Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
European Journal of Nutrition
Published in: European Journal of Nutrition 1/2017

01-02-2017 | Original Contribution

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

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

Published in: European Journal of Nutrition | Issue 1/2017

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
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
2.
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
3.
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
4.
Holub BJ (2009) Docosahexaenoic acid (DHA) and cardiovascular disease risk factors. Prostaglandins Leukot Essent Fatty Acids 81(2–3):199–204CrossRef
5.
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
6.
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
7.
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
8.
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
9.
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.
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.
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
Metadata
Title
Understanding the cholesterol metabolism-perturbing effects of docosahexaenoic acid by gas chromatography–mass spectrometry targeted metabonomic profiling
Authors
Priti Bahety
Thi Hai Van Nguyen
Yanjun Hong
Luqi Zhang
Eric Chun Yong Chan
Pui Lai Rachel Ee
Publication date
01-02-2017
Publisher
Springer Berlin Heidelberg
Published in
European Journal of Nutrition / Issue 1/2017
Print ISSN: 1436-6207
Electronic ISSN: 1436-6215
DOI
https://doi.org/10.1007/s00394-015-1053-4

Other articles of this Issue 1/2017

European Journal of Nutrition 1/2017 Go to the issue

Letter to the Editor

Are Belgian toddlers over-eating?

Original Contribution

Effect of virgin olive oil and thyme phenolic compounds on blood lipid profile: implications of human gut microbiota

Original Contribution

Body mass index cut-points to identify cardiometabolic risk in black South Africans

Original Contribution

Association between body weight and composition and plasma 25-hydroxyvitamin D level in the Diabetes Prevention Program

Review

Acute effects of caffeine-containing energy drinks on physical performance: a systematic review and meta-analysis

Original Contribution

Adherence to the DASH diet in relation to psychological profile of Iranian adults
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits