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Metabolic Significance of Fatty Acid Elongation
Stockholm University, Faculty of Science, The Wenner-Gren Institute . (Anders Jacobsson)
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: urn:nbn:se:su:diva-34815ISBN: 978-91-7155-993-7 (print)OAI: oai:DiVA.org:su-34815DiVA: diva2:285691
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
List of papers
1. Norepinephrine and rosiglitazone synergistically induce Elovl3 expression in brown adipocytes
Open this publication in new window or tab >>Norepinephrine and rosiglitazone synergistically induce Elovl3 expression in brown adipocytes
2007 (English)In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 293, no 5, E1159-68 p.Article in journal (Refereed) Published
Abstract [en]

The Elovl3 gene, which putatively encodes for a protein involved in the elongation of saturated and monounsaturated fatty acids in the C20–C24 range, is expressed in murine liver, skin, and brown adipose tissue (BAT). In BAT, Elovl3 is dramatically upregulated during tissue activation in response to cold exposure, and functional data imply that ELOVL3 is a critical enzyme for lipid accumulation in brown adipocytes during the early phase of tissue recruitment. The activation of BAT is controlled by sympathetic nerve activity and norepinephrine release. By using primary cultures of brown adipocytes, we show here that the induced Elovl3 gene expression is synergistically regulated by norepinephrine and the peroxisome proliferator-activated receptor (PPAR) γ ligand rosiglitazone. In addition, the potency of rosiglitazone to induce Elovl3 expression was several orders of magnitude higher than for the PPARα and PPARδ ligands WY-14643 and L-165041, respectively. The maximal increase in mRNA level by norepinephrine and rosiglitazone is achieved by induced transcription as well as increased mRNA stability, and the whole process requires novel protein synthesis. We conclude that norepinehrine and PPARγ, despite having different roles in brown adipocyte activation and differentiation, cooperate in expanding the intracellular lipid pool by synergistically stimulating Elovl3 expression.

Place, publisher, year, edition, pages
American Physiological Society, 2007
Keyword
fatty acid synthesis; fatty acid elongation; very long-chain fatty acids; lipid metabolism; peroxisome proliferator-activated receptor-γ
National Category
Natural Sciences
Identifiers
urn:nbn:se:su:diva-21011 (URN)10.1152/ajpendo.00213.2007 (DOI)000250800500005 ()17726147 (PubMedID)
Available from: 2008-01-18 Created: 2008-01-18 Last updated: 2017-12-13Bibliographically approved
2. Ablation of the very long chain fatty acid elongase ELOVL3 in mice leads to constrained lipid storage and resistance to diet-induced obesity
Open this publication in new window or tab >>Ablation of the very long chain fatty acid elongase ELOVL3 in mice leads to constrained lipid storage and resistance to diet-induced obesity
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2010 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 24, no 11, 4366-4377 p.Article in journal (Refereed) Published
Abstract [en]

Although saturated and monounsaturated very-long-chain fatty acids (VLCFA) have long been associated with undesirable effects on health, including obesity, heart failure and atherosclerosis, the physiological role of endogenous synthesis is largely unknown. The fatty acid elongase ELOVL3 is involved in the synthesis of C20-C24 saturated and monounsaturated VLCFA mainly in liver, brown and white adipose tissue and in triglyceride rich glands such as the sebaceous and meibomian glands. Here we show that ablation of ELOVL3 leads to reduced adiponectin levels, constrained expansion of adipose tissue and resistance against diet-induced obesity, a situation that is more exaggerated in female mice. Both female and male knockout mice show reduced hepatic lipogenic gene expression and triglyceride content, a situation, which is associated with, reduced expression of PPARg and its target genes. As a consequence, the VLDL-triglyceride level in serum is significantly reduced. Remarkably, despite increased energy expenditure, markedly reduced serum levels of leptin and increased expression of orexigenic peptides in the hypothalamus, the Elovl3-/- mice do not compensate by increased food intake. Thus, these results reveal that C20-C22 saturated and monounsaturated VLCFA produced by ELOVL3 are indispensable for appropriate synthesis of liver triglycerides, fatty acid uptake and storage in adipose tissue.

National Category
Zoology
Identifiers
urn:nbn:se:su:diva-34391 (URN)10.1096/fj.09-152298 (DOI)000283861100024 ()
Available from: 2010-01-12 Created: 2010-01-08 Last updated: 2017-12-12Bibliographically approved
3. Concealed metabolic effects in adipose depots and liver of Elovl3-/- mice
Open this publication in new window or tab >>Concealed metabolic effects in adipose depots and liver of Elovl3-/- mice
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The Elovl3 gene belongs to a highly conserved family of microsomal enzymes involved in the formation of very long-chain fatty acids (VLCFAs). The recognized role for the enzyme is to control the elongation of saturated and monounsaturated fatty acids up to 24 carbons in length. Elovl3 was originally identified as a highly expressed gene in brown adipose tissue (BAT) upon cold exposure, however significant amounts of transcript can also be found in liver, kidney, white adipose tissue (WAT), heart and in the sebaceous glands of the skin. We have recently seen that Elovl3 ablation gives rise to diminished body weight. These mice are resistant to diet-induced obesity and both female and male knockout mice have reduced hepatic lipogenic gene expression and TG secretion as well as a decreased ratio between energy intake and energy expenditure.

In an attempt to identify early markers of metabolic disturbance, we used mice at an age before the onset of impaired weight gain is recognized to analyze the expression of genes involved in lipid metabolism in liver, brown and inguinal white adipose tissue, where Elovl3 is significantly expressed under normal conditions. Furthermore, we analyzed the expression under conditions when energy intake exceeds energy expenditure and during increased energy demand.

Here we show that besides BAT, Elovl3 expression is also regulated in depot specific adipose tissue at different ambient temperatures. We also show that, in addition to impaired expression of both liver (MUP1) and adipose derived (leptin and adiponectin) factors, the Elovl3-/- mice have decreased adipose mass and TG levels already at 30°C, suggesting that factors other than skin barrier dysfunction are involved in the metabolic disturbance associated with Elovl3 ablation.

National Category
Natural Sciences
Identifiers
urn:nbn:se:su:diva-34401 (URN)
Available from: 2010-01-12 Created: 2010-01-08 Last updated: 2011-03-18Bibliographically approved
4. ELOVL2 overexpression enhances triacylglycerol synthesis in 3T3-L1 and F442A cells.
Open this publication in new window or tab >>ELOVL2 overexpression enhances triacylglycerol synthesis in 3T3-L1 and F442A cells.
2007 (English)In: FEBS Letters, ISSN 0014-5793, Vol. 581, no 17, 3157-63 p.Article in journal (Refereed) Published
Abstract [en]

Elongation of very long-chain fatty acids (ELOVL) members were overexpressed in two preadipocyte cell lines, ELOVL2 and ELOVL3 in 3T3-L1 cells, and ELOVL1–3 in F442A cells. Cells overexpressing ELOVL2, whose preferred substrates are arachidonic acid (AA, C20:4n−6) and eicosapentaenoic acid (EPA, C20:5n−3), showed an enhanced triacylglycerol (TAG) synthesis and subsequent accumulation of lipid droplets. Incorporation of fatty acid (FA) but not of glucose into TAG was enhanced by ELOVL2-overexpression. Two lipogenic genes encoding diacylglycerol acyltransferase-2 (DGAT2) and fatty acid-binding protein-4 (FABP4, aP2) were induced in ELOVL2-overexpressing cells, whereas no such effect was seen on the fatty acid synthase (FAS) gene.

Place, publisher, year, edition, pages
Elsevier, 2007
Keyword
3T3-L1 Cells, Adipocytes/*metabolism, Animals, Cells; Cultured, Fatty Acids/metabolism, Gene Expression Regulation, Glucose/metabolism, Lipid Metabolism/genetics, Membrane Proteins/*genetics/metabolism, Mice, NIH 3T3 Cells, Transfection, Triglycerides/*biosynthesis
National Category
Natural Sciences
Identifiers
urn:nbn:se:su:diva-21012 (URN)10.1016/j.febslet.2007.05.081 (DOI)000248145800005 ()17583696 (PubMedID)
Available from: 2008-05-29 Created: 2008-05-29 Last updated: 2011-03-18Bibliographically approved
5. Dominant negative effect on male fertility and sperm maturation by haploinsufficiency of ELOVL2 in mouse
Open this publication in new window or tab >>Dominant negative effect on male fertility and sperm maturation by haploinsufficiency of ELOVL2 in mouse
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

ELOVL2 is a member of the mammalian microsomal enzyme family (ELOVL) involved in the elongation of very long-chain fatty acids (VLCFAs) including polyunsaturated fatty acids (PUFAs). Specifically, ELOVL2 is suggested to mediate the rate-limiting condensation reaction in the elongation of PUFAs of C20 and C22 carbons in length. These PUFAs are required for various physiological functions including, regulation of the composition and fluidity of cell membranes, signalling and gene expression. Moreover, certain PUFAs can be oxygenated forming eicosanoids which are implicated in a variety of signalling pathways. The expression of Elovl2 is highest in testis and liver, but significant amounts of transcripts can also be found in kidney, brain, lung and white adipose tissue. Here, we show that ablation of Elovl2 in mice results in a complete absence of VLCPUFAs with 24-30 carbon atoms of the n-6 family in the testis, and that these fatty acids are indispensable for normal spermatogenesis and fertility. Ablation of Elovl2 was associated with a complete arrest of spermatogenesis with seminiferous tubule displaying only spermatogonia and primary spermatocytes without further germinal cells. The Elovl2+/- mice exhibited abnormal sperm morphology with rounded, condensed head, instead of the normal elongated and hooked head seen in wild-type mice. Intercrosses of Elovl2+/- mice displayed both pre- and post-meiotic deficiency of spermatogenesis. These results indicate a novel mechanism involving ELOVL2-derived fatty acids in mammalian spermatogenesis.

National Category
Natural Sciences
Identifiers
urn:nbn:se:su:diva-34406 (URN)
Available from: 2010-01-12 Created: 2010-01-08 Last updated: 2011-03-18Bibliographically approved
6. Physiological regulation of fatty acid elongase and desaturase expression in mouse liver and brown adipose tissue
Open this publication in new window or tab >>Physiological regulation of fatty acid elongase and desaturase expression in mouse liver and brown adipose tissue
(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:nbn:se:su:diva-34409 (URN)
Available from: 2010-01-12 Created: 2010-01-08 Last updated: 2011-03-18Bibliographically approved

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