapeutischer Konsequenz

Bei Senioren mit Prostatakarzinom auf Anämie achten!

Update Innere Medizin