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Physiological regulation of fatty acid elongase and desaturase expression in mouse liver and brown adipose tissue
Stockholm University, Faculty of Science, The Wenner-Gren Institute .
Stockholm University, Faculty of Science, The Wenner-Gren Institute .
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Fatty acid elongases and desaturases act in concert in modifying the fatty acid acyl chain in respect of length and degree of unsaturation, respectively. The initial and rate-controlling condensation reaction of very-long-chain fatty acid (VLCFA) elongation is catalysed by the elongase enzymes referred to as elongation of very-long-chain fatty acids (ELOVLs). The desaturases introduce a double bond at a specific position on the acyl chain of fatty acids and can be divided into two distinct families referred to as stearoyl-CoA desaturases (SCDs), and fatty acid desaturases (FADS). Both the desaturases and elongases display distinct fatty acid substrate specificity depending on the chain length and degree of unsaturation. Of the elongases; ELOVL1, ELOVL3, ELOVL6 and ELOVL7 prefer saturated and monounsaturated fatty acids as substrate; and ELOVL2, ELOVL4 and ELOVL5 are selective for polyunsaturated fatty acids (PUFAs). Likewise, SCDs prefer saturated fatty acids while FADS favour PUFAs. Although the general function of the Elovl, Scd, and Fads, genes is known, the physiological consequence of the tissue-specific demand for VLCFAs and PUFAs produced by the different elongases is not fully understood. In order to understand their regulation and physiological role, we have investigated the expression of both elongases and desaturases in mouse liver and BAT, in respect of diurnal variation, temperature dependent regulation and nutritional influence.

National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:su:diva-34409OAI: oai:DiVA.org:su-34409DiVA: diva2:284672
Available from: 2010-01-12 Created: 2010-01-08 Last updated: 2011-03-18Bibliographically approved
In thesis
1. Metabolic Significance of Fatty Acid Elongation
Open this publication in new window or tab >>Metabolic Significance of Fatty Acid Elongation
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Very long-chain fatty acids (VLCFAs), including polyunsaturated fatty acids (PUFAs), are essential lipids whose functional diversity is made possible by variation in their chain length and degree of unsaturation. Fatty acids can either be derived directly from the diet or they can be synthesized de novo through lipogenesis, up to 16 carbons in length by fatty acid synthase. Further elongation into VLCFAs is catalysed by the enzymes referred to as elongation of very long-chain fatty acids (ELOVLs). Seven ELOVL proteins have been identified, all of which display distinct fatty acid substrate specificity. The enclosed papers discuss issues regarding the regulation, function and contribution to lipid composition of the Elovl genes with special emphasis on Elovl2 and Elovl3.

In primary brown adipocytes the Elovl3 gene was shown to be regulated by all three PPAR isoforms, involving both transcriptional activation and mRNA stability. In an attempt to clarify the role of ELOVL3 in whole-body lipid homeostasis, the metabolic effects associated with Elovl3 ablation in mice were investigated. Elovl3-ablated mice were lean and showed markedly reduced triglyceride and leptin levels in serum. In addition, the mice were completely resistant to diet-induced obesity, associated with a reduced hepatic lipogenic gene expression and triglyceride content.

Over-expression of Elovl2 in cells promoted accumulation of lipid droplets, associated with enhanced fatty acid uptake and induction of PPARγ target genes. To further assess the in vivo function of ELOVL2, the Elovl2 gene was disrupted in mice by homologous recombination. Elovl2-ablated mice exhibited a severe reduction of the elongation products of C24:5n-6 in the testis, indicating a novel role of ELOVL2 in the formation of very-long-chain PUFAs ≥C26. In addition, Elovl2+/- male mice displayed both pre- and post-meiotic deficiency of spermatogenesis. These results specify an indispensable function of ELOVL2-derived fatty acids, which can give new insights into nutritional intervention as an aid in assisting male fertility problems.

Place, publisher, year, edition, pages
Stockholm: Department of Physiology, Stockholm University, 2010. 54 p.
National Category
Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-34815 (URN)978-91-7155-993-7 (ISBN)
Public defence
2010-02-11, Hörsalen, Frescati backe 107, Svante Arrhenius väg 21 A, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defence, the following papers were unpublished and had status as follows: Paper 2: Submitted. Paper 3: Manuscript. Paper 5: Manuscript. Paper 6: Manuscript.Available from: 2010-01-21 Created: 2010-01-12 Last updated: 2011-03-17Bibliographically approved

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