Different Effects of Eicosapentaenoic and Docosahexaenoic Acids on Atherogenic High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice

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Abstract

Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, can progress to steatohepatitis (NASH) and advanced liver damage, such as that from liver cirrhosis and cancer. Recent studies have shown the benefits of consuming n-3 polyunsaturated fatty acids (PUFAs) for the treatment of NAFLD. In the present study, we investigated and compared the effects of the major n-3 PUFAs—eicosapentaenoic acid (EPA, C20:5) and docosahexaenoic acid (DHA, C22:6)—in preventing atherogenic high-fat (AHF) diet-induced NAFLD. Mice were fed the AHF diet supplemented with or without EPA or DHA for four weeks. Both EPA and DHA reduced the pathological features of AHF diet-induced NASH pathologies such as hepatic lobular inflammation and elevated serum transaminase activity. Intriguingly, EPA had a greater hepatic triacylglycerol (TG)-reducing effect than DHA. In contrast, DHA had a greater suppressive effect than EPA on AHF diet-induced hepatic inflammation and ROS generation, but no difference in fibrosis. Both EPA and DHA could be effective for treatment of NAFLD and NASH. Meanwhile, the two major n-3 polyunsaturated fatty acids might differ in a relative contribution to pathological intermediate steps towards liver fibrosis.

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Most cited references 29

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Distribution, interconversion, and dose response of n−3 fatty acids in humans

Linda Arterburn, Eileen Hall, Harry Oken (2006)

n-3 Fatty acids have important visual, mental, and cardiovascular health benefits throughout the life cycle. Biodistribution, interconversion, and dose response data are reviewed herein to provide a basis for more rational n-3 dose selections. Docosahexaenoic acid (DHA) is the principal n-3 fatty acid in tissues and is particularly abundant in neural and retinal tissue. Limited storage of the n-3 fatty acids in adipose tissue suggests that a continued dietary supply is needed. A large proportion of dietary alpha-linolenic acid (ALA) is oxidized, and because of limited interconversion of n-3 fatty acids in humans, ALA supplementation does not result in appreciable accumulation of long-chain n-3 fatty acids in plasma. Eicosapentaenoic acid (EPA) but not DHA concentrations in plasma increase in response to dietary EPA. Dietary DHA results in a dose-dependent, saturable increase in plasma DHA concentrations and modest increases in EPA concentrations. Plasma DHA concentrations equilibrate in approximately 1 mo and then remain at steady state throughout supplementation. DHA doses of approximately 2 g/d result in a near maximal plasma response. Both dietary DHA and EPA reduce plasma arachidonic acid concentrations. Tissue contents of DHA and EPA also increase in response to supplementation with these fatty acids. Human milk contents of DHA are dependent on diet, and infant DHA concentrations are determined by their dietary intake of this fatty acid. We conclude that the most predictable way to increase a specific long-chain n-3 fatty acid in plasma, tissues, or human milk is to supplement with the fatty acid of interest.

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Molecular mediators of hepatic steatosis and liver injury.

Jeffrey Browning, Jay Horton (2004)

Obesity and its associated comorbidities are among the most prevalent and challenging conditions confronting the medical profession in the 21st century. A major metabolic consequence of obesity is insulin resistance, which is strongly associated with the deposition of triglycerides in the liver. Hepatic steatosis can either be a benign, noninflammatory condition that appears to have no adverse sequelae or can be associated with steatohepatitis: a condition that can result in end-stage liver disease, accounting for up to 14% of liver transplants in the US. Here we highlight recent advances in our understanding of the molecular events contributing to hepatic steatosis and nonalcoholic steatohepatitis.

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Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease.

Zhiping Li, Shiqi Yang, Huizhi Lin … (2003)

Ob/ob mice, a model for nonalcoholic fatty liver disease (NAFLD), develop intestinal bacterial overgrowth and overexpress tumor necrosis factor alpha (TNF-alpha). In animal models for alcoholic fatty liver disease (AFLD), decontaminating the intestine or inhibiting TNF-alpha improves AFLD. Because AFLD and NAFLD may have a similar pathogenesis, treatment with a probiotic (to modify the intestinal flora) or anti-TNF antibodies (to inhibit TNF-alpha activity) may improve NAFLD in ob/ob mice. To evaluate this hypothesis, 48 ob/ob mice were given either a high-fat diet alone (ob/ob controls) or the same diet + VSL#3 probiotic or anti-TNF antibodies for 4 weeks. Twelve lean littermates fed a high-fat diet served as controls. Treatment with VSL#3 or anti-TNF antibodies improved liver histology, reduced hepatic total fatty acid content, and decreased serum alanine aminotransferase (ALT) levels. These benefits were associated with decreased hepatic expression of TNF-alpha messenger RNA (mRNA) in mice treated with anti-TNF antibodies but not in mice treated with VSL#3. Nevertheless, both treatments reduced activity of Jun N-terminal kinase (JNK), a TNF-regulated kinase that promotes insulin resistance, and decreased the DNA binding activity of nuclear factor kappaB (NF-kappaB), the target of IKKbeta, another TNF-regulated enzyme that causes insulin resistance. Consistent with treatment-related improvements in hepatic insulin resistance, fatty acid beta-oxidation and uncoupling protein (UCP)-2 expression decreased after treatment with VSL#3 or anti-TNF antibodies. In conclusion, these results support the concept that intestinal bacteria induce endogenous signals that play a pathogenic role in hepatic insulin resistance and NAFLD and suggest novel therapies for these common conditions.

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Author and article information

Contributors

Hervé Guillou: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 22 June 2016

Publication date Collection: 2016

Volume: 11

Issue: 6

Electronic Location Identifier: e0157580

Affiliations

[1 ]Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305–8575, Japan

[2 ]Department of Nutritional Science and Food Safety, Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo 156–8502, Japan

[3 ]International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305–8575, Japan

[4 ]Department of Internal Medicine, Faculty of Medicine, Niigata University, 1–754 Asahimachi, Niigata 951–8510, Japan

[5 ]AMED-CREST, Japan Agency for Medical Research and Development (AMED), 1-7-1, Ohte-machi, Chiyoda-ku, Tokyo, 100–0004, Japan

INRA, FRANCE

Author notes

Competing Interests: Masanori Nakakuki and Hiroyuki Kawano are employees of Mochida Pharmaceutical Co. Ltd., which funded this study and provided highly purified EPA ethyl ester. There are no other potential conflicts of interest relevant to this article. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Conceived and designed the experiments: TM H. Shimano. Performed the experiments: NSK TM MK HO. Analyzed the data: NSK TM MK HO SH YT MI KK HI SY H. Suzuki KM DN N. Yahagi YN H. Sone N. Yamada H. Shimano. Wrote the paper: NSK TM H. Shimano.

* E-mail: hshimano@ 123456md.tsukuba.ac.jp

Article

Publisher ID: PONE-D-16-08942

DOI: 10.1371/journal.pone.0157580

PMC ID: 4917109

PubMed ID: 27333187

SO-VID: 02a56a15-4b68-4b8f-bbdf-5ee20337bcb5

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 1 March 2016

Date accepted : 1 June 2016

Page count

Figures: 7, Tables: 1, Pages: 19

Funding

Funded by: Grants-in-Aid for Scientific Research

Award ID: 22117502

Award Recipient : Hitoshi Shimano

Funded by: Program to Disseminate Tenure Tracking System from the Ministry of Science, Education, Culture, and Technology of Japan

Award Recipient : Takashi Matsuzaka

This work was supported by Grants-in-Aid for Scientific Research 22117502 (to H.S.), 15H03093 (to T.M.), and Program to Disseminate Tenure Tracking System (to T.M.) from the Ministry of Science, Education, Culture, and Technology of Japan. This work was also supported in part by Mochida Pharmaceutical Co. Ltd., who also provided highly purified EPA ethyl ester. Co-author Hiroyuki Kawano and Masanori Nakakuki are employed by Mochida Pharmaceutical Co. Ltd. Mochida Pharmaceutical Co. Ltd. provided support in the form of salary for Hiroyuki Kawano and Masanori Nakakuki, but had no additional role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Different Effects of Eicosapentaenoic and Docosahexaenoic Acids on Atherogenic High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice

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Abstract

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PLOS Climate

Most cited references 29

Distribution, interconversion, and dose response of n−3 fatty acids in humans

Molecular mediators of hepatic steatosis and liver injury.

Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease.

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