Hydroxytyrosol prevents reduction in liver activity of Δ-5 and Δ-6 desaturases, oxidative stress, and depletion in long chain polyunsaturated fatty acid content in different tissues of high-fat diet fed mice

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Abstract

Background

Eicosapentaenoic acid (EPA, C20:5n-3), docosahexaenoic acid (DHA, C22:6n-3) and arachidonic acid (AA, C20:4n-6) are long-chain polyunsaturated fatty acids (LCPUFAs) with relevant roles in the organism. EPA and DHA are synthesized from the precursor alpha-linolenic acid (ALA, C18:3n-3), whereas AA is produced from linoleic acid (LA, C18:2n-6) through the action of Δ5 and Δ6-desaturases. High-fat diet (HFD) decreases the activity of both desaturases and LCPUFA accretion in liver and other tissues. Hydroxytyrosol (HT), a natural antioxidant, has an important cytoprotective effects in different cells and tissues.

Methods

Male mice C57BL/6 J were fed a control diet (CD) (10% fat, 20% protein, 70% carbohydrates) or a HFD (60% fat, 20% protein, 20% carbohydrates) for 12 weeks. Animals were daily supplemented with saline (CD) or 5 mg HT (HFD), and blood and the studied tissues were analyzed after the HT intervention. Parameters studied included liver histology (optical microscopy), activity of hepatic desaturases 5 and 6 (gas-liquid chromatography of methyl esters derivatives) and antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase by spectrophotometry), oxidative stress indicators (glutathione, thiobarbituric acid reactants, and the antioxidant capacity of plasma), gene expression assays for sterol regulatory element-binding protein 1c (SREBP-1c) (qPCR and ELISA), and LCPUFA profiles in liver, erythrocyte, brain, heart, and testicle (gas-liquid chromatography).

Results

HFD led to insulin resistance and liver steatosis associated with SREBP-1c upregulation, with enhancement in plasma and liver oxidative stress status and diminution in the synthesis and storage of n-6 and n-3 LCPUFAs in the studied tissues, compared to animals given control diet. HT supplementation significantly reduced fat accumulation in liver and plasma as well as tissue metabolic alterations induced by HFD. Furthermore, a normalization of desaturase activities, oxidative stress-related parameters, and tissue n-3 LCPUFA content was observed in HT-treated rats over control animals.

Conclusions

HT supplementation prevents metabolic alterations in desaturase activities, oxidative stress status, and n-3 LCPUFA content in the liver and extrahepatic tissues of mice fed HFD.

Electronic supplementary material

The online version of this article (doi:10.1186/s12944-017-0450-5) contains supplementary material, which is available to authorized users.

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Most cited references 53

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Polyunsaturated fatty acids and their metabolites in brain function and disease.

Richard Bazinet, Sophie Layé (2014)

The brain is highly enriched with fatty acids. These include the polyunsaturated fatty acids (PUFAs) arachidonic acid and docosahexaenoic acid, which are largely esterified to the phospholipid cell membrane. Once PUFAs are released from the membrane, they can participate in signal transduction, either directly or after enzymatic conversion to a variety of bioactive derivatives ('mediators'). PUFAs and their mediators regulate several processes within the brain, such as neurotransmission, cell survival and neuroinflammation, and thereby mood and cognition. PUFA levels and the signalling pathways that they regulate are altered in various neurological disorders, including Alzheimer's disease and major depression. Diet and drugs targeting PUFAs may lead to novel therapeutic approaches for the prevention and treatment of brain disorders.

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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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Structure, function, and dietary regulation of delta6, delta5, and delta9 desaturases.

Manabu T Nakamura, Takayuki Nara (2004)

Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Degree of unsaturation of fatty acids affects physical properties of membrane phospholipids and stored triglycerides. In addition, metabolites of polyunsaturated fatty acids are used as signaling molecules in many organisms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. While HUFAs may be required for cold tolerance in plants and fish, the primary role of HUFAs in mammals is cell signaling. Arachidonic acid is required as substrates for eicosanoid synthesis, while docosahexaenoic acid is required in visual and neuronal functions. Desaturases in mammals are regulated at the transcriptional level. Reflecting overlapping functions, three desaturases share a common mechanism of a feedback regulation to maintain products in membrane phospholipids. At the same time, regulation of Delta9 desaturase differs from Delta6 and Delta5 desaturases because its products are incorporated into more diverse lipid groups. Combinations of multiple transcription factors achieve this sophisticated differential regulation.

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Author and article information

Contributors

Rodrigo Valenzuela: +56 2 29786014 , rvalenzuelab@med.uchile.cl

Journal

Journal ID (nlm-ta): Lipids Health Dis

Journal ID (iso-abbrev): Lipids Health Dis

Title: Lipids in Health and Disease

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-511X

Publication date (Electronic): 11 April 2017

Publication date PMC-release: 11 April 2017

Publication date Collection: 2017

Volume: 16

Electronic Location Identifier: 64

Affiliations

[1 ]ISNI 0000 0004 0385 4466, GRID grid.443909.3, Nutrition Department, Faculty of Medicine, , University of Chile, ; Independencia 1027, Casilla, 70000 Santiago 7, Chile

[2 ]ISNI 0000 0004 0385 4466, GRID grid.443909.3, , Lipid Center, Institute of Nutrition and Food Technology (INTA), University of Chile, ; Santiago, Chile

[3 ]ISNI 0000 0004 0385 4466, GRID grid.443909.3, Medical Technology Department, Faculty of Medicine, , University of Chile, ; Santiago, Chile

[4 ]ISNI 0000 0001 2172 9456, GRID grid.10798.37, Biochemistry Department. Faculty of Biochemistry, , University of Litoral, ; Santa Fe, Argentina

[5 ]ISNI 0000 0004 0385 4466, GRID grid.443909.3, Molecular and Clinical Pharmacology Program, Institute of Biomedical Science, Faculty of Medicine, , University of Chile, ; Santiago, Chile

Article

Publisher ID: 450

DOI: 10.1186/s12944-017-0450-5

PMC ID: 5387240

PubMed ID: 28395666

SO-VID: 178895d5-d6aa-485c-8c0f-800dc2b1dcd8

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 22 January 2017

Date accepted : 9 March 2017

Funding

Funded by: FONDECYT (National Fund for Scientific and Technological Development)

Award ID: 11140174

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ScienceOpen disciplines: Biochemistry

Keywords: hydroxytyrosol,oxidative stress,antioxidant capacity,δ5/δ6 desaturase activity,lcpufa,liver and extrahepatic tissues

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ScienceOpen disciplines: Biochemistry

Keywords: hydroxytyrosol, oxidative stress, antioxidant capacity, δ5/δ6 desaturase activity, lcpufa, liver and extrahepatic tissues

Hydroxytyrosol prevents reduction in liver activity of Δ-5 and Δ-6 desaturases, oxidative stress, and depletion in long chain polyunsaturated fatty acid content in different tissues of high-fat diet fed mice

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Conclusions

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GLUT4 biology

Most cited references 53

Polyunsaturated fatty acids and their metabolites in brain function and disease.

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

Structure, function, and dietary regulation of delta6, delta5, and delta9 desaturases.

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