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Metabolic Significance of Fatty Acid Elongation

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Metabolic Significance of Fatty Acid Elongation Doctoral thesis from the department of Physiology, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden Metabolic significance of fatty acid elongation Damir Zadravec Stockholm 2010 © Damir Zadravec, Stockholm 2010 ISBN 978-91-7155-993-7 Printed in Sweden by Universitetsservice AB, Stockholm 2010 Distributor: Stockholm University Library Dedicated to the future reader ABSTRACT Very long-chain fatty acids (VLCFAs) including polyunsaturated fatty acids (PUFAs) are essential lipids whose functional diversity is enabled by variation in their chain length and degree of unsaturation. Although the simplest form of lipids, the length and pattern of the aliphatic chain of fatty acids is essential for their function, and accordingly, proper elongation and desaturation of fatty acids is important in the maintenance of lipid homeostasis. Fatty acids can either be derived directly from the diet or they can be synthesized de novo through lipogenesis. Fatty acids up to 16 carbons in length are synthesized in the cytosol by the multifunctional protein fatty acid synthase (FAS). Further elongation into VLCFAs is catalysed by the elongase enzymes referred to as elongation of very long-chain fatty acids (ELOVLs), residing in the ER. To date, seven ELOVL proteins (ELOVL1-7) have been identified, with ELOVL1, ELOVL3, ELOVL6 and ELOVL7 preferring saturated and monounsaturated fatty acids as substrate; and ELOVL2, ELOVL4 and ELOVL5 being selective for PUFAs. Recent findings have highlighted the necessity for proper lipid composition in the maintenance of normal whole-body energy homeostasis. Therefore, there is a drive in understanding the tissue-specific contribution of fatty acid modifying enzymes. 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. The regulation of ELOVL3, which is suggested to control the synthesis of saturated and monounsaturated fatty acids of up to 24 carbons in length, was investigated using primary cultures and animal studies. In primary brown adipocytes the 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 liver and whole-body lipid homeostasis, I have investigated the metabolic effects associated with Elovl3-ablation and impaired synthesis of saturated and monounsatureated VLCFAs in mice. 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 by homologous recombination in mouse. Elovl2-ablated mice exhibited an almost complete abolishment of the elongation products of C24:5n-6; that is C26:5n-6, C28:5n-6 and C30:5n-6, indicating a novel role of ELOVL2 in the formation of very-long-chain PUFAs (VLCPUFAs) ≥C26. Elovl2+/- male mice displayed both pre- and post-meiotic deficiency of spermatogenesis. These results specify that ELOVL2-derived fatty acids are indispensable for normal spermatogenesis and give new insights in nutritional intervention as an aid in assisting male fertility problems. This thesis is based on the following papers, which are referred to in the text by their respective Roman numerals. I. Jörgensen JA, Zadravec D and Jacobsson A. (2007) Norepinephrine and rosiglitazone synergistically induce Elovl3 expression in brown adipocytes. Am. J. Physiol. Endocrinol. Metab. 293(5): 1159-68 II. Zadravec D, Brolinson A, Fisher RM, Carneheim C, Csikasz RI, Bertrand-Michel J, Borén J, Guillou H, Rudling M, and Jacobsson A. (2009) Ablation of the very long chain fatty acid elongase ELOVL3 in mice leads to constrained lipid storage and resistance to diet-induced obesity Submitted III. Zadravec D, Brolinson A. and Jacobsson, A. (2010) Concealed metabolic effects in adipose depots and liver of Elovl3-/- mice Manuscript IV. Kobayashi T, Zadravec D and Jacobsson A. (2007) ELOVL2 overexpression enhances triacylglycerol synthesis in 3T3-L1 and F442A cells. FEBS Lett. 581(17): 3157-63 V. Zadravec D, Tvrdik P, Guillou H, Haslam R, Kobayashi T, Napier J, Capecchi MR and Jacobsson A. (2010) Dominant negative effect on male fertility and sperm maturation by haploinsufficiency of ELOVL2 in mouse Manuscript VI. Zadravec D and Jacobsson, A. (2010) Physiological regulation of fatty acid elongase and desaturase expression in mouse liver and brown adipose tissue. Manuscript METABOLIC SIGNIFICANCE OF FATTY ACID ELONGATION 1. INTRODUCTION .....................................................................................................................11 2. ORIGIN OF FATTY ACIDS ....................................................................................................11 3. FATE OF FATTY ACIDS ........................................................................................................13 3.1. Adipose tissue.....................................................................................................................14 3.2. Energy and fatty acid homeostasis. ....................................................................................15 4. FATTY ACID SYNTHESIS.....................................................................................................16 5. MAMMALIAN ELONGASES.................................................................................................18 5.1. Elongases involved in the elongation of saturated and monounsaturated fatty acids.........20 5.1.1. Elovl6...........................................................................................................................21 5.1.2. Elovl1...........................................................................................................................22 5.1.3. Elovl3...........................................................................................................................22 5.1.3.1. Elovl3 regulation in brown adipose tissue............................................................23 5.1.3.2. Elovl3 expression in white adipose tissue ............................................................24 5.1.3.3. Elovl3-ablated mice are resistant to diet-induced weight gain .............................24 5.1.4. Elovl7...........................................................................................................................26 5.2. Elongases involved in the elongation of PUFAs................................................................27 5.2.1. Elovl5...........................................................................................................................27 5.2.2. Elovl2...........................................................................................................................29 5.2.2.1. Attenuated PUFA synthesis in Elovl2-/- mice.......................................................30 5.2.2.2. Impaired fertility in Elovl2+/- male mice ..............................................................31 5.2.2.3. Necessity of ELOVL2-derived fatty acids during embryogenesis.......................32 5.2.3. Elovl4...........................................................................................................................32 6. DESATURATION OF FATTY ACIDS ...................................................................................34 6.1. Acyl chain desaturation performed by stearoyl-CoA desaturases (SCDs).........................34 6.2. Acyl chain desaturation of PUFA performed by fatty acid desaturases (FADS)...............35 7. DISCUSSION............................................................................................................................36 8. ACKNOWLEDGEMENTS.......................................................................................................41 9. REFERENCES ..........................................................................................................................41 ABBREVIATIONS ACC Acetyl-CoA carboxylase BAT Brown adipose tissue DGAT Diacylglycerol acyltransferase ELOVL Elongation of very long chain fatty acids ER Endoplasmic reticulum FADS Fatty acid desaturase FAS Fatty acid synthase gWAT Gonadal white adipose tissue HADC 3-hydroxyacyl-CoA dehydratase iWAT Inguinal white adipose tissue LXR Liver X receptor PPAR Peroxisome proliferator-activated receptor PUFA Polyunsaturated fatty acid SCD Stearoyl-CoA desaturase SREBP Sterol regulatory element-binding protein STGD3 Stargardt-like macular dystrophy TG Triacylglycerol UCP1 Uncoupling protein-1 WAT White adipose tissue VLCFA Very long-chain fatty acid VLCPUFA Very long-chain polyunsaturated fatty acid VLDL Very low density lipoprotein 1. INTRODUCTION Very long-chain fatty acids (VLCFAs) including polyunsaturated fatty acids (PUFAs) are essential lipids whose functional diversity is enabled by variation in their chain length and degree of unsaturation. With the big variety in lipid molecules it is not surprising that they have received more attention recently, as more pathophysiological syndromes are being ascribed to impaired lipid homeostasis. Except for obesity and its subsequent complications, several additional diseases are associated with
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