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Regulation of Elovl and fatty acid metabolism
Stockholm University, Faculty of Science, The Wenner-Gren Institute .
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Fatty acids are important regulators in the control of mammalian energy homeostasis. They are ingested in the diet but a significant amount are also endogenously produced by de novo lipogenesis. Fatty acid elongation beyond 16 carbons (palmitic acid) can occur to generate very long chain fatty acids (VLCFA), a process that is initiated by the rate-limiting condensation reaction. To date, six mammalian enzymes responsible for this reaction, ELOVL1-6 (Elongation of very long chain fatty acid), have been characterized. All of them exert substrate specificity and tissue-specific gene expression. In this thesis, factors that regulate fatty acid metabolism and, in particular, fatty acid synthesis and elongation will be presented.

The enclosed papers discuss issues as to how Elovl3 is regulated in liver and in different adipose depots and what effects ablation of this enzyme causes to lipid homeostasis. Hepatic Elovl3 gene expression followed a circadian rhythm, present exclusively in sexually mature male mice. In contrast to the expression of several other lipogenic genes, Elovl3 gene expression was not affected by fasting or refeeding. Instead, the gene expression was influenced by steroid hormones such as glucocorticoids and sex hormones.

Interestingly, despite reduced levels of leptin, Elovl3-ablated mice were shown to be resistant to diet induced weight gain, which seemed to be due to a decreased ratio between energy intake and energy expenditure. This phenotype was more pronounced in female mice.

Place, publisher, year, edition, pages
Stockholm: Wenner-Grens institut för experimentell biologi , 2009. , 58 p.
Keyword [en]
fatty acid metabolism, fatty acid elongation
National Category
Dentistry
Research subject
Physiology
Identifiers
URN: urn:nbn:se:su:diva-8469ISBN: 978-91-7155-798-8 (print)OAI: oai:DiVA.org:su-8469DiVA: diva2:200324
Public defence
2009-02-27, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 8 C, Stockholm, 10:00
Opponent
Supervisors
Note
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 3: Manuscript.Available from: 2009-02-05 Created: 2009-01-28 Last updated: 2011-02-23Bibliographically approved
List of papers
1. Steroid hormones control circadian Elovl3 expression in mouse liver
Open this publication in new window or tab >>Steroid hormones control circadian Elovl3 expression in mouse liver
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2008 (English)In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 149, no 6, 3158-3166 p.Article in journal (Refereed) Published
Abstract [en]

The Elovl3 gene belongs to the Elovl gene family, which encodes for enzymes involved in the elongation of very long chain fatty acids. 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 on cold exposure. Here we show that hepatic Elovl3 mRNA expression follows a distinct diurnal rhythm exclusively in mature male mice, with a sharp increase early in the morning Zeitgeber time (ZT) 20, peaks around ZT2, and is back to basal level at the end of the light period at ZT10. In female mice and sexually immature male mice, the Elovl3 expression was constantly low. Fasting and refeeding mice with chow or high-fat diet did not alter the Elovl3 mRNA levels. However, animals that were exclusively fed during the day for 9 d displayed an inverted expression profile. In addition, we show that Elovl3 expression is transcriptionally controlled and significantly induced by the exposure of the synthetic glucocorticoid dexamethasone. Taken together, these data suggest that Elovl3 expression in mouse liver is under strict diurnal control by circulating steroid hormones such as glucocorticoids and androgens. Finally, Elovl3 expression was found to be elevated in peroxisomal transporter ATP-binding cassette, subfamily D(ALD), member 2 ablated mice and suppressed in ATP-binding cassette subfamily D(ALD) member 2 overexpressing mice, implying a tight cross talk between very long chain fatty acid synthesis and peroxisomal fatty acid oxidation

Keyword
Androgens/*pharmacology, Animals, Circadian Rhythm/*physiology, Gene Expression Profiling, Gene Expression Regulation, Glucocorticoids/*pharmacology, Liver/drug effects/*metabolism, Male, Membrane Proteins/drug effects/*genetics, Mice, Mice; Inbred Strains, PPAR alpha/pharmacology, Transcription; Genetic
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-25706 (URN)10.1210/en.2007-1402 (DOI)000256053100054 ()
Note
Part of urn:nbn:se:su:diva-8469Available from: 2009-02-05 Created: 2009-01-28 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. Gender specific Elovl3 expression and metabolic activity in adipose tissue depots
Open this publication in new window or tab >>Gender specific Elovl3 expression and metabolic activity in adipose tissue depots
Manuscript (Other academic)
Identifiers
urn:nbn:se:su:diva-25708 (URN)
Note
Part of urn:nbn:se:su:diva-8469Available from: 2009-02-05 Created: 2009-01-28 Last updated: 2010-01-13Bibliographically approved
4. β3-adrenergic receptors stimulate glucose uptake in brown adipocytes by two mechanisms independently of GLUT4 translocation
Open this publication in new window or tab >>β3-adrenergic receptors stimulate glucose uptake in brown adipocytes by two mechanisms independently of GLUT4 translocation
2006 (English)In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 147, no 12, 5730-5739 p.Article in journal (Refereed) Published
Abstract [en]

To identify the mechanisms whereby norepinephrine induces glucose uptake in brown adipose tissue, we used mouse brown adipocytes in culture. Proliferating brown adipocytes had high levels of glucose transporter (GLUT) 1 mRNA and low levels of GLUT4 mRNA. The ratio of GLUT4/GLUT1 mRNA expression increased during differentiation, and mature brown adipocytes had high levels of GLUT4 mRNA. The endogenous adrenergic neurotransmitter norepinephrine induced a potent increase in GLUT1 mRNA and a decrease of GLUT4 mRNA in mature brown adipocytes. The norepinephrine effect was mimicked by isoprenaline and CL 316243 and was thus mediated by beta(3)-adrenergic receptors. The cAMP analog 8-bromoadenosine-cAMP partly mimicked the response on GLUT1 mRNA increase and fully mimicked the GLUT4 mRNA decrease. We found no involvement of alpha(1) or alpha(2)-adrenergic receptors on GLUT1 or GLUT4 mRNA transcription. Norepinephrine treatment led to a large increase of GLUT1 protein amount in brown adipocytes as visualized with immunocytochemical staining and subcellular fractionation. A large part of the newly synthesized GLUT1 was found in the plasma membrane (PM). The potent transcriptional inhibitor actinomycin D fully abolished this increase of GLUT1 protein at all time points examined. Norepinephrine treatment shifted GLUT4 from the PM to an intracellular vesicular compartment. Norepinephrine increased 2-deoxy-D-glucose uptake 2-fold at an early time point ( 1 h) and 4-fold at later time point ( 5 h). Addition of actinomycin D did not block the early phase but blocked a large part of the later phase of 2-deoxy-D-glucose uptake. These results imply that adrenergic stimulation through beta(3)-adrenergic receptors induces glucose uptake in brown adipocytes via two mechanisms: 1) a mechanism not dependent on GLUT1 and GLUT4 translocation, 2) a mechanism that is dependent on de novo synthesis of GLUT1 protein and increase of GLUT1 protein at the PM.

National Category
Natural Sciences
Identifiers
urn:nbn:se:su:diva-25709 (URN)10.1210/en.2006-0242 (DOI)
Available from: 2009-02-05 Created: 2009-01-28 Last updated: 2017-12-13Bibliographically approved

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