Omega 3 e omega 6:Omega 3 e omega 6:funzione in età pediatricafunzione in età pediatrica

Carlo AgostoniCarlo Agostoni

Fondazione IRCCS Cà GrandaFondazione IRCCS Cà Granda

Ospedale Maggiore PoliclinicoOspedale Maggiore Policlinico

Dipartimento di Scienze Cliniche e di ComunitàDipartimento di Scienze Cliniche e di Comunità

Università di MilanoUniversità di Milano

carlo.agostoni@unimi.itcarlo.agostoni@unimi.it agostoc@tin.itagostoc@tin.it

LA FISIOLOGIA

ACIDI GRASSI POLINSATURIACIDI GRASSI POLINSATURI

n-6 n-3 acido linoleico18:2 acido alfa-linolenico18:3

delta6desaturasi

elongasi

delta5desaturasi acido arachidonico 20:4 acido eicosapentaenoico 20:5

elongasi delta6 desaturasi

beta-ossidazione perossisomale

acido docosaesaenoico 22:6

LCPUFA acidi grassi polinsaturi

a lunga catena

Precursori

Hwang D et al

The effect of dietary level of a-linolenic acid (18:3v3) on the content of its metabolites in liver lipids.

J Nutr. 128: 427S–433S, 1998.

DHA

EPA

Left panel: Suppression of the metabolism of 0.6% of dietary calories of 18:2v6 by increasing levels of dietary 18:3v3, as measured in liver lipids. Right panel: Suppression of the metabolism of 1% of calories of 18:3v3 by increasing levels of dietary 18:2v6 as indicated by changes in liver fatty acids.

ARA

Hulbert AJ et al

nellenelle

Quale rapporto ottimale omega6/omega3 ? Nel corso dell’evoluzione circa 1

Oggi nelle diete occidentale circa 15:1 Consigliato da 10:1 a 5:1 (età evolutiva)

Forse ottimale da 3:1 a 5:1

LA FISIOPATOLOGIA

P Calder et al

Fatty acids and eicosanoids are peroxisome proliferator–activated receptor (PPAR) ligands Hwang D

P Calder et al

randomized, double-blind, placebo-controlled trial provided children, (ages 5–7 years; n¼37) who had low intakes of DHA, with a dietary supplement containing AA (20–30mg daily) and DHA

(14–21mg daily) or a placebo supplement for 7 months.

Journal of Pediatric Gastroenterology and Nutrition 2008; 46:570

Mazurak V et al

Unstimulated (US), b-lactoglobulin (BLG), ibuprofen (IB) or lipopolysaccharide (LPS)

Miles BA et al

A systematic review included 23 studies. Evidence is seen for a fairly consistent, but modest, benefit of marine n-3 PUFAs on joint swelling and pain, duration of morning stiffness, global assessments of pain and disease activity, and use of non-steroidal anti-inflammatory drugs..

Nobili V et al, Pediatr Obes 2012 , on-line

Liver biopsy at 18-24 monthsafter starting DHA supplementationSteatosic patients

effect on statosis but not on fibrosis (inflammation?)

n-3 PUFA enhance hepatic fatty acid oxidation and inhibit fatty acid synthesis and VLDL secretion by regulating gene expression

PUFA (DHA) control of hepaticmetabolic processes Chem Phys Lipids 2008;153:3-13

LA GENETICA

Ameur A et al

• Haplotype D is associated with increased FADS activity. • Intriguingly, the distance between FADS1 and FADS2 has been reduced (through a deletion) from over 75 kb in monkeys to only 11 kb in humans. • This deletion brought the promoters of FADS1and FADS2 closer to each other, with a resulting coordinated regulation of FADS expression.

DIFFERENT RESULTS WITH LCPUFA trialsDifferent capacity of endogenous synthesis

based on individual genetic background

Glaser C, Maternal and Child Nutr 2011; 7(S2): 27

FADS3 function not characterized

No association was found between genetic variants and DHA variance, which would support the concept that little DHA is synthesized endogenously, and DHA serum concentrations are primarily determined by the dietary supply of preformed DHA from fish and other sources.

The effect size of SNPs was very high: genetic variants explained as much as 28.5% of the variation in serum AA contents in this cohort of free-living individuals with considerable variation in lifestyle and dietary habits. The reconstructed haplotypes predicted some 12% and 10% of the variation of the AA precursors

Glaser C et al, Maternal and Child Nutrition 2011;7 (Suppl 2): 27

DHA in forebrainin 34 infantsup to 2 years

EPA

ARACHIDONIC ACID

ADRENICACID

LINOLEICACID

OLEIC ACID

GENETIC VARIATIONS AND PUFA METABOLISM FIRST MODEL

Adapted from Lattka E et al, Ann Nutr Metab 2012; 60 (Suppl 3):8-17

Association between breastfeeding and IQ moderated by the genetic polymorphism Rs174575 in the FADS2 gene in 2 independent birth cohorts. BF children carrying the C allele showed an IQ point advantage an IQ advantage relative to those not BF . Breastfeeding had no effect on IQ of GG homozygotes.

Caspi A , PNAS 2007; 104:18860

Steer CD, Plos One 2010;5:e11570

In contrast to Caspi study, GG children exhibited the greatest difference between feeding methods . Breastfed children performed similarly irrespective of child genotype

whereas formula fed GG children performed worse than other children on formula milk.

GENETIC VARIATIONS AND PUFA METABOLISM SECOND MODEL

Adapted from Lattka E et al, Ann Nutr Metab 2012; 60 (Suppl 3):8-17

inflammation

High-Oleic acidSunflower Oil

inflammation

These results are the first to show that intake of EPA+DHA for 26 wk can alter the gene

expression profiles of PBMCs to a more antiinflammatory and antiatherogenic status.

Other than FADS

Adapted from Lattka E et al, Ann Nutr Metab 2012; 60 (Suppl 3):8-17

GENETIC VARIATIONS AND PUFA METABOLISM THIRD MODEL

CVD risk factors

Scaglioni S et al

BACKGROUND

Other than FADS

Adapted from Lattka E et al, Ann Nutr Metab 2012; 60 (Suppl 3):8-17

GENETIC VARIATIONS AND PUFA METABOLISM FINAL MODEL

inflammationCVD risk factors

GLI STILI DI VITA: IL MODELLO DEL FUMO

Agostoni et al, Lancet 1998; 352:1703

LC-PUFA daily intakes by the infant (mg/kg)1

1st day 3rd monthS NS S NS

AA 8.1±1.7 5.7±1.2 12.1±1.9 18.2±1.8DHA 5.3±1.4 3.2±0.6 5.5±0.8 10.4±1.1

Agostoni et al, Arch Dis Child 2008;93:414

non-smokers (reference), smokers (>5 cigarettes per day) who either stopped within the first trimester of pregnancy (early smokers) or who continued througout pregnancy (late smokers). Agostoni et al, Arch Dis Child 2008;93:414

Neonatal sample at 4 days

Agostoni et al, J Pediatr 2005;147:857

Omega 3 e omega 6:Omega 3 e omega 6:funzione in età pediatricafunzione in età pediatrica

La composizione lipidica delle membrane dipende da fattori genetici ed ambientali.

La quota e composizione degli omega 3 dipende più di altri acidi grassi dalla dieta

La quota degli omega 3 (DHA) si associa allo sviluppo strutturale e funzionale degli organi a maggiore componente lipidica (fegato, sistema nervoso centrale)

Il bilancio tra omega3 ed omega6 è un elemento regolatore di processi infiammatori ed immunitari

Fabbisogni ed effetti sono significativamente associati alla componente genetica