Skip to main content
  • More from ADA
    • Diabetes
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care
  • Subscribe
  • Log in
  • My Cart
  • Follow ada on Twitter
  • RSS
  • Visit ada on Facebook
Diabetes Care

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • Special Article Collections
    • ADA Standards of Medical Care
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • Special Article Collections
    • ADA Standards of Medical Care
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Journal Policies
    • Instructions for Authors
    • ADA Peer Review
  • More from ADA
    • Diabetes
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in
  • My Cart

Search

  • Advanced search
Diabetes Care
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • Special Article Collections
    • ADA Standards of Medical Care
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • Special Article Collections
    • ADA Standards of Medical Care
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Journal Policies
    • Instructions for Authors
    • ADA Peer Review
Emerging Treatments and Technologies

Purified Eicosapentaenoic Acid Reduces Small Dense LDL, Remnant Lipoprotein Particles, and C-Reactive Protein in Metabolic Syndrome

  1. Noriko Satoh, MD, PHD1,
  2. Akira Shimatsu, MD, PHD1,
  3. Kazuhiko Kotani, MD, PHD1,
  4. Naoki Sakane, MD, PHD1,
  5. Kazunori Yamada, MD, PHD2,
  6. Takayoshi Suganami, MD, PHD3,
  7. Hideshi Kuzuya, MD, PHD2 and
  8. Yoshihiro Ogawa, MD, PHD34
  1. 1Clinical Research Institute for Endocrine Metabolic Diseases, National Hospital Organization, Kyoto Medical Center, Kyoto, Japan
  2. 2Diabetes Center, National Hospital Organization, Kyoto Medical Center, Kyoto, Japan
  3. 3Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
  4. 4Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstitution of Tooth and Bone, Tokyo Medical and Dental University, Tokyo, Japan
  1. Address correspondence and reprint requests to Noriko Satoh MD, PhD, Clinical Research Institute for Endocrine Metabolic Diseases, National Hospital Organization, Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan. E-mail: nsato{at}kyotolan.hosp.go.jp
Diabetes Care 2007 Jan; 30(1): 144-146. https://doi.org/10.2337/dc06-1179
PreviousNext
  • Article
  • Figures & Tables
  • Info & Metrics
  • PDF
Loading
  • CETP, cholesteryl ester transfer protein
  • CRP, C-reactive protein
  • CVD, cardiovascular disease
  • EPA, eicosapentaenoic acid
  • n-3 PUFA, n-3 unsaturated fatty acid
  • RLP, remnant lipoprotein particle
  • sdLDL, small dense LDL

Eicosapentaenoic acid (EPA), one representative of n-3 unsaturated fatty acids (n-3 PUFAs), is clinically used for its lipid-lowering effects (1). n-3 PUFAs were shown to exert various physiological functions such as antiplatelet actions (by antagonizing effects of arachidonic acid) and plaque stabilization (2,3). Several epidemiological studies have explored antiatherogenic and cardioprotective effects of n-3 PUFA that are abundantly contained in fish oil (4). Dyslipidemia accompanying the metabolic syndrome is often associated with elevated levels of remnant lipoprotein particles and small dense LDL (sdLDL), which are newly recognized risk factors for cardiovascular disease (CVD) (5). It was reported that fish oil improved lipoprotein subclass profiles in subjects with an atherogenic lipoprotein phenotype (6). Besides EPA, docosahexaenoic acid and cholesterol are present in fish oil (7), but it is not clear whether purified EPA independently affects lipoprotein subclass profiles. Therefore, we used purified EPA ethyl ester and examined effects of EPA on atherogenic sdLDL particles and remnant lipoprotein particles in the metabolic syndrome, a precursor of CVD. Furthermore, sdLDL has been reported to synergistically interact with inflammation in pathophysiologic processes leading to CVD (8). Therefore, we simultaneously measured effects of EPA on C-reactive protein (CRP), a marker of inflammation, and examined how alteration of lipoprotein profiles by EPA affects systemic inflammation.

RESEARCH DESIGN AND METHODS—

A total of 44 Japanese obese type 2 diabetic patients were recruited in our clinics (Table 1). All patients satisfied the definition and diagnostic criteria of the metabolic syndrome proposed by the National Metabolic Syndrome Criteria Study Group of Japan in 2005 (9). Accordingly, an individual is diagnosed with metabolic syndrome if he or she has central adiposity plus two or more of the following three factors: 1) raised concentration of triglycerides (≥150 mg/dl) or reduced concentration of HDL cholesterol (<40 mg/dl); 2) raised blood pressure: systolic blood pressure (≥130 mmHg) or diastolic blood pressure (≥85 mmHg) or treatment of previously diagnosed hypertension; and 3) raised fasting plasma glucose concentration (≥110 mg/dl). The thresholds for waist circumference to define central adiposity were ≥85 cm for men and ≥90 cm for women. The study protocol was approved by the ethical committee on human research of the Kyoto Medical Center, and all participants gave written informed consent. Patients were assigned to one of the following treatment groups (a single-blind and a run-in period randomization, which patients received): 1) treated for 3 months with either diet alone (the control group) (8 men and 14 women; mean ± SE age 51.6 ± 3.2 years) or 2) diet plus EPA (1.8 g daily) (the EPA group) (8 men and 14 women; mean age 51.6 ± 2.8 years). The subjects in the EPA group received an EPA capsule containing highly purified (>98%) EPA ethyl ester. Patient’s diets are based on the Japan Atherosclerosis Society Guidelines for Diagnosis and Treatment of Atherosclerotic Cardiovascular Diseases, consisting of 25 kcal/kg of ideal body weight per day (60% of total energy as carbohydrates, 15–20% as protein, and 20–25% as fat with the ratio of polyunsaturated, monounsaturated, and saturated fatty acids being 3:4:3). Lipid-lowering medications such as statins and fibrates were excluded.

At the beginning and at the end of the study, we measured BMI, serum levels of EPA and arachidonic acid, and glycolipid parameters according to standard procedures. Remnant lipoprotein particle (RLP) cholesterol and RLP triglycerides were measured using an assay kit (Japan Immunoresearch Laboratories, Takasaki, Japan) (10). Plasma cholesteryl ester transfer protein (CETP) activity was measured using an assay kit (BioVision, Mountain View, CA) (11). LDL cholesterol subfractions were separated using the Quantimetrix Lipoprotein LDL system (12). According to the specific subfractions of LDL cholesterol obtained by this system (LDL3–7:sdLDL), the sdLDL proportion was defined as the percentage of sdLDL over the whole amount of LDL (13). Plasma level of CRP was measured by the latex-enhanced assay using the particle-enhanced technology performed on the Behring BN nephelometer (Dade Behring, Marburg, Germany) (14). Data are presented as mean ± SE, and P < 0.05 was considered statistically significant. Repeated-measures ANOVA (control and EPA groups × before and after treatment) was used to access the comparative effects of EPA treatment on the measured variables. A two-tailed, paired t test was applied for the evaluation of changes from baseline conditions to those at 3 months. Comparisons of the means between the two groups at baseline or posttreatment were performed by Student’s t test. All statistical analyses were performed using the Stat View program version 5.0 for Windows (SAS Institute, Cary, NC).

RESULTS—

There were no significant differences between the control and EPA groups for all measured variables at baseline (Table 1). Treatment with EPA significantly increased EPA and EPA/arachidonic acid levels, while it decreased arachidonic acid levels compared with baseline levels (P < 0.01). Differences of EPA and EPA/arachidonic acid levels at 3 month were observed between the control and EPA groups (P < 0.01). EPA also caused significant overall effects on RLP triglyceride, CETP activity, sdLDL, and the proportion of sdLDL and CRP by repeated-measures ANOVA. There were also significant reductions in values compared with baseline by paired t test, despite no changes in BMI, fasting plasma glucose, A1C, insulin concentration, and HDL cholesterol in both groups. Significant reductions of total cholesterol, LDL cholesterol, triglycerides, and RLP cholesterol in the EPA group was observed (P = 0.035, 0.004, 0.047, and 0.035, respectively) by two-tailed, paired t test, although there were no significant overall effects on those parameters by repeated-measures ANOVA. Increases in EPA/arachidonic acid for 3 months inversely correlated with decreases in RLP cholesterol, sdLDL, and CRP for 3 months (P = 0.0379, 0.0479, and 0.0467, respectively). Furthermore, reduction in CRP with EPA treatment for 3 months showed a significant positive correlation with reductions in RLP cholesterol and sdLDL for 3 months (P = 0.0075 and 0.0142, respectively).

CONCLUSIONS—

This study is the first to demonstrate that EPA significantly reduces serum sdLDL and CRP in the metabolic syndrome. Reduction of sdLDL by EPA treatment in this study is believed to be due to a suppression of triglycerides production in the liver by EPA. In addition, since CETP is an important enzyme in cholesterol metabolism—responsible for the transfer of cholesteryl esters from HDL to LDLs (11)—degradation of CETP activity by EPA treatment may also have contributed to the decrease in the generation of remnants and sdLDL. Furthermore, we detected that reductions in RLP cholesterol and sdLDL also correlated with a decrease in CRP by EPA, which was consistent with a previous report (8) showing that LDL particle size had a strong inverse association with CRP. Atherogenic sdLDL particles are susceptible to oxidative modifications; then, oxidized LDL is easily taken into macrophages through damaged endothelial cells, thereby inducing inflammation and early atherosclerotic lesions (5,15). On the other hand, CRP has also been shown to accelerate LDL modifications during inflammatory processes (8). These findings suggest that EPA may be capable of preventing the progression of atherosclerosis in the metabolic syndrome by suppressing reciprocal interactions of atherogenic lipoproteins and inflammation. There are several reports demonstrating that n-3 PUFA does not decrease CETP protein mass and CRP (16,17). This may be caused by the differences outlined in the research designs and methods of each report.

Recently, the Japan EPA Lipid Intervention Study reported that EPA provided further benefits in preventing major coronary events without changing reductions in LDL cholesterol levels (18). Considering the improvements in lipoprotein profiles by EPA in this study, EPA may exert cardioprotective effects not by changing the quantity but by improving the quality of LDL cholesterol.

Collectively, the present study is the first to demonstrate that purified EPA reduces sdLDL, remnants, and CRP, thereby potentially leading to the reduction in development of atherosclerosis and CVD in the metabolic syndrome.

View this table:
  • View inline
  • View popup
Table 1—

Baseline characteristics and effects of EPA on metabolic parameters, lipoprotein profiles, and CRP

Acknowledgments

This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and research grants for cardiovascular diseases (16C-2 and 17C-5 to N.S.) from the Ministry of Health, Labor, and Welfare, the Smoking Research Foundation.

We thank Seiho Kouno and Hajime Yamakage for their valuable discussions, and Kokoro Tsuzaki for her excellent technical assistance.

Footnotes

  • A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C Section 1734 solely to indicate this fact.

    • Accepted October 6, 2006.
    • Received June 7, 2006.
  • DIABETES CARE

References

  1. ↵
    Mizuguchi K, Yano T, Tanaka Y, Ishibashi M, Masada A, Mizota M, Fukutake K, Saito Y: Mechanism of the lipid-lowering effect of ethyl all-cis-5,8,11,14,17- icosapentaenoate. Eur J Pharmacol 231:121–127, 1993
    OpenUrlCrossRefPubMed
  2. ↵
    Hirai A, Terano T, Hamazaki T, Sajiki J, Kondo S, Ozawa A, Fujita T, Miyamoto T, Tamura Y, Kumagai A: The effects of the oral administration of fish oil concentrate on the release and the metabolism of [14C]arachidonic acid and [14C]eicosapentaenoic acid by human platelets. Thromb Res 28:285–298, 1982
    OpenUrlCrossRefPubMedWeb of Science
  3. ↵
    Thies F, Garry JM, Yaqoob P, Rerkasem K, Williams J, Shearman CP, Gallagher PJ, Calder PC, Grimble RF: Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial. Lancet 361:477–485, 2003
    OpenUrlCrossRefPubMedWeb of Science
  4. ↵
    Hu FB, Bronner L, Willett WC, Stampfer MJ, Rexrode KM, Albert CM, Hunter D, Manson JE: Fish and omega-3 fatty acid intake and risk of coronary heart disease in women. JAMA 287:1815–1821, 2002
    OpenUrlCrossRefPubMedWeb of Science
  5. ↵
    Krauss RM: Lipids and lipoproteins in patients with type 2 diabetes. Diabetes Care 27:1496–1504, 2004
    OpenUrlAbstract/FREE Full Text
  6. ↵
    Wilkinson P, Leach C, Ah-Sing EE, Hussain N, Miller GJ, Millward DJ, Griffin BA: Influence of alpha-linolenic acid and fish-oil on markers of cardiovascular risk in subjects with an atherogenic lipoprotein phenotype. Atherosclerosis 181:115–124, 2005
    OpenUrlCrossRefPubMedWeb of Science
  7. ↵
    Nozaki S, Matsuzawa Y, Hirano K, Sakai N, Kubo M, Tarui S: Effects of purified eicosapentaenoic acid ethyl ester on plasma lipoproteins in primary hypercholesterolemia. Int J Vitam Nutr Res 62:256–260, 1992
    OpenUrlPubMed
  8. ↵
    St-Pierre AC, Cantin B, Dagenais GR, Mauriege P, Bernard PM, Despres JP, Lamarche B: Low-density lipoprotein subfractions and the long-term risk of ischemic heart disease in men: 13-year follow-up data from the Quebec Cardiovascular Study. Arterioscler Thromb Vasc Biol 25:553–559, 2005
    OpenUrlAbstract/FREE Full Text
  9. ↵
    Matsuzawa Y: Metabolic syndrome: definition and diagnostic criteria in Japan. J Atheroscler Thromb 12:301, 2005
    OpenUrlCrossRefPubMedWeb of Science
  10. ↵
    Kugiyama K, Doi H, Takazoe K, Kawano H, Soejima H, Mizuno Y, Tsunoda R, Sakamoto T, Nakano T, Nakajima K, Ogawa H, Sugiyama S, Yoshimura M, Yasue H: Remnant lipoprotein levels in fasting serum predict coronary events in patients with coronary artery disease. Circulation 99:2858–2860, 1999
    OpenUrlAbstract/FREE Full Text
  11. ↵
    Bisgaier CL, Minton LL, Essenburg AD, White A, Homan R: Use of fluorescent cholesteryl ester microemulsions in cholesteryl ester transfer protein assays. J Lipid Res 34:1625–1634, 1993
    OpenUrlAbstract
  12. ↵
    Hoefner DM, Hodel SD, O’Brien JF, Branum EL, Sun D, Meissner I, McConnell JP: Development of a rapid, quantitative method for LDL subfractionation with use of the Quantimetrix Lipoprint LDL System. Clin Chem 47:266–274, 2001
    OpenUrlAbstract/FREE Full Text
  13. ↵
    Lee W, Min WK, Chun S, Jang S, Kim JQ, Lee do H, Park JY, Park H, Son JE: Low-density lipoprotein subclass and its correlating factors in diabetics. Clin Biochem 36:657–661, 2003
    OpenUrlCrossRefPubMedWeb of Science
  14. ↵
    Satoh N, Ogawa Y, Usui T, Tagami T, Kono S, Uesugi H, Sugiyama H, Sugawara A, Yamada K, Shimatsu A, Kuzuya H, Nakao K: Antiatherigenic effect of pioglitazone in type 2 diabetic patients irrespective of the responsiveness to its antidiabetic effect. Diabetes Care 26:2493–2499, 2003
    OpenUrlAbstract/FREE Full Text
  15. ↵
    Zhu H, Xia M, Hou M, Tang Z, Li Y, Ma J, Ling W: Ox-LDL plays dual effect in modulating expression of inflammatory molecules through LOX-1 pathway in human umbilical vein endothelial cells. Front Biosci 10:2585–2594, 2005
    OpenUrlCrossRefPubMed
  16. ↵
    Calabresi L, Villa B, Canavesi M, Sirtori CR, James RW, Bernini F, Franceschini G: An omega-3 polyunsaturated fatty acid concentrate increases plasma high-density lipoprotein 2 cholesterol and paraoxonase levels in patients with familial combined hyperlipidemia. Metabolism 53:153–158, 2004
    OpenUrlCrossRefPubMedWeb of Science
  17. ↵
    Madsen T, Christensen JH, Blom M, Schmidt EB: The effect of dietary n-3 fatty acids on serum concentrations of C-reactive protein: a dose-response study. Br J Nutr 89:517–522, 2003
    OpenUrlCrossRefPubMedWeb of Science
  18. ↵
    Yokoyama M: Effects of eicosapentaenoic acid (EPA) on major cardiovascular events in hypercholesterolemic patients: the Japan EPA Lipid Intervention Study (JELIS) (AHA late-breaking clinical trial abstract). Circulation 112:3362, 2005
    OpenUrlFREE Full Text
PreviousNext
Back to top
Diabetes Care: 30 (1)

In this Issue

January 2007, 30(1)
  • Table of Contents
  • About the Cover
  • Index by Author
Sign up to receive current issue alerts
View Selected Citations (0)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word about Diabetes Care.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Purified Eicosapentaenoic Acid Reduces Small Dense LDL, Remnant Lipoprotein Particles, and C-Reactive Protein in Metabolic Syndrome
(Your Name) has forwarded a page to you from Diabetes Care
(Your Name) thought you would like to see this page from the Diabetes Care web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Purified Eicosapentaenoic Acid Reduces Small Dense LDL, Remnant Lipoprotein Particles, and C-Reactive Protein in Metabolic Syndrome
Noriko Satoh, Akira Shimatsu, Kazuhiko Kotani, Naoki Sakane, Kazunori Yamada, Takayoshi Suganami, Hideshi Kuzuya, Yoshihiro Ogawa
Diabetes Care Jan 2007, 30 (1) 144-146; DOI: 10.2337/dc06-1179

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Add to Selected Citations
Share

Purified Eicosapentaenoic Acid Reduces Small Dense LDL, Remnant Lipoprotein Particles, and C-Reactive Protein in Metabolic Syndrome
Noriko Satoh, Akira Shimatsu, Kazuhiko Kotani, Naoki Sakane, Kazunori Yamada, Takayoshi Suganami, Hideshi Kuzuya, Yoshihiro Ogawa
Diabetes Care Jan 2007, 30 (1) 144-146; DOI: 10.2337/dc06-1179
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • RESEARCH DESIGN AND METHODS—
    • RESULTS—
    • CONCLUSIONS—
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Tables
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Autologous Umbilical Cord Blood Transfusion in Young Children With Type 1 Diabetes Fails to Preserve C-Peptide
  • Effects of MK-0941, a Novel Glucokinase Activator, on Glycemic Control in Insulin-Treated Patients With Type 2 Diabetes
  • Diabetes Antibody Standardization Program
Show more Emerging Treatments and Technologies

Similar Articles

Navigate

  • Current Issue
  • Standards of Care Guidelines
  • Online Ahead of Print
  • Archives
  • Submit
  • Subscribe
  • Email Alerts
  • RSS Feeds

More Information

  • About the Journal
  • Instructions for Authors
  • Journal Policies
  • Reprints and Permissions
  • Advertising
  • Privacy Policy: ADA Journals
  • Copyright Notice/Public Access Policy
  • Contact Us

Other ADA Resources

  • Diabetes
  • Clinical Diabetes
  • Diabetes Spectrum
  • Scientific Sessions Abstracts
  • Standards of Medical Care in Diabetes
  • BMJ Open - Diabetes Research & Care
  • Professional Books
  • Diabetes Forecast

 

  • DiabetesJournals.org
  • Diabetes Core Update
  • ADA's DiabetesPro
  • ADA Member Directory
  • Diabetes.org

© 2021 by the American Diabetes Association. Diabetes Care Print ISSN: 0149-5992, Online ISSN: 1935-5548.