Endogenous production of omega-3 fatty acids in milk · •Omega-3 (ω3) polyunsaturated fatty...

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Animal Biotechnology and Genomics Education Endogenous production of omega-3 fatty acids in milk Alison Van Eenennaam, Ph.D. Cooperative Extension Specialist Animal Biotechnology and Genomics [email protected] Phone: 530 752-7942

Transcript of Endogenous production of omega-3 fatty acids in milk · •Omega-3 (ω3) polyunsaturated fatty...

Page 1: Endogenous production of omega-3 fatty acids in milk · •Omega-3 (ω3) polyunsaturated fatty acids (PUFA) are well documented for their beneficial health effects •Used to treat

Animal Biotechnology and Genomics Education

Endogenous production of omega-3 fatty acids in milk

Alison Van Eenennaam, Ph.D.

Cooperative Extension Specialist Animal Biotechnology and Genomics

[email protected]

Phone: 530 752-7942

Page 2: Endogenous production of omega-3 fatty acids in milk · •Omega-3 (ω3) polyunsaturated fatty acids (PUFA) are well documented for their beneficial health effects •Used to treat

Animal Biotechnology and Genomics Education

Overview

• The importance of omega-3 (aka ω3 or n3) polyunsaturated fatty acids (n3 PUFAs)

• Pathways of biosynthesis • The problem with ruminants • A biotech work around • In vitro results • In vivo results • Road blocks • Conclusions

Page 3: Endogenous production of omega-3 fatty acids in milk · •Omega-3 (ω3) polyunsaturated fatty acids (PUFA) are well documented for their beneficial health effects •Used to treat

Animal Biotechnology and Genomics Education

What is an omega-3 fatty acid ?

In the omega system the numbering refers to the first carbon with a double bond relative to the carbon at the methyl end of the molecule.

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Animal Biotechnology and Genomics Education

Pathways of polyunsaturated fatty acid synthesis. Enzymes are indicated in ovals and major

products are boxed

18:2n6 20:3n6 18:3n3 20:4n3

18:3n6 20:4n6 18:4n3 20:5n3

Δ5/Δ6

fat-2

Δ5/Δ6

fat-1

Zebrafish

Modification of milk fatty acid composition

Vertebrates lack

the fatty acid desaturase

enzymes required for

the synthesis of linoleic

acid (LA, 18:2n-6) and

alpha-linolenic acid

(ALA, 18:3n-3), and are

therefore dependent on

dietary sources to obtain

these essential PUFA.

The nematode

Caenorhabditis elegans

is able to synthesize ALA

from LA by virtue of an

endogenous omega-3

fatty acid desaturase

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The diet of our ancestors was higher in fiber, rich in fruits, vegetables, lean meat, and fish.

The diet was less dense in calories, lower in total fat and saturated fat, and contained approximately equal amounts of ω6 and ω3 PUFAs

In Western diets, the current ratio of ω6 to ω3 PUFAs is about 10 to 20:1, indicating that Western diets are deficient in ω3 fatty acids compared with

the diet on which humans evolved

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ω3 is good for me

• Omega-3 (ω3) polyunsaturated fatty acids (PUFA) are well documented for their beneficial health effects

• Used to treat and prevent coronary heart disease, cancer, metabolic syndrome, Crohn disease, rheumatoid arthritis, inflammatory and immune-based diseases, autoimmune diseases, even schizophrenia

• The average intake of ω3 PUFA is about 1.6 grams/day in the United States. Nutrition scientists suggest the daily intake should be closer to 2.85 grams/day

ω3

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Which would you rather eat to

lower your risk of heart disease ?

A. B.

Omega-3 dairy products coming soon.....

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Animal Biotechnology and Genomics Education

Modification of milk fat to benefit human health

• Ruminant milk is high in saturated fat and does not contain high levels of PUFAs as a result of rumen biohydrogenation

• The incorporation of low levels (400 mg/day) of ω3 PUFAs in milk has been found to have significant human health benefits

• How can the fatty acid composition of milk be improved to benefit human health ?

ω3

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Fatty acid composition of

bovine milk

Environmental approaches

• Bypass rumen

• Add it to the milk

Genetic approach

• Provide desaturases

(ω3)

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Hypothetical effect of desaturases on

fatty acid composition of bovine milk

18:1n-9

18:3n-3

ALA

18:2n-6 LA

FAT-2

FAT-1

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Phospholipid vs. Triacylglycerol

The C. elegans Fat 1 omega-3 desaturase operates on acyl groups that are esterified to phospholipids and so it is called an acyl-lipid desatuarase (rather than a CoA desaturase)

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In vitro proof of concept – Kerri Morimoto (MS)

CMV promoter fat-2fat-1 TK polyAEF-1 alpha promoterSV40 polyACMV promoter fat-2fat-1 TK polyAEF-1 alpha promoterSV40 polyA

• Two desaturases cloned into pBUD • Adenovirus transfected into HC11 • Analyzed fatty acid composition of transfected cells three days after transfection

Omega-3 Delta-12

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0

2

4

6

8

10

12

14

16

18

LacZ Control

Fat-1/Fat-2

b

0

2

4

6

8

10

C16:1 C18:1n-9 C18:2 n-6 (LA) C18:3 n-3 (ALA) C20:4 n-6 (AA) C20:5 n-3 (EPA)

Fatty Acids

b

Mol %

Fatty A

cid

s

18:1n-9

18:3n-3

ALA

18:4n-3 20:4n-3 20:5n-3

EPA

20:4n-6

AA

20:3n-618:3n-618:2n-6

LA

FAT-2

FAT-1 FAT-1 FAT-1 FAT-1

18:1n-9

18:3n-3

ALA

18:4n-3 20:4n-3 20:5n-3

EPA

20:4n-6

AA

20:3n-618:3n-618:2n-6

LA

FAT-2

FAT-1 FAT-1 FAT-1 FAT-1

a

0

2

4

6

8

10

12

14

16

18

LacZ Control

Fat-1/Fat-2

b

0

2

4

6

8

10

C16:1 C18:1n-9 C18:2 n-6 (LA) C18:3 n-3 (ALA) C20:4 n-6 (AA) C20:5 n-3 (EPA)

Fatty Acids

b

Mol %

Fatty A

cid

s

18:1n-9

18:3n-3

ALA

18:4n-3 20:4n-3 20:5n-3

EPA

20:4n-6

AA

20:3n-618:3n-618:2n-6

LA

FAT-2

FAT-1 FAT-1 FAT-1 FAT-1

18:1n-9

18:3n-3

ALA

18:4n-3 20:4n-3 20:5n-3

EPA

20:4n-6

AA

20:3n-618:3n-618:2n-6

LA

FAT-2

FAT-1 FAT-1 FAT-1 FAT-1

a Phospholipids

Triaclyglycerides

Pathways of polyunsaturated fatty acid synthesis. Enzymes are indicated in ovals and major

products are boxed

18:2n6 20:3n6 18:3n3 20:4n3

18:3n6 20:4n6 18:4n3 20:5n3

Δ5/Δ6

fat-2

Δ5/Δ6

fat-1

Zebrafish

0

2

4

6

8

10

12

14

16

18

LacZ Control

Fat-1/Fat-2

b

0

2

4

6

8

10

C16:1 C18:1n-9 C18:2 n-6 (LA) C18:3 n-3 (ALA) C20:4 n-6 (AA) C20:5 n-3 (EPA)

Fatty Acids

b

Mo

l %

Fa

tty A

cid

s

18:1n-9

18:3n-3

ALA

18:4n-3 20:4n-3 20:5n-3

EPA

20:4n-6

AA

20:3n-618:3n-618:2n-6

LA

FAT-2

FAT-1 FAT-1 FAT-1 FAT-1

18:1n-9

18:3n-3

ALA

18:4n-3 20:4n-3 20:5n-3

EPA

20:4n-6

AA

20:3n-618:3n-618:2n-6

LA

FAT-2

FAT-1 FAT-1 FAT-1 FAT-1

a

0

2

4

6

8

10

12

14

16

18

LacZ Control

Fat-1/Fat-2

b

0

2

4

6

8

10

C16:1 C18:1n-9 C18:2 n-6 (LA) C18:3 n-3 (ALA) C20:4 n-6 (AA) C20:5 n-3 (EPA)

Fatty Acids

b

Mo

l %

Fa

tty A

cid

s

18:1n-9

18:3n-3

ALA

18:4n-3 20:4n-3 20:5n-3

EPA

20:4n-6

AA

20:3n-618:3n-618:2n-6

LA

FAT-2

FAT-1 FAT-1 FAT-1 FAT-1

18:1n-9

18:3n-3

ALA

18:4n-3 20:4n-3 20:5n-3

EPA

20:4n-6

AA

20:3n-618:3n-618:2n-6

LA

FAT-2

FAT-1 FAT-1 FAT-1 FAT-1

a

C18:2 n6 C18:3 n3

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Animal Biotechnology and Genomics Education

Animals can metabolize ALA to form n3 long chain PUFA through a series of desaturation and elongation steps

18:1n-9

18:3n-3

ALA

18:4n-3 20:4n-3 20:5n-3

EPA

20:4n-6

AA

20:3n-618:3n-618:2n-6

LA

FAT-2

FAT-1 FAT-1 FAT-1 FAT-1

18:1n-9

18:3n-3

ALA

18:4n-3 20:4n-3 20:5n-3

EPA

20:4n-6

AA

20:3n-618:3n-618:2n-6

LA

FAT-2

FAT-1 FAT-1 FAT-1 FAT-1

Linoleic Acid

-Linolenic Acid

Arachidonic Acid

Eicosapentaenoic Acid

n-6

n-3

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In vivo proof of concept using Fat 1 gene - Beth Kao (MS)

Transgenic mice (C57/BL6 x DBA) were generated by pronuclear microinjection of the SalI/NotI fragment fragment cut from the AVE013 vector, containing the C. elegans omega-3 fatty acid desaturase (Fat 1) under the control of the goat beta-casein promoter of the pBC1 mammary expression vector (Invitrogen).

AVE013 (pBC1+FAT1)

22844 bp

Delta15 desaturase

Ampicillin resisitance (bla)

Beta-casein intron 1

Beta-casein intron 7

Beta-casein intron 8

Goat Beta-Casein Promoter

Bla promoter

pBR322-derived origin

TATA box

Beta-casein 3' genomic DNA

Beta-casein exon 1 (untranslated)

Beta-casein exon 2 (partial; untranslated)

Beta-casein exon 7 (partial; untranslated)

Beta-casein exon 8 (untranslated)

Beta-casein exon 9 (untranslated)

2X beta-globin insulator

SalI (14236)

Not I (8359)

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Introducing Hugh....

Hemizygous sire that produced the Fat 1-12 mice – sired over 25 litters to date – he turned 2 on Saturday so we had a party

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Fat 1-12 line had a single insertion site

Southern analysis of the FAT 1-12 transgenic mice. Lane 1: EcoRI digested founder, lane 2: EcoRI digested F2 mouse, lane 3: HindIII digested founder, lane 4: HindIII digested F2 mouse, lane 5: 1kb Extend Ladder (Invitrogen). Banding pattern suggests a tail to tail ( )

orientation of two transgenes in a single insertion site.

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Milking day at the mouse house

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Good transgene expression – full length Fat 1 expression

mouse beta-casein

fat-1 CDS

Goat beta casein 5’ UTR / fat-1 intron spanning primers

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Animal Biotechnology and Genomics Education

Milk triacylglycerol fatty acid composition

0

2

4

6

8

10

12

14

C18:2n6 C18:3n3 C20:4n6 C20:5n3

Fatty Acids

Mo

l %

Fa

tty A

cid

s

Control

Transgenic

*

***** **

Purina 5015 mouse chow (11% total fat) 28% linoleic acid (18:2n6) 0.7% α-linolenic acid (18:3n3)

Page 21: Endogenous production of omega-3 fatty acids in milk · •Omega-3 (ω3) polyunsaturated fatty acids (PUFA) are well documented for their beneficial health effects •Used to treat

Animal Biotechnology and Genomics Education

0

2

4

6

8

10

12

14

16

18

20

C18:2n6 C18:3n3 C20:4n6 C20:5n3

Fatty Acids

Mo

l %

Fa

tty A

cid

s

Control

Transgenic**

*** ** ***

Purina 5015 mouse chow (11% total fat) 28% linoleic acid (18:2n6) 0.7% α-linolenic acid (18:3n3)

Milk phospholipid fatty acid composition

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Fatty Acids of Brain Lipids from 15 Day Old Mice

0

2

4

6

8

10

12

14

16

C18:2n6

C18:3n3

C20:4n6

C22:2 n6

C20:5n3

C22:3 n3

C22:4 n6

C22:5 n6

C22:5n3

C22:6n3

Fatty Acid

Mo

l %

Fatt

y A

cid

Control

Transgenic

*

***

**

**

**

***

*

*

*

n6 DPA n3 DHA

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In mammalian brains, long-chain PUFA begin to accumulate in the brain during the last days of gestation.

The accretion rate of DHA is the most concentrated compared to other fatty acids

The majority of brain growth, or the “brain growth spurt,” begins after birth and takes place during the first few weeks post-parturition

Afterward, the adult brain has been described to tenaciously retain the long-chain PUFA, even during n3 and n6 fatty acid dietary deficiency

Model for infant nutrition ?

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Animal Biotechnology and Genomics Education

Do mouse pups nursed on Fat1 transgenic dams have increased plasma n3 LC-PUFA levels and higher rates of DHA accretion in the brain ?

• Eight transgenic females and eight nontransgenic full sib control females were placed on a high safflower oil diet (11.5% fat: 69% 18:2n6 LA, 16% oleic acid 18:1, 3% stearic acid 18:0, and 10% palmitic acid 16:0) from breeding to 21 days post-parturition.

• There were 33 pups reared in each treatment group.

• No difference in growth rate was observed.

Page 25: Endogenous production of omega-3 fatty acids in milk · •Omega-3 (ω3) polyunsaturated fatty acids (PUFA) are well documented for their beneficial health effects •Used to treat

Animal Biotechnology and Genomics Education

Mouse milk fat is ~ 1 % phospholipid

Fatty Acids of Milk Phospholipids

0

5

10

15

20

25

C18 C18:1

cis9&10

C18:2n6 C18:3n3 C20:4n6 C20:5n3 C22:5 n6 C22:5n3 C22:6n3

Fatty Acids

% M

ol Fatt

y A

cid

Control

Transgenic

***

***

***

*

Safflower mouse chow (11.5% total fat) 69% linoleic acid (18:2n6) 0.168 % -linolenic acid (18:3n3) 0% n6 or n3 PUFA

Page 26: Endogenous production of omega-3 fatty acids in milk · •Omega-3 (ω3) polyunsaturated fatty acids (PUFA) are well documented for their beneficial health effects •Used to treat

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Fatty Acids of Milk Triacylglycerols

0

5

10

15

20

25

C18 C18:1

cis9&10

C18:2n6 C18:3n3 C20:4n6 C20:5n3 C22:5 n6 C22:5n3 C22:6n3

Fatty Acids

% M

ol Fa

tty A

cid

Control

Transgenic

**

*****

Mouse milk fat is ~ 99 % triacylglycerol

No significant difference in n6 DPA or DHA

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Fatty acids of plasma lipids in 21 day pups nursed on control or transgenic dams

Fatty Acids of Plasma Lipids in 21 Day Old Mice

0.000

5.000

10.000

15.000

20.000

25.000

30.000

C18 C18:1

cis9&10

C18:2n6 C18:3n3 C20:4n6 C20:5n3 C22:5 n6 C22:5n3 C22:6n3

Fatty Acids

% M

ol F

atty

Acid

Control

Transgenic

*****

**

***

Page 28: Endogenous production of omega-3 fatty acids in milk · •Omega-3 (ω3) polyunsaturated fatty acids (PUFA) are well documented for their beneficial health effects •Used to treat

Animal Biotechnology and Genomics Education

Brain Lipids of 21 Day Old Mice

0.000

2.000

4.000

6.000

8.000

10.000

12.000

14.000

16.000

C18:2n6 C18:3n3 C20:4n6 C20:5n3 C22:5 n6 C22:5n3 C22:6n3

Fatty Acids

% M

ol F

atty

Acid

Control

Transgenic

***

***

**

***

***

***

Brain lipids of 21 day pups nursed on control or transgenic dams

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Brain fatty acid time course of pups nursed on control or transgenic dams

0

2

4

6

8

10

12

14

16

Day 0 Day 12 Day 21

% m

ol fa

tty

ac

ids

n6 DPA Control

n6 DPA TG

n3 DHA Control

n3 DHA TG

n3 DHA

n6 DPA

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Animal Biotechnology and Genomics Education

Conclusions from Fat 1 studies

Nursing transgenic dams increased levels of n3 PUFA in the

plasma and brain of pups

Nursing transgenic dams increased the amount of DHA in the

brain over time despite no significant increase of DHA in milk

Pups nursed on nontransgenic dams possessed only ~50% of

the DHA in the brain at 21 days, and had significantly elevated

levels of n6 docosapentaenoic acid (DPA, 22:5n6) in the plasma

and brain despite no significant difference of n6 DPA in milk

Other studies have found that during n3 PUFA deficiency, neural

DHA composition decreases significantly, and n6 DPA replaces

DHA in the n3 deficient tissues.

Significant DHA deficiency states are associated with decreased

behavioral function in animal models.

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Animal Biotechnology and Genomics Education

What about Fat 2 ?

18:1n-9

18:3n-3

ALA

18:2n-6 LA

FAT-2

FAT-1

Fat 1 is sufficient in monogastrics

but in ruminants need Fat 2 too

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Control pup raised on Fat 2 dam

Fat 2 pup raised on control dam

10-day old pups – two litters both of 7 babies

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10-day old pups – two litters both of 7 babies – individual weights. Some Fat 2 babies never make it beyond 11-12 days

1 2 3 4 5 6 7

0

2

4

6

8

Grams

Mouse number

2-14 Dam

Control Dam

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Animal Biotechnology and Genomics Education

FAT2 babies never grow as well as FAT1 or C57 controls

0

2

4

6

8

10

12

10 21

Age (days)

Gra

ms

Fat1-8

fat2-1

fat2-22

fat2-27

Fat2-14 never made it to 21 days

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Animal Biotechnology and Genomics Education

Other researchers have noted agalactia with a ∆12 desaturase

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Animal Biotechnology and Genomics Education

Future work

Solve the Fat 2/∆12 desaturase problem

Cross Fat 2 with Fat 1 mice

Obtain In vivo proof of concept

Move into a ruminant

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Animal Biotechnology and Genomics Education

Conclusion

Increasing the proportion of ω3 fatty acids found in ruminant products offers a way to improve the nutritional content of an important component of the American diet.

The development of sustainable dietary sources of land-based beef and dairy products rich in ω3 polyunsaturated fatty acids would provide a compelling example of how animal biotechnology could be utilized to produce functional foods for the enhancement of human health.

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Animal Biotechnology and Genomics Education

Acknowledgements

Alison Van Eenennaam Laboratory, UC Davis – Beth Kao (Fat 1 mouse studies)

– Kristine Lewis (Mouse Colony Management)

Ed DePeters Laboratory, UC Davis

– Scott Taylor (Milk Analysis)

Juan Medrano Laboratory, UC Davis – Kerri Morimoto (In vitro proof of concept in HC11 cells)

John Browse Laboratory, Washington State Institute of Biological Chemistry, Washington State University, Pullman, WA for C. elegans fat-1 and fat-2 cDNA.

Supported by NIH grant 1R03HD047193-01