Parenteral nutrition (PN) is often associated with the deterioration of liver functions (PNALD). Omega-3 polyunsaturated fatty acids (PUFA) were reported to alleviate PNALD but the underlying mechanisms have not been fully unraveled yet. Using omics´ approach, we determined serum and liver lipidome, liver proteome, and liver bile acid profile as well as markers of inflammation and oxidative stress in rats administered either ω-6 PUFA based lipid emulsion (Intralipid) or ω-6/ω-3 PUFA blend (Intralipid/Omegaven) via the enteral or parenteral route. In general, we found that enteral administration of both lipid emulsions has less impact on the liver than the parenteral route. Compared with parenterally administered Intralipid, PN administration of ω-3 PUFA was associated with 1. increased content of eicosapentaenoic (EPA)- and docosahexaenoic (DHA) acids-containing lipid species; 2. higher abundance of CYP4A isoenzymes capable of bioactive lipid synthesis and the increased content of their potential products (oxidized EPA and DHA); 3. downregulation of enzymes involved CYP450 drug metabolism what may represent an adaptive mechanism counteracting the potential negative effects (enhanced ROS production) of PUFA metabolism; 4. normalized anti-oxidative capacity and 5. physiological BAs spectrum. All these findings may contribute to the explanation of ω-3 PUFA protective effects in the context of PN.

1st Faculty of Medicine Charles University Prague Czechia

Center of Experimental Medicine Institute for Clinical and Experimental Medicine Prague Czechia

Czech Centre for Phenogenomics Vestec Czechia

Department of Pathology Institute for Clinical and Experimental Medicine Prague Czechia

Institute of Hematology and Blood Transfusion Prague Czechia

Proteomics Core Facility BIOCEV Faculty of Science Charles University Prague Czechia

University of Chemistry and Technology Prague Czechia

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Mizock BA. Immunonutrition and critical illness: an update. Nutrition. 2010;26:701–707. doi: 10.1016/j.nut.2009.11.010. PubMed DOI

Cahova, M., Bratova, M. & Wohl, P. Parenteral Nutrition-Associated Liver Disease: The Role of the Gut Microbiota. Nutrients9, 10.3390/nu9090987 (2017). PubMed PMC

Gabe SM, Culkin A. Abnormal liver function tests in the parenteral nutrition fed patient. Frontline Gastroenterol. 2010;1:98–104. doi: 10.1136/fg.2009.000521. PubMed DOI PMC

Tillman EM. Review and clinical update on parenteral nutrition-associated liver disease. Nutr Clin Pract. 2013;28:30–39. doi: 10.1177/0884533612462900. PubMed DOI

Tillman EM, Helms RA, Black DD. Eicosapentaenoic acid and docosahexaenoic acid synergistically attenuate bile acid-induced hepatocellular apoptosis. JPEN J Parenter Enteral Nutr. 2012;36:36–42. doi: 10.1177/0148607111409588. PubMed DOI

Ren T, et al. Lipid emulsions in parenteral nutrition: current applications and future developments. Expert Opin Drug Deliv. 2013;10:1533–1549. doi: 10.1517/17425247.2013.824874. PubMed DOI

Bharadwaj S, Gohel T, Deen OJ, DeChicco R, Shatnawei A. Fish oil-based lipid emulsion: current updates on a promising novel therapy for the management of parenteral nutrition-associated liver disease. Gastroenterol Rep (Oxf) 2015;3:110–114. doi: 10.1093/gastro/gov011. PubMed DOI PMC

Roche LD. Oxidative stress: the dark side of soybean-oil-based emulsions used in parenteral nutrition. Oxid Antioxid. Med Sci. 2012;1:11–14. doi: 10.5455/oams.100412.rv.002. DOI

Burns DL, Gill BM. Reversal of parenteral nutrition-associated liver disease with a fish oil-based lipid emulsion (Omegaven) in an adult dependent on home parenteral nutrition. JPEN J Parenter Enteral Nutr. 2013;37:274–280. doi: 10.1177/0148607112450301. PubMed DOI

Gura KM, et al. Safety and efficacy of a fish-oil-based fat emulsion in the treatment of parenteral nutrition-associated liver disease. Pediatrics. 2008;121:e678–686. doi: 10.1542/peds.2007-2248. PubMed DOI

Lauriti G, et al. Incidence, prevention, and treatment of parenteral nutrition-associated cholestasis and intestinal failure-associated liver disease in infants and children: a systematic review. JPEN J Parenter Enteral Nutr. 2014;38:70–85. doi: 10.1177/0148607113496280. PubMed DOI

Nandivada P, et al. Mechanisms for the effects of fish oil lipid emulsions in the management of parenteral nutrition-associated liver disease. Prostaglandins Leukot Essent Fatty Acids. 2013;89:153–158. doi: 10.1016/j.plefa.2013.02.008. PubMed DOI

Im DS. Omega-3 fatty acids in anti-inflammation (pro-resolution) and GPCRs. Prog Lipid Res. 2012;51:232–237. doi: 10.1016/j.plipres.2012.02.003. PubMed DOI

Poudyal H, Panchal SK, Diwan V, Brown L. Omega-3 fatty acids and metabolic syndrome: effects and emerging mechanisms of action. Prog Lipid Res. 2011;50:372–387. doi: 10.1016/j.plipres.2011.06.003. PubMed DOI

Kuda O. Bioactive metabolites of docosahexaenoic acid. Biochimie. 2017;136:12–20. doi: 10.1016/j.biochi.2017.01.002. PubMed DOI

Anjani K, et al. Circulating phospholipid profiling identifies portal contribution to NASH signature in obesity. J Hepatol. 2015;62:905–912. doi: 10.1016/j.jhep.2014.11.002. PubMed DOI

Lin L, et al. Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017;66:432–448. doi: 10.1002/hep.29033. PubMed DOI

Luczaj W, et al. Plasma lipidomic profile signature of rheumatoid arthritis versus Lyme arthritis patients. Arch Biochem Biophys. 2018;654:105–114. doi: 10.1016/j.abb.2018.07.021. PubMed DOI

Poorani R, Bhatt AN, Dwarakanath BS, Das UN. COX-2, aspirin and metabolism of arachidonic, eicosapentaenoic and docosahexaenoic acids and their physiological and clinical significance. Eur J Pharmacol. 2016;785:116–132. doi: 10.1016/j.ejphar.2015.08.049. PubMed DOI

Jump DB. The biochemistry of n-3 polyunsaturated fatty acids. J Biol Chem. 2002;277:8755–8758. doi: 10.1074/jbc.R100062200. PubMed DOI

Konkel A, Schunck WH. Role of cytochrome P450 enzymes in the bioactivation of polyunsaturated fatty acids. Biochim Biophys Acta. 2011;1814:210–222. doi: 10.1016/j.bbapap.2010.09.009. PubMed DOI

Samuelsson B, Dahlen SE, Lindgren JA, Rouzer CA, Serhan CN. Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science. 1987;237:1171–1176. doi: 10.1126/science.2820055. PubMed DOI

Lopez-Vicario C, et al. Pro-resolving mediators produced from EPA and DHA: Overview of the pathways involved and their mechanisms in metabolic syndrome and related liver diseases. Eur J Pharmacol. 2016;785:133–143. doi: 10.1016/j.ejphar.2015.03.092. PubMed DOI

Shoieb SM, El-Sherbeni AA, El-Kadi AOS. Subterminal hydroxyeicosatetraenoic acids: Crucial lipid mediators in normal physiology and disease states. Chem Biol Interact. 2019;299:140–150. doi: 10.1016/j.cbi.2018.12.004. PubMed DOI

Campbell WB, Falck JR. Arachidonic acid metabolites as endothelium-derived hyperpolarizing factors. Hypertension. 2007;49:590–596. doi: 10.1161/01.HYP.0000255173.50317.fc. PubMed DOI

Fleming I. Vascular cytochrome p450 enzymes: physiology and pathophysiology. Trends Cardiovasc Med. 2008;18:20–25. doi: 10.1016/j.tcm.2007.11.002. PubMed DOI

McGiff JC, Quilley J. 20-HETE and the kidney: resolution of old problems and new beginnings. Am J Physiol. 1999;277:R607–623. doi: 10.1152/ajpregu.1999.277.3.R607. PubMed DOI

Miyata N, Roman RJ. Role of 20-hydroxyeicosatetraenoic acid (20-HETE) in vascular system. J Smooth Muscle Res. 2005;41:175–193. doi: 10.1540/jsmr.41.175. PubMed DOI

Seubert JM, Zeldin DC, Nithipatikom K, Gross GJ. Role of epoxyeicosatrienoic acids in protecting the myocardium following ischemia/reperfusion injury. Prostaglandins Other Lipid Mediat. 2007;82:50–59. doi: 10.1016/j.prostaglandins.2006.05.017. PubMed DOI PMC

Spector AA. Arachidonic acid cytochrome P450 epoxygenase pathway. J Lipid Res. 2009;50(Suppl):S52–56. doi: 10.1194/jlr.R800038-JLR200. PubMed DOI PMC

Arterburn LM, Hall EB, Oken H. Distribution, interconversion, and dose response of n-3 fatty acids in humans. Am J Clin Nutr. 2006;83:1467S–1476S. doi: 10.1093/ajcn/83.6.1467S. PubMed DOI

Arnold C, et al. Arachidonic acid-metabolizing cytochrome P450 enzymes are targets of {omega}-3 fatty acids. J Biol Chem. 2010;285:32720–32733. doi: 10.1074/jbc.M110.118406. PubMed DOI PMC

Fer M, et al. Cytochromes P450 from family 4 are the main omega hydroxylating enzymes in humans: CYP4F3B is the prominent player in PUFA metabolism. J Lipid Res. 2008;49:2379–2389. doi: 10.1194/jlr.M800199-JLR200. PubMed DOI

Lauterbach B, et al. Cytochrome P450-dependent eicosapentaenoic acid metabolites are novel BK channel activators. Hypertension. 2002;39:609–613. doi: 10.1161/hy0202.103293. PubMed DOI

Yore MM, et al. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell. 2014;159:318–332. doi: 10.1016/j.cell.2014.09.035. PubMed DOI PMC

Syed I, et al. Palmitic Acid Hydroxystearic Acids Activate GPR40, Which Is Involved in Their Beneficial Effects on Glucose Homeostasis. Cell Metab. 2018;27:419–427 e414. doi: 10.1016/j.cmet.2018.01.001. PubMed DOI PMC

Nelson AT, et al. Stereochemistry of Endogenous Palmitic Acid Ester of 9-Hydroxystearic Acid and Relevance of Absolute Configuration to Regulation. J Am Chem Soc. 2017;139:4943–4947. doi: 10.1021/jacs.7b01269. PubMed DOI PMC

Kuda O, et al. Nrf2-Mediated Antioxidant Defense and Peroxiredoxin 6 Are Linked to Biosynthesis of Palmitic Acid Ester of 9-Hydroxystearic Acid. Diabetes. 2018;67:1190–1199. doi: 10.2337/db17-1087. PubMed DOI PMC

Grundt H, Nilsen DW, Mansoor MA, Nordoy A. Increased lipid peroxidation during long-term intervention with high doses of n-3 fatty acids (PUFAs) following an acute myocardial infarction. Eur J Clin Nutr. 2003;57:793–800. doi: 10.1038/sj.ejcn.1601730. PubMed DOI

Hayes JD, Pulford DJ. The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol. 1995;30:445–600. doi: 10.3109/10409239509083491. PubMed DOI

Miloudi K, et al. The mode of administration of total parenteral nutrition and nature of lipid content influence the generation of peroxides and aldehydes. Clin Nutr. 2012;31:526–534. doi: 10.1016/j.clnu.2011.12.012. PubMed DOI

Arisue A, et al. Effect of an omega-3 lipid emulsion in reducing oxidative stress in a rat model of intestinal ischemia-reperfusion injury. Pediatr Surg Int. 2012;28:913–918. doi: 10.1007/s00383-012-3144-0. PubMed DOI PMC

Lavoie JC, Mohamed I, Nuyt AM, Elremaly W, Rouleau T. Impact of SMOFLipid on Pulmonary Alveolar Development in Newborn Guinea Pigs. JPEN J Parenter Enteral Nutr. 2018;42:1314–1321. doi: 10.1002/jpen.1153. PubMed DOI

Vlaardingerbroek H, et al. New generation lipid emulsions prevent PNALD in chronic parenterally fed preterm pigs. J Lipid Res. 2014;55:466–477. doi: 10.1194/jlr.M044545. PubMed DOI PMC

Schoemaker MH, et al. Tauroursodeoxycholic acid protects rat hepatocytes from bile acid-induced apoptosis via activation of survival pathways. Hepatology. 2004;39:1563–1573. doi: 10.1002/hep.20246. PubMed DOI

Greim H, et al. Mechanism of cholestasis. 6. Bile acids in human livers with or without biliary obstruction. Gastroenterology. 1972;63:846–850. PubMed

Higuchi H, Gores GJ. Bile acid regulation of hepatic physiology: IV. Bile acids and death receptors. Am J Physiol Gastrointest Liver Physiol. 2003;284:G734–738. doi: 10.1152/ajpgi.00491.2002. PubMed DOI

Park SE, et al. A chenodeoxycholic derivative, HS-1200, induces apoptosis and cell cycle modulation via Egr-1 gene expression control on human hepatoma cells. Cancer Lett. 2008;270:77–86. doi: 10.1016/j.canlet.2008.04.038. PubMed DOI

Sokol RJ, et al. Human hepatic mitochondria generate reactive oxygen species and undergo the permeability transition in response to hydrophobic bile acids. J Pediatr Gastroenterol Nutr. 2005;41:235–243. doi: 10.1097/01.MPG.0000170600.80640.88. PubMed DOI

Yang JI, et al. Bile acid-induced TGR5-dependent c-Jun-N terminal kinase activation leads to enhanced caspase 8 activation in hepatocytes. Biochem Biophys Res Commun. 2007;361:156–161. doi: 10.1016/j.bbrc.2007.07.001. PubMed DOI

Allen K, Jaeschke H, Copple BL. Bile acids induce inflammatory genes in hepatocytes: a novel mechanism of inflammation during obstructive cholestasis. Am J Pathol. 2011;178:175–186. doi: 10.1016/j.ajpath.2010.11.026. PubMed DOI PMC

Woolbright BL, Jaeschke H. Novel insight into mechanisms of cholestatic liver injury. World J Gastroenterol. 2012;18:4985–4993. doi: 10.3748/wjg.v18.i36.4985. PubMed DOI PMC

Goulet O, Joly F, Corriol O, Colomb-Jung V. Some new insights in intestinal failure-associated liver disease. Curr Opin Organ Tran. 2009;14:256–261. doi: 10.1097/MOT.0b013e32832ac06f. PubMed DOI

Lee S, et al. Current clinical applications of omega-6 and omega-3 fatty acids. Nutr Clin Pract. 2006;21:323–341. doi: 10.1177/0115426506021004323. PubMed DOI

Hodin CM, et al. Total parenteral nutrition induces a shift in the Firmicutes to Bacteroidetes ratio in association with Paneth cell activation in rats. J Nutr. 2012;142:2141–2147. doi: 10.3945/jn.112.162388. PubMed DOI

Wang HY, et al. A lipidomics study reveals hepatic lipid signatures associating with deficiency of the LDL receptor in a rat model. Biol Open. 2016;5:979–986. doi: 10.1242/bio.019802. PubMed DOI PMC

Koelmel JP, et al. LipidMatch: an automated workflow for rule-based lipid identification using untargeted high-resolution tandem mass spectrometry data. BMC Bioinformatics. 2017;18:331. doi: 10.1186/s12859-017-1744-3. PubMed DOI PMC

Masuda T, Tomita M, Ishihama Y. Phase transfer surfactant-aided trypsin digestion for membrane proteome analysis. J Proteome Res. 2008;7:731–740. doi: 10.1021/pr700658q. PubMed DOI

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