PROS AND CONS OF CHOLINE SUPPLEMENTATION.

Transcription

1 PROS AND CONS OF CHOLINE SUPPLEMENTATION. Steven H. Zeisel, MD, PhD Professor of Nutrition and Pediatrics University of North Carolina at Chapel Hill Director, UNC Nutrition Research Institute Director, UNC Nutrition Obesity Research Center

2 STEVEN ZEISEL DISCLOSURES AFFILIATION/FINANCIAL INTERESTS Grants/Research Support: Scientific Advisory Board/Consultant: Honorarium for this talk: CORPORATE ORGANIZATION NIH, USDA, Nestle, Hershey, Egg Nutrition Center Dupont Nutrition, Metabolon, Nutrigene Sciences, Genovive, American Pistachio Growers. Wyeth (Nestle) Stock Shareholder: Nutrigene Sciences

3 CHOLINE IOM designated as essential nutrient in 1998 Needed for membranes, acetylcholine, methylation Important for liver and muscle function Critical for fetal brain development

4 mg/100g food FOOD CHOLINE Daily requirement estimated at 550 mg From

5 MOST AMERICANS DO NOT EAT ENOUGH CHOLINE Males AI Females pregnancy AI mg/day

6 ENDOGENOUS SYNTHESIS OF CHOLINE Phosphatidylethanolamine N- methyltransferase (PEMT) 3 S-adenosylmethionine + phosphatidylethanolamine phosphatidylcholine FASEB J 21: , 2007

7 DIETARY REQUIREMENT FOR CHOLINE 77% of Men 80% of Postmenopausal Women 44% of Premenopausal Women Need to Eat Choline (fatty liver, muscle damage)

8 IN LOW CHOLINE FATTY LIVER DEVELOPS Mean Liver/Spleen CPK Level fat (U/L) ratio * Normal Diet Depletion Repletion Phase Of Study Am J Clin Nutr 2007;85:

9 EXPORT OF FAT FROM LIVER REQUIRES CHOLINE triacylglycerol phosphatidylcholine apoprotein VLDL

10 ARE SOME PEOPLE ESPECIALLY SENSITIVE TO DIETARY CHOLINE? Single nucleotide polymorphisms (SNPs)

11 SNPS CAUSE METABOLIC INEFFICIENCIES Metabolism Nutrient Metabolite No SNP Nutrient Metabolite metabolite Metabolite SNP DIET DELIVERS METABOLITE

12 NAFLD PREDICTED BY CHOLINE SNPs Fatty liver Lowest Highest Group Group Variant alleles triacylglycerol phosphatidylcholine apoprotein VLDL FASEB J :

13 LOW CHOLINE IN 10% OF PEOPLE RESULTS IN MUSCLE DAMAGE Mean CPK Level (U/L) * Normal Diet Depletion Repletion Phase Of Study American Journal of Clinical Nutrition 85(5): , 2007

14 LOW CHOLINE IN 10% OF PEOPLE RESULTS IN MUSCLE DAMAGE FASEB J 2014;28: FASEB J :

15 Europe Asia Mexico Africa AA AG GG Need more choline rs SLC44A1 A G

16 Europe Asia Mexico Africa GG GA AA rs Need more choline CHKB G A

17 REQUIREMENT FOR CHOLINE - GENDER 77% of Men 80% of Postmenopausal Women 44% of Premenopausal Women WHY DON T 56% OF YOUNG WOMEN NEED CHOLINE? V

18 ENDOGENOUS SYNTHESIS OF CHOLINE INDUCED BY ESTROGEN Phosphatidylethanolamine N- methyltransferase (PEMT) + 3 S-adenosylmethionine + phosphatidylethanolamine phosphatidylcholine Estrogen

19 PEMT INDUCED BY ESTROGEN Mouse Rat hepatocyte Human RNA RNA Activity Activity FASEB Journal 21: , 2007

20 REQUIREMENT FOR CHOLINE - GENDER IF THEY COULD MAKE THEIR OWN CHOLINE, WHY DO 44% OF YOUNG WOMEN STILL NEED CHOLINE? V

21 SNP PEMT rs PREVENTS INDUCTION BY ESTROGEN Phosphatidylethanolamine N- methyltransferase (PEMT) + 3 S-adenosylmethionine + phosphatidylethanolamine X phosphatidylcholine Estrogen J. Biol. Chem. 286: , 2011

22 PEMT SNP RESULTS IN NO RESPONSE TO ESTROGEN No alleles (GG) 1 allele (GC) 2 alleles (CC) Phosphatidylethanolamine N- methyltransferase (PEMT) X 3 S-adenosylmethionine + phosphatidylcholine phosphatidylethanolamine Primary human hepatocytes. Rs ; Rx moxesterol for 24 h. J. Biol. Chem. 286: , 2011

23 PEMT rs FREQUENCY Europe Asia Mexico Africa GG GC CC rs Need more choline PEMT G C

24 CHOLINE IN PREGNANCY & LACTATION Maternal blood = 10 µm Amniotic fluid = 140 µm Mediated uptake of choline across the placenta. Breast milk rich in choline compounds 1500 µm Mediated transport of choline across the mammary gland. Graphics:

25 SERUM CHOLINE HIGH DURING FIRST YEAR IN HUMANS 35 Serum Free Choline, µmol/l Adult level 0 Postnatal day Ilcol et al., J Nutr Biochem. 2005;16:

26 26 24 CHOLINE DURING Choices BRAIN Before DEVELOPMENT 20 IMPROVES Maze is MEMORY Empty 18 CRITICAL PERIODS 22 OF Blocks of 3 Sessions control prenatal 6-11 prenatal postnatal 1-15 postnatal postnatal dams 200 mg/day in water pups 300 mg/kg sc From Meck and Williams Neurosci Biobehav Rev. 27(4):385-99, 2003

27 LIFELONG EFFECT OF CHOLINE Neurosci Biobehav Rev. 27:385-99, 2003

28 1 st & 2 nd TRIMESTER MATERNAL CHOLINE INTAKE PREDICTS MEMORY IN CHILD AT 7 Yr Wide Range Assessment of Memory and Learning, Second Edition (WRAML2), Design and Picture Memory subtests at age 7 y among 890 mother-child pairs in Project Viva, eastern Massachusetts, to Replotted from: Boeke C E et al. Am. J. Epidemiol. 2013;177:

29 PRE- & POSTNATAL CRITICAL PERIOD FOR CHOLINE Rodent gives birth on day E21 - Hippocampus develops E12-E18 Human equivalent = ~25 weeks gestation - 4 yrs postnatal

30 MATERNAL CHOLINE MODULATES HOW FETAL NEURAL PROGENITORS DIVIDE Low Control

31 NEUROGENESIS IS MODULATED BY CHOLINE E17 Neural progenitors in fetal brain were reduced if mother (mouse) fed a low vs. control choline diet during pregnancy. Low choline Normal choline Nestin-CFPnuc transgenic mice

32 NEUROGENESIS IS MODULATED BY CHOLINE CORTEX E17 Late-born neurons missing in cortex layers 2-6

33 NEUROGENESIS IS ALTERED BY EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) Activation of the EGF receptor in late progenitor cells stimulates cell proliferation, migration, and astrocyte differentiation. Differences in the level of EGFR expression determine how progenitor cells interpret an extrinsic signal at specific stages of development. EGFR is upregulated at midgestation in the mouse telencephalon. From

34 LOW CHOLINE ATTENUATES RESPONSE TO EGF pegfr perk1/2 pakt NPCs

35 EFFECT OF CHOLINE MEDIATED BY EGFR PROTEIN REDUCTION

36 NPC GROWTH RESTORED BY TRANSFECTION WITH EGFR

37 LOW CHOLINE DECREASES EGFR SYNTHESIS DESPITE NORMAL mrna Egfr mrna cyclohexamide

38 IN NPCs LOW CHOLINE ALTERS mir-129 EXPRESSION 3 Fold change Overexpressed Underexpressed

39 IN NPCs EGFR DECREASED BY mir-129 EGFR

40 EFFECT OF LOW CHOLINE MEDIATED BY LOSS OF EGFR

41 OTHER COMMON SNPS ALTER CHOLINE REQUIREMENT BHMT FASEB J. 20, (2006); 28: (2014) PROC.NAT.ACAD.SCI. USA 102: (2005)

42 CHOLINE AND SPERM DYSFUNCTION FASEB J 2014;28:

43 MEN WITH CHDH rs12676 G233T

44 CHDH rs12676 G233T DYSMORPHIC MITOCHONDRIA PLoS One. 2012;7(4):e doi: /journal.pone

45 CHDH rs12676 G233T LOW ATP CHDH PLoS One. 2012;7(4):e doi: /journal.pone

46 Europe Asia Mexico Africa GG GT TT rs12676 CHDH G T Need more choline

47 LOW CHOLINE (METHYL DEFICIENT) DIET RESULTS IN LIVER CANCER Number tumors % 100% Cancer Nodules 10 0 Low 0% Ctl N=45 N=45 Ghoshal &Farber. Carcinogenesis 5: , 1984

48 DELETION OF Bhmt RESULTS IN LIVER CANCER BHM T

49 AT 1 YR DELETION OF Bhmt RESULTS IN LIVER CANCER J Biol Chem. 2011;286:

50 DO HUMANS WITH BHMT SNPS GET LIVER CANCER??? Europe Asia Mexico Africa GG GA AA Need more choline rs BHMT G A

51 SUMMARY: CHOLINE & HEALTH Subpopulations (SNPs) with special needs. Fatty Liver Muscle Critical nutrient for brain development Sperm function Cancer

52 WILL CHOLINE STORY LAST? Year 2364, Star Trek Next Generation

53 Thank you A. Johnson K-A. da Costa M. Spencer Y. Wang Y-W. Teng L. Fischer E. Yen J. Owen M. Niculescu K. Corbin C. Craciunescu N. Surzenko M. Mehedint M. Resseguie H-M. Hwang S. Orena W. Sha M. Kohlmeier W. Friday E. Pjetri X. Zhu J. Song X. Zhou D. Lupu S. Goodson Collaborators: Jan Blusztajn, Tina Williams, Wei Jia, Tim Garrow, Joe Galanko Funding: NIH (NIDDK, ODS, NIA), USDA, Bill & Melinda Gates Foundation, Nestle.