Nutritional Phospholipid Development and Application DPA 24:5 ω6 24:6 ω3 Δ6 DS Conversion < 1%...

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Nutritional phospholipid development and applications Dr. Thierry COSTE
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Transcript of Nutritional Phospholipid Development and Application DPA 24:5 ω6 24:6 ω3 Δ6 DS Conversion < 1%...

  • Nutritional phospholipid development and applications

    Dr. Thierry COSTE

  • What are phospholipids?

  • Phospholipids

    phosphatidic acid PA

    Phosphatidylcholine PC

    Phosphatidylethanolamine PE

    phosphatidylserine PS

    phosphatidylglycerol PG

    phosphatidylinositol PI

  • Polar head(hydrophilic)

    Non polar tails(hydrophobic)

    Amphiphilic properties of phospholipids

  • Lecithins (phospholipids) => emulsifiers

  • Structures in aqueous solution

  • From liposome to cell membrane

  • Why phospholipids can be so important as food

    supplements?

  • Dietary intake of phospholipids

    Dietary intake of phospholipids has diminished due to: - mad cow disease (decrease in brain and liver consumption), - replacement of lecithin in food by other emulsifiers.

    Triglycerides between 80 and 120 g Phospholipids 2-3 g instead of 4-6 g

  • No RDI for phospholipids

    It exists no Reference Dietary Intakes (RDI) for phospholipids because we do not know the organism requirements and human body can synthesize them.

    Innis et al. 2003, J Pediatr 143: 351-6

    => But for example as you can see in this figure, an excess in synthesis of PC can have a metabolic price: an increase in homocysteine levels.

  • Phospholipid applications

  • Health applications

  • 1- Hyperlipidemia

  • Classic use of soybean lecithins

    Dose g

    Duration days

    Cholesterolemia Triglyceridemia Reference

    1-2 244 No effect No effect 1

    6-18 84 Decrease Decrease 2

    18 10 No effect No effect 3

    1) ter Welle et al. 1974, Acta Med Scand 195: 267-71 2) Brook et al. 1986, Biochem Med Metab Biol 35: 31-9 3) Greten et al. 1980, Atherosclerosis 36: 81-8

  • 2- Baby food

  • Feeding infants with Mothers milk is the Best !

    The Golden Standard

    One of the reason is the presence of LC-PUFA: DHA & ARA

  • Garcia et al. 2011, J Pediatr Gastroenterol Nutr 53: 206-12

    Lipid composition of human milk

    3-4 days postpartum 6-10 days postpartum 30 days postpartum

  • Garcia et al. 2011, J Pediatr Gastroenterol Nutr 53: 206-12

    Respective contribution of TG & PL

    LC-PUFA ARA DHA Proportion in TG, wt% TFA 0.31 0.18 (0.05-0.76) 0.30 0.28 (0.00-0.95) Proportion in PL, wt% TFA 2.83 1.30 (0.81-4.59) 2.34 0.91 (0.93-4.34)

    Contribution of TG, % 90.0 6.5 78.0 32.8 Contribution of PL, % 9.9 6.5 21.9 32.8

    Adapted from Table 3: Respective contribution of human milk TG and PL to ARA and DHA supply.

    Thus, the contribution of phospholipids can be more important as much than their fatty acids are usually not used for -oxidation.

  • Feeding infants with Mothers milk is the Best !

    But, in case this is not possible, you absolutely need to provide DHA and ARA in

    form of phospholipids with your formula

    For this purpose, only egg yolk lipids bring DHA and ARA in form of phospholipids

    similarly to Mothers milk lipids

    Infant formula

  • 3- Liver

  • Phosphatidylcholine and alcoholic hepatic steatosis

    Baboons

    Lieber et al. 1994, Gastroenterology 106: 152-9

    => PC with the dose of 2.8 g/1000 kcal, prevents the development of fibrosis and cirrhosis in baboons following a diet with 50% of caloric ration in form of ethanol.

    Baboons with PC

  • Chronic hepatitis

    Gundermann et al. 2011, Pharmacol Rep 63: 643-59

    => This meta-analysis of 9 studies (409 patients) shows global improvement of 26% in the phosphatidylcholine supplemented groups.

  • 4- Stress

  • PS & PA against mental stress

    3 weeks treatment 80 patients 20-45 years old

    Hellhammer J et al. Stress 2004, 7: 119-26.

  • => The ACTH and cortisol increases, normally induced by stress, are significantly lower with a preventive treatment of 400 mg of phosphatidylserine + phosphatidic acid.

    PS & PA against mental stress: results

    Hellhammer J et al. Stress 2004, 7: 119-26.

  • PS & PA against mental stress: results

    => The salivary cortisol increase is also significantly lower with the preventive treatment of 400 mg of phosphatidylserine + phosphatidic acid.

    Hellhammer J et al. Stress 2004, 7: 119-26.

  • 5- Brain

  • Phosphatidylserine levels in tissues

    Tissues (human) PS in % of total cell phospholipid

    Brain myeline 21

    Brain white matter 16

    Brain grey matter 13

    Retina 8-16

    Red blood cells 14

    Platelets 9

    Lung, spleen, amniotic fluid 8

    Liver, heart, skeletal muscle 3

    Kidney 1

    Plasma Traces

  • First source of phosphatidylserine

    Firstly, phosphatidylserine was manufactured from cerebral cortex of beef.

  • PS and cognitive decline

    Patients (n)

    Age years

    PS dose in mg

    Time weeks

    Beneficial effects Ref

    149 50-75 300 12 Amelioration of 3/5 tests in patients and 4/5 among most

    affected patients

    1

    425 65-93 300 26 Amelioration in behaviour and cognitive parameters

    2

    1) Crook et al. Neurology 1991, 41 : 644-9

    2) Cenacchi et al. Aging 1993, 5 : 123-33

  • First source of phosphatidylserine

    => But the mad cow disease made disappear this source.

  • Phosphatidylserine manufacturing

    - bacteria (not so stable during time)

  • PS and cognitive decline

    Patients (n)

    Age years

    PS dose in mg

    Time weeks

    Beneficial effects Ref

    149 50-75 300 12 Amelioration of 3/5 tests in patients and 4/5 among most

    affected patients

    1

    425 65-93 300 26 Amelioration in behaviour and cognitive parameters

    2

    120 > 57 300 or 600

    12 No significant amelioration 3

    1) Crook et al. Neurology 1991, 41 : 644-9

    2) Cenacchi et al. Aging 1993, 5 : 123-33

    3) Jorissen et al. Nutr Neurosci 2001, 4 : 121-34

  • Phosphatidylserine manufacturing

    - bacteria (more stable with less residual activity) - vegetable (cabbage)

  • PS and cognitive decline

    Patients (n)

    Age years

    PS dose in mg

    Time weeks

    Beneficial effects Ref

    149 50-75 300 12 Amelioration of 3/5 tests in patients and 4/5 among most

    affected patients

    1

    425 65-93 300 26 Amelioration in behaviour and cognitive parameters

    2

    120 > 57 300 or 600

    12 No significant amelioration 3

    78 50-69 100 or 300

    26 Amelioration of memory in patients with memory

    complaints

    4

    1) Crook et al. Neurology 1991, 41 : 644-9

    2) Cenacchi et al. Aging 1993, 5 : 123-33

    3) Jorissen et al. Nutr Neurosci 2001, 4 : 121-34

    4) Kato-Kataoka et al. J Clin Biochem Nutr 2010, 47 : 246-55

  • Sources to manufacture the PS

    Generally, soy phospholipids (rich in phosphatidylcholine) are used as raw material. There is also a new PS available, made from sunflower phospholipids.

    Moreover, marine or egg yolk sources can be used (because they are also rich in phosphatidylcholine) as raw material to obtain phosphatidylserine containing omega 3.

  • PS-DHA/EPA and cognitive decline

    Patients (n)

    Age years

    Dose PS-DHA/EPA

    in mg

    Time weeks

    Beneficial effects Ref

    8 (pilot study)

    60 300-37.5 6 Amelioration of memory among patients with memory

    complaints

    1

    157 50-90 300-79 15 Amelioration of memory among patients with memory

    complaints

    2

    1) Richter et al. Clin Interv Aging 2010, 5 : 313-6

    2) Vakhapova et al. Dement Geriatr Cogn Disord 2010, 29 : 467-74

  • Vectors for omega 3 fatty acids

  • What are omega 3 fatty acids?

  • Alpha linolenic acid (ALA, C18:3 3)

    Eicosapentaenoic acid (EPA, C20:5 3)

    Docosahexaenoic acid (DHA, C22:6 3)

    Main omega 3 fatty acids

    40

  • Why omega 3 fatty acids are so important as food

    supplements?

  • Polyunsaturated fatty acid metabolism

    18:2 6

    18:3 6

    20:3 6

    20:4 6

    22:4 6

    22:5 6

    12 DS

    E

    24:4 6

    24:5 6

    Mammals

    - Plants - Invertebrates

    E AA

    LA

    18:1 9

    E

    -ox

    Endoplasmic reticulum

    Peroxisome

    DS = Desaturase E = Elongase -ox = -oxidation

    Arachidonic acid

    18:3 3

    18:4 3

    20:4 3

    20:5 3

    22:5 3

    22:6 3

    15 DS

    24:5 3

    24:6 3

    E

    E EPA

    DHA

    ALA

    E

    -ox

    Eicosapentaenoic acid

    Docosahexaenoic acid

    6 DS

    5 DS

    6 DS

  • Strong competition for 6 desaturase

    18:3 3

    18:4 3

    22:6 3

    18:2 6

    18:3 6

    22:5 6

    24:5 3

    24:6 3 24:4 6

    24:5 6

    DHA

    LA ALA

    -ox

    Endoplasmic reticulum

    Peroxisome DS = Desaturase -ox = -oxidation

    -ox

    SA GLA

    DPA

    24:6 3 24:5 6

    6 DS Conversion < 1%

  • Why focusing on DHA ?

  • Omega 3 levels in human tissues

    DHA is the most abundant omega 3 fatty acid in human cell membranes because this fatty acid is essential for the cell functionality.

    Arterburn et al. 2006, Am J Clin Nutr 83: 1467S-76S

  • DHA and erythrocyte deformability Animal supplementation study

    => Supplementation with DHA induces an accretion of DHA in erythrocyte membranes resulting in a better deformability, contrary to supplementation with EPA, which can counteract this effect.

    Poschl JM et al. Thromb Res 81: 283-8, 1996

  • Phosphatidylcholine DHA (PC-DHA)

    500 ps dynamics of PC (C18:0 and DHA), courtesy from Dr. Scott Feller

  • Why focusing on DHA in form of phospholipids ?

  • A similar bioavailability

    DHA 8mg/kg 40 days in female rats

    Plasma g/ml

    Erythrocyte mg/g PL

    Hepatic tissue mg/g PL

    Adipose tissue

    mg/g lipids Placebo (olive oil) 80 12.5 45 4.5

    Phospholipids 150 (+90%) 27.5 (+120%) 90 (+100%) 9 (+100%)

    Monoacylglycerides* 160 (+100%) 25 (+100%) 80 (+80%) 8.5 (+90%)

    Triglycerides** 145 (+80%) 22.5 (+80%) 70 (+55%) 7 (+55%)

    Ethyl esters*** 150 (+90%) 17.5 (+40%) 40 (-10%) 5 (+10%)

    * Not available in the market ** Available as fish or micro-algae oils *** Available as medical drug (for example Omacor)

    Animal supplementation study

    Valenzuela A et al. Ann Nutr Metab 49: 325-32, 2005

  • Cell membrane

    Wikimedia commons, LadyofHats Mariana Ruiz

  • A better bioaccretion in tissue membranes

    DHA 8mg/kg 40 days in female rats

    Plasma g/ml

    Erythrocyte mg/g PL

    Hepatic tissue mg/g PL

    Adipose tissue

    mg/g lipids Placebo (olive oil) 80 12.5 45 4.5

    Phospholipids 150 (+90%) 27.5 (+120%) 90 (+100%) 9 (+100%)

    Monoacylglycerides* 160 (+100%) 25 (+100%) 80 (+80%) 8.5 (+90%)

    Triglycerides** 145 (+80%) 22.5 (+80%) 70 (+55%) 7 (+55%)

    Ethyl esters*** 150 (+90%) 17.5 (+40%) 40 (-10%) 5 (+10%)

    * Not available in the market ** Available as fish or micro-algae oils *** Available as medical drug (for example Omacor)

    Animal supplementation study

    Valenzuela A et al. Ann Nutr Metab 49: 325-32, 2005

  • A better bioaccretion into brain

    => Less than 1% of the ingested dose of DHA was found in brain and the phospholipids form permits a two-fold accretion in older rats when compared to triglyceride form.

    Graf et al. 2010, Prostaglandins Leukot Essent Fatty Acids 83: 89-96

  • A better resistance to oxidation In vitro study

    => DHA in the form of phospholipids is more resistant to the oxidative degradation than DHA in the form of triglycerides or ethyl esters.

    Song et al. 1997, Biosci Biotechnol Biochem 61: 2085-8

    -97%

    -64%

    -10%

  • To resume

    DHA form Triglycerides Ethyl esters Phospholipids History of human consumption

    ++ - ++

    Bioaccretion + +/- ++ Oxidative stability -- - ++ Choline - - ++ Phosphorus - - ++

    => Phospholipids are the better form to bring DHA to human organism.

  • Marine phospholipid developments

  • Marine phospholipids: raw materials

    Marine phospholipids

    Krill oil Fish eggs: Caviar phospholipids

  • Health applications of Krill oil

    Krill oil Premenstrual syndrome2

    Hyperlipidemia1

    Inflammation/arthritis3

    1) Bunea R et al. Altern Med Rev 2004, 9: 420-8

    2) Sampalis F et al. Altern Med Rev 2003, 8: 171-9

    3) Deutsch L J Am Coll Nutr 2007, 26: 39-48

  • Marine phospholipids: composition

    Phospholipid distribution Fatty acid distribution

  • Marine phospholipids: comparison

    Raw materials Krill Caviar History of human consumption

    - ++

    Oxidation stability ++ ++ Taste impact - - Choline ++ ++ EPA ++ + DHA + ++ Astaxanthin ++ ++ Vitamin E + + Bioavailability + +

    => Caviar phospholipids extracted from fish eggs present higher DHA levels than phospholipids extracted from Krill.

  • Marine phospholipids & psoriasis

    Dupont 2006, Phytothrapie 1: 15-22

    6 months of treatment

    with 400 mg daily

  • Caviar phospholipids & psoriasis

  • Formulating agent

  • Overview on typical phospholipid formulations

    Fricker et al. 2010, Pharm Res 27: 1469-86

  • Aspirin-Phosphatidylcholine

  • Thank you for your attention