Omega-3, självproducerat eller via dieten? Anders Jacobsson Stockholms Universitet

Transkript

1 Omega-3, självproducerat eller via dieten? Anders Jacobsson Stockholms Universitet DU BLIR VAD DU ÄTER!?

2 World Consumption of Oils and Fats (FAO) World consumption of oils and fats has grown steadily during the last twenty five years. 'Oil World' statistics indicate that consumption in the last five years has increased from a level of some 152 million tones in 2007 to 183 million tones in 2012 World Production of Oils and Fats (FAO) Production of oils and fats totaled 183 million tones in 2012 of which palm oil and soybean production were respectively 51 million tones and 42 million tones, thus together accounting for 50% of the total. World average per capita consumption of all oils and fats has also grown progressively each year during the last decade from a level of 18.9 kg in 2001 to 25.9 kg in Consumption per capita is closely related to income. In 2012, per capita consumption was some 55 kg and 59 kg in the US and the EU27 respectively Animal fat Vegetable fat Typical fish oil supplements O HO

3 FAS 16:0 18:0 ELOVL7 20:0 SCD, 9 ELOVL6 SCD, 9 SCD, 9 20:1 (n-11) 16:1 (n-7) 18:1 (n-7) 18:1 (n-9) 20:1 (n-9) Med undantag för linolsyra (18:2 n-6) och linolensyra (18:3 n-3), kan däggdjur tillverka de flesta fettsyrorna genom successiva steg av kedjeförlängning och desaturering. 18:2 (n-9) 18:2 (n-6) 20:2 (n-9) 20:2 (n-6) 20:3 (n-9) DIET 18:3 (n-3) 18:3 (n-6) ELOVL5 18:4 (n-3) 20:3 (n-6) 20:4 (n-6) 20:4 (n-3) 20:5 (n-3) 22:0 22:1 (n-11) ELOVL3 22:1 (n-9) 22:4 (n-6) ELOVL2 22:5 (n-6) 22:5 (n-3) 22:6 (n-3) ELOVL1 24:0 24:1 (n-9) 24:5 (n-3) 24:4 (n-6) 24:5 (n-6) 28:4 (n-6) 30:5 (n-6) 24:6 (n-3) 26:0 34:5 (n-6) 34:6 (n-3) O HO 30:0

4 FAS 16:0 SCD, 9 16:1 (n-7) Med undantag för linolsyra (18:2 n-6) och linolensyra (18:3 n-3), kan däggdjur tillverka de flesta fettsyrorna genom successiva steg av kedjeförlängning och desaturering. ELOVL6 18:1 (n-7) DIET 18:0 ELOVL7 20:0 18:1 (n-9) SCD, 9 SCD, 9 20:1 (n-11) 20:1 (n-9) 18:3 (n-3) 18:2 (n-9) 18:2 (n-6) 18:3 (n-6) 18:4 (n-3) ELOVL5 20:4 (n-3) 20:5 (n-3) 20:2 (n-6) 20:3 (n-6) 20:4 (n-6) 20:2 (n-9) 20:3 (n-9) ELOVL1 22:0 24:0 ELOVL3 22:1 (n-11) 22:1 (n-9) 24:1 (n-9) 7 Elongases 3 Desaturases DESATURATION ELOVL2 22:5 (n-3) 22:4 (n-6) 22:5 (n-6) 24:5 (n-3) 24:4 (n-6) 24:5 (n-6) 28:4 (n-6) 30:5 (n-6) 22:6 (n-3) 24:6 (n-3) 26:0 ELONGATION 34:5 (n-6) 34:6 (n-3) 30:0

5 - väl bevarade enzymreaktioner J Cell Biol May 1;149(3): Role of a New Mammalian Gene Family in the Biosynthesis of Very Long Chain Fatty Acids and Sphingolipids Petr Tvrdik,* Rolf Westerberg,* Sandra Silve, Abolfazl Asadi,* Andreas Jakobsson,* Barbara Cannon,* Gerard Loison, Anders Jacobsson,* 1 65 ELOVL1 MEA VVNLYHELMK HADPR ELOVL2 MEQLKAFDNE VNAFLDNMFG PRDSR ELOVL3 MDTSMNF SRGLKMDLMQ PYDFE Sur4p MNTTTSTVIA AVADQFQSLN SSSSCFLKVH VPSIENP.FG IELWPIFSKV FEYFSG..YP AEQFE Fen1p MN SLVTQYAAPL FERYPQLHDY LPTLERPFFN ISLWEHFDDV VTRVTNGRFV PSEFQ Elo1p MVSDWKNFC LEKASR...F RPTIDRPFFN IYLWDYFNRA VGWATAGRFQ PKDFE ELOVL1 I..QSYPLMG SPLLITSILL TYVYFILSLG PRIMANRKPF QLRGFMIVYN FSLVILSLYI VYEFL ELOVL2 V..RGWFLLD SYLPTFILTI TYLLSIW.LG NKYMKNRPAL SLRGILTLYN LAITLLSAYM LVELI ELOVL3 TFQDLRPFLE EYWVSSFLIV VVYLLLIVVG QTYMRTRKSF SLQRPLILWS FFLAIFSILG TLRMW Sur4p FIHNKTFLAN GYHAVSIIIV YYIIIFGGQA ILRALNASPL KFKLLFEIHN LFLTSISLVL WLLML Fen1p FIAGELPLST LPPVLYAITA YYVIIFGGRF LLS..KSKPF KLNGLFQLHN LVLTSLSLTL LLLMV Elo1p FTVGKQPLSE PRPVLLFIAM YYVVIFGGRS LVK..SCKPL KLRFISQVHN LMLTSVSFLW LILMV ELOVL1 MSGWLSTYTW RC.DPIDFSN SPEALRMVRV AWLFMLSKVI ELMDTVIFIL RKKDGQVTFL HVFHH ELOVL2 LSSWEGGYNL QC.QNLDSAG EGD.VRVAKV LWWYYFSKLV EFLDTIFFVL RKKTNQITFL HVYHH ELOVL3 KFMATVMFTV GLKQTVCFAI YTDDAVVRFW SFLFLLSKVV ELGDTAFIIL RKR..PLIFV HWYHH Sur4p EQLVPMVYHN GLFWSIC.SK EAFAPKLVTL YYLNYLTKFV ELIDTVFLVL RRK..KLLFL HTYHH Fen1p EQLVPIIVQH GLYFAIC.NI GAWTQPLVTL YYMNYIVKFI EFIDTFFLVL KHK..KLTFL HTYHH Elo1p EQMLPIVYRH GLYFAVC.NV ESWTQPMETL YYLNYMTKFV EFADTVLMVL KHR..KLTFL HTYHH ELOVL1 SVLPWSWWWG IKIAPGGMGS FHAMINSSVH VVMYLYYGLS ALGPVAQPYL WWKKHMTAIQ LIQFV ELOVL2 ASMFNIWWCV LNWIPCGQSF FGPTLNSFIH ILMYSYYGLS VF.PSMHKYL WWKKYLTQAQ LVQFV ELOVL3 STVLLFTSFG YKNKVPSGGW F.MTMNFGVH SVMYTYYTMK A.AKLKHPNL.LPMVITSLQ ILQMV Sur4p GATALLCYTQ LIGRT.SVEW VVILLNLGVH VIMYWYYFLS SCG...IRV WWKQWVTRFQ IIQFL Fen1p GATALLCYTQ LMGTT.SISW VPISLNLGVH VVMYWYYFLA ARG...IRV WWKEWVTRFQ IIQFV Elo1p GATALLCYNQ LVGYT.AVTW VPVTLNLAVH VLMYWYYFLS ASG...IRV WWKAWVTRLQ IVQFM ELOVL1 LVSLHI......SQ YYFMPSCNYQ YPIIIHLIWM YGT..IFFIL FSNFWYHSYT K...G ELOVL2 LTITHT......LS AVVKP.CGFP FGCLIFQS.S YMM..TLVIL FLNFYIQTYR KKPVK ELOVL3 LGTIFG......IL NYIWRQEKGC HTTTEHFFWS FMLYGTYFIL FAHFFHRAYL RPKGK Sur4p IDLVFVYFAT YTFYAHKYL. DGILPNKGTC YGTQAAAAYG YLILTSYLLL FISFYIQSYK KGGKK Fen1p LDIGFIYFAV YQKAVHLYF..PILPHCGDC VGSTTATFAG CAIISSYLVL FISFYINVYK RKGTK Elo1p LDLIVVYYVL YQKIVAAYFK NACTPQCEDC LGSMTAIAAG AAILTSYLFL FISFYIEVYK RGSAS 326 ELOVL1 KRLPRAVQQN GAPATTKVKA N ELOVL2 KELQEKEVKN GFPKAHLIVA NGMTDKKAQ ELOVL3 VASKSQ Sur4p TVKKESEVSG SVASGSSTGV KTSNTKVSSR KA Fen1p TSRVVKRAHG GVAAKVNEYV NVDLKNVPTP SPSPKPQHRR KR Elo1p GKKKINKNN ~30% homologi jäst - människa

6 SCD, 9 1. Substrat- and Produktspecificitet 16:0 16:1 (n-7) ELOVL6 DIET 18:1 (n-7) 18:0 SCD, 9 18:1 (n-9) 18:2 (n-9) 18:2 (n-6) 18:3 (n-3) 18:3 (n-6) 18:4 (n-3) ELOVL5 ELOVL7 20:0 20:1 (n-11) 20:1 (n-9) 20:2 (n-9) 20:2 (n-6) 20:3 (n-6) 20:3 (n-9) 20:4 (n-3) 20:5 (n-3) 20:4 (n-6) 22:0 22:1 (n-11) ELOVL3 22:1 (n-9) 22:4 (n-6) ELOVL2 22:5 (n-6) 22:5 (n-3) 22:6 (n-3) ELOVL1 24:0 24:1 (n-9) Desatauration 24:5 (n-3) 24:4 (n-6) 24:5 (n-6) 28:4 (n-6) 30:5 (n-6) 24:6 (n-3) Elongation 26:0 34:5 (n-6) 34:6 (n-3) 30:0

7 16:0 SCD, 9 ELOVL6 16:1 (n-7) 2. Cell- och Tidsspecifik expression 18:0 ELOVL7 20:0 22:0 ELOVL1 24:0 26:0 18:1 (n-7) Tissue SCD, 9 20:1 (n-11) 22:1 (n-11) ELOVL3 18:1 (n-9) 20:1 (n-9) 22:1 (n-9) 24:1 (n-9) 18:2 (n-9) 18:2 (n-6) 20:2 (n-9) (Ohno et al., PNAS 2010) 20:2 (n-6) ELOVL/TFIIb Desatauration Elongation :3 (n-3) 18:3 (n-6) 20:3 (n-6) 20:3 (n-9) 0 18:4 (n-3) 20:4 (n-3) 20:5 (n-3) 20:4 (n-6) 22:4 (n-6) 22:5 (n-6) 22:5 (n-3) 24:5 (n-3) 24:4 (n-6) 24:5 (n-6) 34:5 (n-6) ELOVL Zt 28:4 (n-6) 30:5 (n-6) Elovl1 Elovl2 Elovl3 Elovl5 Elovl6 ELOVL2 22:6 (n-3) 24:6 (n-3) 34:6 (n-3) 30:0

8 FAS SCD, 9 För att tillmötesgå cell- och vävnadsspecifika behov 16:0 16:1 (n-7) ELOVL6 18:1 (n-7) DIET 18:0 SCD, 9 18:1 (n-9) 18:2 (n-9) 18:2 (n-6) 18:3 (n-3) 18:3 (n-6) 18:4 (n-3) ELOVL7 20:0 22:0 ELOVL1 24:0 SCD, 9 20:1 (n-11) 20:1 (n-9) ELOVL3 22:1 (n-11) 22:1 (n-9) 24:1 (n-9) 20:2 (n-6) ELOVL5 20:2 (n-9) 20:3 (n-9) CELLMEMBRAN Fosfolipider Sfingolipider 7 Elongases LIPIDDROPPAR 3 Desaturases Triglycerider Waxestrar DESATURATION Sterolesterar 20:3 (n-6) 20:4 (n-6) 20:4 (n-3) 20:5 (n-3) 22:4 (n-6) ELOVL2 22:5 (n-6) 22:5 (n-3) 24:5 (n-3) 24:4 (n-6) 24:5 (n-6) 28:4 (n-6) 30:5 (n-6) 22:6 (n-3) 24:6 (n-3) 26:0 ELONGATION 34:5 (n-6) 34:6 (n-3) 30:0

9 Fleromättat fett DIET 18:2 (n-6) 18:3 (n-3) 18:3 (n-6) 18:4 (n-3) ELOVL5 20:4 (n-3) 20:5 (n-3) 20:2 (n-6) 20:3 (n-6) 20:4 (n-6) CELLMEMBRAN Fosfolipider Sfingolipider 7 Elongases LIPIDDROPPAR 3 Desaturases Triglycerider Waxestrar DESATURATION Sterolesterar ELOVL2 22:5 (n-3) 22:4 (n-6) 22:5 (n-6) 24:5 (n-3) 24:4 (n-6) 24:5 (n-6) 28:4 (n-6) 30:5 (n-6) 22:6 (n-3) 24:6 (n-3) 34:5 (n-6) 34:6 (n-3)

10 Omega-6 och Omega-3 DIET 18:3 (n-3) 18:4 (n-3) ELOVL5 18:2 (n-6) 18:3 (n-6) 20:4 (n-3) 20:5 (n-3) 20:3 (n-6) 20:4 (n-6) 22:4 (n-6) 22:5 (n-6) 22:5 (n-3) 22:6 (n-3) ELOVL2 -ox 24:4 (n-6) 24:5 (n-6) -ox 24:5 (n-3) 24:6 (n-3) 26:4 (n-6) 26:5 (n-6) 26:6 (n-3) 28:4 (n-6) 28:5 (n-6) 28:6 (n-3) 30:4 (n-6) 30:5 (n-6) 30:6 (n-3) n-6 n-3

11 Omega-3 DIET 18:3 (n-3) 18:4 (n-3) ELOVL5 20:4 (n-3) 20:5 (n-3) EPA 22:5 (n-3) DHA 22:6 (n-3) ELOVL2 -ox 24:5 (n-3) 24:6 (n-3) 26:6 (n-3) 28:6 (n-3) 30:6 (n-3) n-3

12 Omega-3 is good for you! Omega-3 DHA fat dampens brain inflammation to lower stroke risk, improves cognitive function Omega-3 fats hold the key to curing depression in the elderly Omega-3 fatty acids lower heart disease and dementia risk markers Eating fish helps prevent preterm births, suggests new study Super Omega-3 fat protects the heart and arteries and can prevent blindness Omega-3s are incredibly potent anti-inflammatory supplements Obtain cellular health with Omega 3 Fatty Acids Consume more omega-3s to protect your eyesight Prevent and Treat Heart Disease by Optimizing Omega-3 Fats Vegetable fat Typical fish oil supplements Fish oil lowers risk of breast cancer by 32 percent Animal fat Omega-3 Fat DHA: Harness the Power and Slash Risk of Diabetes and Brain Aging Green Tea and DHA: Nutrients Promote Health and Assist Weight Loss Omega-3 Fatty Acids Shown to Combat Obesity Omega 3s reduce risk of colon cancer New research: omega-3s may O treat male infertility Omega-3 Fatty Acids Prevent Heart Disease, Slow Aging and Delay Telomere Shortening HO New study: omega-3s may treat schizophrenia, ADD, Huntington s and other nervous system diseases

13 Omega-3, självproducerat eller via dieten? Betydelsen av genetiken Current Evidence Linking Polyunsaturated Fatty Acids with Cancer Risk and Progression. (Azrad et al., Front Oncology, 2013). Epidemiologic studies provide an inconsistent picture of the associations between dietary PUFAs and cancer. This discrepancy may reflect the difficulties in collecting accurate dietary data; however, it also may reflect genetic variation in PUFA metabolism which has been shown to modify physiological levels of PUFAs and cancer risk. Genome-wide association study of plasma polyunsaturated fatty acids in the InCHIANTI Study. (Tanaka et al., PLoS Genet. 2009).show that polymorphisms of genes encoding enzymes in the metabolism of PUFA contribute to plasma concentrations of fatty acids. A genome-wide perspective of genetic variation in human metabolism (Illig et al., Nature Genetics 2010).. FADS1 and ELOVL2 polymorphism is associated with disorders such as cardiovascular and metabolic diseases

14 ELOVL5, FADS1 o FADS2 finns i alla celler ELOVL2 är unik i specifika celler DIET 18:3 (n-3) 18:4 (n-3) ELOVL5 18:3 (n-6) Hjärna 20:3 (n-6) 20:4 (n-6) Mjölkkörtlar Immunceller Lever 20:4 (n-3) 20:5 (n-3) 22:5 (n-3) EPA DHA 22:6 (n-3) ELOVL2 Reproduktionsorgan Placenta 24:5 (n-6) -ox 24:5 (n-3) 24:6 (n-3) 26:6 (n-3) 28:6 (n-3) 30:6 (n-3) n-3

15 Levern och systemiska effekter DIET 18:3 (n-3) 18:4 (n-3) ELOVL5 18:3 (n-6) 20:4 (n-3) 20:5 (n-3) 20:3 (n-6) 20:4 (n-6) EPA Lever 22:5 (n-3) DHA 22:6 (n-3) ELOVL2 -ox 24:5 (n-3) 24:6 (n-3) n-3

16 Biologisk funktion? - Knockout möss.

17 Crucial role SCD, of 9 ELOVL6 in obesity-induced insulin resistance (Matsuzaka, 2007, Nature Med.) 16:0 16:1 (n-7) ELOVL6 DIET 18:1 (n-7) 18:0 SCD, 9 18:1 (n-9) 18:2 (n-9) 18:2 (n-6) 18:3 (n-3) 18:3 (n-6) 18:4 (n-3) ELOVL5 ELOVL7 20:0 22:0 20:1 (n-11) 22:1 (n-11) ELOVL3 20:1 (n-9) 22:1 (n-9) 20:2 (n-9) 20:2 (n-6) Deletion of ELOVL3 leads to constrained lipid storage (Zadravec, 2010, FASEB J.) Deletion of ELOVL5 leads to fatty liver through activation of SREBP-1c and lipogenesis in mice (Moon, 2009, J Lipid Res.) 20:3 (n-6) 20:3 (n-9) 20:4 (n-3) 20:5 (n-3) 20:4 (n-6) 22:4 (n-6) 22:5 ELOVL2 (n-6) 22:5 (n-3) 22:6 (n-3) ELOVL1 26:0 30:0 Loss of functional leads to abrupt skin barrier and neonatal death (Vasireddy, 2007, Hum. Mol. Gen.) Desatauration Decreased VLCFA elongation by ELOVL1 in brain result in 24:0 24:1 (n-9) severe demyelination of the central nervous system (Tvrdik, 2000, J Cell Biol.) Elongation 24:5 (n-3) 24:4 (n-6) 24:5 (n-6) 28:4 (n-6) 30:5 (n-6) 34:5 (n-6) 24:6 (n-3) 34:6 (n-3) A mutation in is associated with macular dystrophy (Zhang, 2001, Nature Gen.)

18 Crucial role SCD, of 9 ELOVL6 in obesity-induced insulin resistance (Matsuzaka, 2007, Nature Med.) 16:0 16:1 (n-7) ELOVL6 DIET 18:1 (n-7) 18:0 SCD, 9 18:1 (n-9) 18:2 (n-9) 18:2 (n-6) 18:3 (n-3) 18:3 (n-6) 18:4 (n-3) ELOVL5 ELOVL7 20:0 22:0 ELOVL1 26:0 30:0 20:1 (n-11) 22:1 (n-11) ELOVL3 20:1 (n-9) 22:1 (n-9) 20:2 (n-9) 20:2 (n-6) Deletion of ELOVL3 leads to constrained lipid storage (Zadravec, 2010, FASEB J.) Desatauration Decreased VLCFA elongation by ELOVL1 in brain result in 24:0 24:1 (n-9) severe demyelination of the central nervous system (Tvrdik, 2000, J Cell Biol.) Elongation Loss of functional leads to abrupt skin barrier and neonatal death (Vasireddy, 2007, Hum. Mol. Gen.) Deletion of ELOVL5 leads to fatty liver through activation of SREBP-1c and lipogenesis in mice (Moon, 2009, J Lipid Res.) 20:3 (n-6) 20:3 (n-9) 20:4 (n-3) 20:5 (n-3) 20:4 (n-6) 22:4 (n-6) 22:5 (n-6) ELOVL2 22:5 (n-3) 24:5 (n-3) 24:4 (n-6) 24:5 (n-6) 28:4 (n-6) 30:5 (n-6) 34:5 (n-6) 22:6 (n-3) 24:6 (n-3) 34:6 (n-3) A mutation in is associated with macular dystrophy (Zhang, 2001, Nature Gen.)

19 Omega-3, självproducerat eller via dieten? 1. Skillnader i biologiska effekter mellan fettsyror från födan och självproducerade? 2. Hur regleras fettsyraproduktionen? 3. Hur påverkar dieten vår fettsyraproduktion? 4. Skillnader mellan individer? DU BLIR VAD DU ÄTER!?

20 Omega-3, självproducerat eller via dieten? 1. Skillnad på biologiska effekter mellan fettsyror från födan och självproducerade? 2. Hur regleras fettsyraproduktionen? 3. Hur påverkar dieten vår fettsyraproduktion? 4. Skillnader mellan individer? DU BLIR VAD DU ÄTER!?

21 Chronic dietary n-3 PUFA intervention improves dyslipidemia and subsequent cardiovascular complications potentially via down-regulation of hepatic SREBP expression and liver lipogenesis - conversion of glucose into fatty acids (Lu et al., Br. J. Nutr., 2011) n-3 PUFA depletion promotes liver steatosis and insulin resistance by increased expression and activation of SREBP (Pachikian et al., PLoS One, 2011) Insulin Glukos Omega-3 PUFA (DHA) SREBP Blodkärl Triglycerider

22 Lipogenes i levern är nedreglerad av SREBP-inducerad PUFA-(DHA)-produktion (Qin et al., BBA, 2009; Moon et al, J. Lipid. Res., 2009) Insulin Glukos Linolenic Acid (18:3) 18: :4 ELOVL5 SREBP 20:5 22:5 DHA 22:6 ELOVL2 Blodkärl Triglycerider

23 Arvet: Egenproducerade fettsyror reglerar lipidbalansen i kroppen. Energiupptag Energiförbränning

24 Arvet: Egenproducerade fettsyror reglerar lipidbalansen i kroppen.

25 Omega-3, självproducerat eller via dieten? 1. Finns det skillnad mellan fettsyror från födan och självproducerade? 2. Hur regleras fettsyraproduktionen? 3. Hur påverkar dieten vår fettsyraproduktion? 4. Hur stora är skillnaderna mellan individer? DU BLIR VAD DU ÄTER!?

26 Försämrad fertilitet i mutanta ELOVL2-möss är stamspecifik. C57Bl/6 X +/+ 129/Sv +/- X +/+ +/- +/- +/+

27 Omega-3, självproducerat eller via dieten? Perspektiv DHA brist.. fertilitet metabolism utveckling-åldrande, beteende cancer Immunförsvar

28 Methylation of the ELOVL2 gene as a new epigenetic marker of age Paolo Garagnani et al., 2012, Aging Cell ELOVL2 shows a progressive increase in methylation that begins since the very first stage of life (Spearman's correlation coefficient = 0.92) and appears to be a very promising biomarker of aging.

29 Omega-3, självproducerat eller via dieten? Anders Jacobsson Stockholms Universitet Relativt hög fiskkonsumtion tycks ha en skyddande effekt.. Men - Litet deltagarantal, stor variation i metodologi och tidvis otillräcklig kontroll av andra orsaksfaktorer påverkar möjligheten att kunna dra någon tydlig slutsats om omega-3- och omega-6- fettsyrors biologiska effekter. Kliniska studier med fler deltagare och bättre kontroll av andra orsaksfaktorer behövs men även djupare kunskap om kopplingen mellan arv (inkl. könsskillnader) och diet behövs. DU ÄR VAD DU ÄTER!?