Skip to main content
Log in

Phytosterol Esterification is Markedly Decreased in Preterm Infants Receiving Routine Parenteral Nutrition

  • Original Article
  • Published:
Lipids

Abstract

Several studies reported the association between total plasma phytosterol concentrations and the parenteral nutrition-associated cholestasis (PNAC). To date, no data are available on phytosterol esterification in animals and in humans during parenteral nutrition (PN). We measured free and esterified sterols (cholesterol, campesterol, stigmasterol, and sitosterol) plasma concentrations during PN in 16 preterm infants (500–1249 g of birth weight; Preterm-PN), in 11 term infants (Term-PN) and in 12 adults (Adult-PN). Gas chromatography–mass spectrometry was used for measurements. Plasma concentrations of free cholesterol (Free-CHO), free phytosterols (Free-PHY) and esterified phytosterols (Ester-PHY) were not different among the three PN groups. Esterified cholesterol (Ester-CHO) was statistically lower in Preterm-PN than Adult-PN. Preterm-PN had significantly higher Free-CHO/Ester-CHO and Free-PHY/Ester-PHY ratios than Adult-PN (Free-CHO/Ester-CHO: 1.1 ± 0.7 vs. 0.6 ± 0.2; Free-PHY/Ester-PHY: 4.1 ± 2.6 vs. 1.3 ± 0.8; *P < 0.05). Free-CHO/Ester-CHO and Free-PHY/Ester-PHY ratios of Term-PN (Free-CHO/Ester-CHO: 1.1 ± 0.4; Free-PHY/Ester-PHY: 2.9 ± 1.7) were not different from either Preterm-PN or from Adult-PN. Plasma Free-CHO/Ester-CHO and Free-PHY/Ester-PHY were unchanged after 24 h on fat-free PN both in Preterm-PN and in Adult-PN. Free-PHY/Ester-PHY did not correlate with phytosterol intake in Preterm-PN. Free-PHY/Ester-PHY of Preterm-PN was positively correlated with the Free-CHO/Ester-CHO and negatively correlated with gestational age and birth weight. In conclusion, PHY were esterified to a lesser extent than CHO in all study groups; the esterification was markedly decreased in Preterm-PN compared to Adult-PN. The clinical consequences of these findings warrant further investigations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

Abbreviations

ACAT:

Acyl-CoA cholesterol acyltransferase

Adult-PN:

Adults on PN

CAMP:

Campesterol

CHO:

Cholesterol

Ester:

Esterified

IV:

Intravenous

LCAT:

Lecithin cholesterol acyltransferase

LE:

Lipid emulsion

NICU:

Neonatal intensive care unit

PHY:

Phytosterols

PN:

Parenteral nutrition

PNAC:

Parenteral nutrition-associated cholestasis

Preterm-PN:

Preterm infants on PN

SITO:

Sitosterol

SO:

Soybean oil

STIGM:

Stigmasterol

Term-PN:

Term infants on PN

Δ:

Difference

References

  1. Kaufman SS, Gondolesi GE, Fishbein TM (2003) Parenteral nutrition associated liver disease. Semin Neonatol 8:375–381

    Article  PubMed  Google Scholar 

  2. La Scala GC, Le Coultre C, Roche BG, Bugmann P, Belli DC (1993) The addition of lipids increases the total parenteral nutrition-associated cholestasis in the rat. Eur J Pediatr Surg 3:224–227

    Article  PubMed  Google Scholar 

  3. Clayton PT, Bowron A, Mills KA, Massoud A, Casteels M, Milla PJ (1993) Phytosterolemia in children with parenteral nutrition-associated cholestatic liver disease. Gastroenterology 105:1806–1813

    Article  CAS  PubMed  Google Scholar 

  4. Whitfield PD, Clayton PT, Muller DP (2000) Effect of intravenous lipid emulsions on hepatic cholesterol metabolism. J Pediatr Gastroenterol Nutr 30:538–546

    Article  CAS  PubMed  Google Scholar 

  5. Llop JM, Virgili N, Moreno-Villares JM, Garcia-Peris P, Serrano T, Forga M, Solanich J, Pita AM (2008) Phytosterolemia in parenteral nutrition patients: implications for liver disease development. Nutrition 24:1145–1152

    Article  CAS  PubMed  Google Scholar 

  6. Bindl L, Lutjohann D, Buderus S, Lentzev MJ, Bergmann K (2000) High plasma levels of phytosterols in patients on parenteral nutrition: a marker of liver dysfunction. J Pediatr Gastroenterol Nutr 31:313–316

    Article  CAS  PubMed  Google Scholar 

  7. Iyer KR, Spitz L, Clayton P (1998) BAPS prize lecture: new insight into mechanisms of parenteral nutrition-associated cholestasis: role of plant sterols. British Association of Paediatric Surgeons. J Pediatr Surg 33:1–6

    Article  CAS  PubMed  Google Scholar 

  8. Pianese P, Salvia G, Campanozzi A, D’Apolito O, Dello Russo A, Pettoello-Mantovani M, Corso G (2008) Sterol profiling in red blood cell membranes and plasma of newborns receiving total parenteral nutrition. J Pediatr Gastroenterol Nutr 47:645–651

    Article  CAS  PubMed  Google Scholar 

  9. Ellegard L, Sunesson A, Bosaeus I (2005) High serum phytosterol levels in short bowel patients on parenteral nutrition support. Clin Nutr 24:415–420

    Article  CAS  PubMed  Google Scholar 

  10. Lin DS, Steiner RD, Merkens LS, Pappu AS, Connor WE (2010) The effects of sterol structure upon sterol esterification. Atherosclerosis 208:155–160

    Article  CAS  PubMed  Google Scholar 

  11. Lembcke J, Ceglarek U, Fiedler GM, Baumann S, Leichtle A, Thiery J (2005) Rapid quantification of free and esterified phytosterols in human serum using APPI-LC-MS/MS. J Lipid Res 46:21–26

    Article  CAS  PubMed  Google Scholar 

  12. Tilvis RS, Miettinen TA (1986) Serum plant sterols and their relation to cholesterol absorption. Am J Clin Nutr 43:92–97

    CAS  PubMed  Google Scholar 

  13. Savini S, D’Ascenzo R, Biagetti C, Serpentini G, Pompilio A, Bartoli A, Cogo PE, Carnielli VP (2013) The effect of 5 intravenous lipid emulsions on plasma phytosterols in preterm infants receiving parenteral nutrition: a randomized clinical trial. Am J Clin Nutr 98:312–318

    Article  CAS  PubMed  Google Scholar 

  14. Xu Z, Harvey KA, Pavlina T, Dutot G, Hise M, Zaloga GP, Siddiqui RA (2012) Steroidal compounds in commercial parenteral lipid emulsions. Nutrients 4:904–921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Forchielli ML, Bersani G, Tala S, Grossi G, Puggioli C, Masi M (2010) The spectrum of plant and animal sterols in different oil-derived intravenous emulsions. Lipids 45:63–71

    Article  CAS  PubMed  Google Scholar 

  16. Sperry WM (1935) Cholesterol esterase in blood. J Biol Chem 111:467–478

    CAS  Google Scholar 

  17. Glomset JA (1968) The plasma lecithins: cholesterol acyltransferase reaction. J Lipid Res 9:155–167

    CAS  PubMed  Google Scholar 

  18. Sperry WM, Stoyanoff VA (1938) The enzymatic synthesis and hydrolysis of cholesterol esters in blood serum. J Biol Chem 126:77–89

    CAS  Google Scholar 

  19. Lee RG, Kelley KL, Sawyer JK, Farese RV, Parks JS, Rudel LL (2004) Plasma cholesteryl esters provided by lecithin:cholesterol acyltransferase and acyl-coenzyme a: cholesterol acyltransferase 2 have opposite atherosclerotic potential. Circ Res 95:998–1004

    Article  CAS  PubMed  Google Scholar 

  20. Piran U, Nishida T (1979) Utilization of various sterols by lecithin-cholesterol acyltransferase as acyl acceptors. Lipids 14:478–482

    Article  CAS  PubMed  Google Scholar 

  21. Macauley SK, Billheimer JT, Ritter KS (1986) Sterol substrate specificity of acyl coenzyme A: cholesterol acyltransferase from the corn earworm, Heliothis zea. J Lipid Res 27:64–71

    CAS  PubMed  Google Scholar 

  22. Tavani DM, Nes WR, Billheimer JT (1982) The sterol substrate specificity of acyl CoA: cholesterol acyltransferase from rat liver. J Lipid Res 23:774–781

    CAS  PubMed  Google Scholar 

  23. Lee RG, Shah R, Sawyer JK, Hamilton RL, Parks JS, Rudel LL (2005) ACAT2 contributes cholesteryl esters to newly secreted VLDL, whereas LCAT adds cholesteryl ester to LDL in mice. J Lipid Res 46:1205–1212

    Article  CAS  PubMed  Google Scholar 

  24. Folch J, Lees M, Sloane Stanley GH (1957) A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 226:497–509

    CAS  PubMed  Google Scholar 

  25. Corso G, Rossi M, De BD, Rossi I, Parenti G, Dello RA (2002) Effects of sample storage on 7- and 8-dehydrocholesterol levels analysed on whole blood spots by gas chromatography-mass spectrometry-selected ion monitoring. J Chromatogr B Analyt Technol Biomed Life Sci 766:365–370

    Article  CAS  PubMed  Google Scholar 

  26. Bhattacharyya AK, Connor WE (1974) Beta-sitosterolemia and xanthomatosis. A newly described lipid storage disease in two sisters. J Clin Invest 53:1033–1043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Vahouny GV, Connor WE, Subramaniam S, Lin DS, Gallo LL (1983) Comparative lymphatic absorption of sitosterol, stigmasterol, and fucosterol and differential inhibition of cholesterol absorption. Am J Clin Nutr 37:805–809

    CAS  PubMed  Google Scholar 

  28. Papadopoulos A, Hamosh M, Chowdhry P, Scanlon JW, Hamosh P (1988) Lecithin-cholesterol acyltransferase in newborn infants: low activity level in preterm infants. J Pediatr 113:896–898

    Article  CAS  PubMed  Google Scholar 

  29. Jain SK (1985) Prematurity and lecithin-cholesterol acyltransferase deficiency in newborn infants. Pediatr Res 19:58–60

    Article  CAS  PubMed  Google Scholar 

  30. Nghiem-Rao TH, Tunc I, Mavis AM, Cao Y, Polzin EM, Firary MF, Wang X, Simpson PM, Patel SB (2015) Kinetics of phytosterol metabolism in neonates receiving parenteral nutrition. Pediatr Res 78:181–189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wang J, Sun F, Zhang DW, Ma Y, Xu F, Belani JD, Cohen JC, Hobbs HH, Xie XS (2006) Sterol transfer by ABCG5 and ABCG8: in vitro assay and reconstitution. J Biol Chem 281:27894–27904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chan YM, Varady KA, Lin Y, Trautwein E, Mensink RP, Plat J, Jones PJ (2006) Plasma concentrations of plant sterols: physiology and relationship with coronary heart disease. Nutr Rev 64:385–402

    Article  PubMed  Google Scholar 

  33. Hukkinen M, Mutanen A, Nissinen M, Merras-Salmio L, Gylling H, Pakarinen MP (2016) Parenteral plant sterols accumulate in the liver reflecting their increased serum levels and portal inflammation in children with intestinal failure. J Parenter Enteral Nutr. [Epub ahead of print]

  34. Karim C, El Kasmi ALA, Devereaux Michael W, Vue Padade M, Zhang Wujuan, Setchell Kenneth D R, Karpen Saul J, Sokol Ronald J (2013) Phytosterols promote liver injury and kupffer cell activation in parenteral nutrition-associated liver disease. Sci Transl Med 5:1–10

    Google Scholar 

  35. Clayton PT, Whitfield P, Iyer K (1998) The role of phytosterols in the pathogenesis of liver complications of pediatric parenteral nutrition. Nutrition 14:158–164

    Article  CAS  PubMed  Google Scholar 

  36. Vlaardingerbroek H, Ng K, Stoll B, Benight N, Chacko S, Kluijtmans LA, Kulik W, Squires EJ, Olutoye O, Schady D, Finegold ML, van Goudoever JB, Burrin DG (2014) New generation lipid emulsions prevent PNALD in chronic parenterally fed preterm pigs. J Lipid Res 55:466–477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zaloga GP (2015) Phytosterols, Lipid Administration, and Liver Disease During Parenteral Nutrition. JPEN J Parenter Enteral Nutr 39:39S–60S

    Article  PubMed  Google Scholar 

  38. Carter BA, Taylor OA, Prendergast DR, Zimmerman TL, Von Furstenberg R, Moore DD, Karpen SJ (2007) Stigmasterol, a soy lipid-derived phytosterol, is an antagonist of the bile acid nuclear receptor FXR. Pediatr Res 62:301–306

    Article  CAS  PubMed  Google Scholar 

  39. Yuan Q, Bie J, Wang J, Ghosh SS, Ghosh S (2013) Cooperation between hepatic cholesteryl ester hydrolase and scavenger receptor BI for hydrolysis of HDL-CE. J Lipid Res 54:3078–3084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors are grateful to the infants’ parents, to the NICU staff and to the adults of the Department of Dietetics and Clinical Nutrition. There are no conflicts of interest to declare. There were 12 authors who contributed to the work. We report below the contribution of each author: VPC was responsible for the design of the study; SS, AC, DP, MS and AP contributed to data collection and analysis; RD, GV, CB, MT and AN contributed to subject recruitment and data collection; PEC was in charge of the statistical analysis. All authors read and approved the final manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Virgilio Paolo Carnielli.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Savini, S., Correani, A., Pupillo, D. et al. Phytosterol Esterification is Markedly Decreased in Preterm Infants Receiving Routine Parenteral Nutrition. Lipids 51, 1353–1361 (2016). https://doi.org/10.1007/s11745-016-4197-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11745-016-4197-y

Keywords

Navigation