New generation lipid emulsions prevent PNALD in chronic parenterally fed preterm pigs

Total parenteral nutrition (TPN) is associated with the development of parenteral nutrition-associated liver disease (PNALD) in infants. Fish oil-based lipid emulsions can reverse PNALD, yet it is unknown if they can prevent PNALD. We studied preterm pigs administered TPN for 14 days with either 100% soybean oil (IL), 100% fish oil (OV), or a mixture of soybean oil, medium chain triglycerides (MCTs), olive oil, and fish oil (SL); a group was fed formula enterally (ENT). In TPN-fed pigs, serum direct bilirubin, gamma glutamyl transferase (GGT), and plasma bile acids increased after the 14 day treatment but were highest in IL pigs. All TPN pigs had suppressed hepatic expression of farnesoid X receptor (FXR), cholesterol 7-hydroxylase (CYP7A1), and plasma 7α-hydroxy-4-cholesten-3-one (C4) concentrations, yet hepatic CYP7A1 protein abundance was increased only in the IL versus ENT group. Organic solute transporter alpha (OSTα) gene expression was the highest in the IL group and paralleled plasma bile acid levels. In cultured hepatocytes, bile acid-induced bile salt export pump (BSEP) expression was inhibited by phytosterol treatment. We show that TPN-fed pigs given soybean oil developed cholestasis and steatosis that was prevented with both OV and SL emulsions. Due to the presence of phytosterols in the SL emulsion, the differences in cholestasis and liver injury among lipid emulsion groups in vivo were weakly correlated with plasma and hepatic phytosterol content. Total parenteral nutrition (TPN) is associated with the development of parenteral nutrition-associated liver disease (PNALD) in infants. Fish oil-based lipid emulsions can reverse PNALD, yet it is unknown if they can prevent PNALD. We studied preterm pigs administered TPN for 14 days with either 100% soybean oil (IL), 100% fish oil (OV), or a mixture of soybean oil, medium chain triglycerides (MCTs), olive oil, and fish oil (SL); a group was fed formula enterally (ENT). In TPN-fed pigs, serum direct bilirubin, gamma glutamyl transferase (GGT), and plasma bile acids increased after the 14 day treatment but were highest in IL pigs. All TPN pigs had suppressed hepatic expression of farnesoid X receptor (FXR), cholesterol 7-hydroxylase (CYP7A1), and plasma 7α-hydroxy-4-cholesten-3-one (C4) concentrations, yet hepatic CYP7A1 protein abundance was increased only in the IL versus ENT group. Organic solute transporter alpha (OSTα) gene expression was the highest in the IL group and paralleled plasma bile acid levels. In cultured hepatocytes, bile acid-induced bile salt export pump (BSEP) expression was inhibited by phytosterol treatment. We show that TPN-fed pigs given soybean oil developed cholestasis and steatosis that was prevented with both OV and SL emulsions. Due to the presence of phytosterols in the SL emulsion, the differences in cholestasis and liver injury among lipid emulsion groups in vivo were weakly correlated with plasma and hepatic phytosterol content. Cholestatic liver disease is one of the most common metabolic problems associated with total parenteral nutrition (TPN) in preterm infants, and it is strongly related to the duration of TPN (1Christensen R.D. Henry E. Wiedmeier S.E. Burnett J. Lambert D.K. Identifying patients, on the first day of life, at high-risk of developing parenteral nutrition-associated liver disease.J. Perinatol. 2007; 27: 284-290Crossref PubMed Scopus (181) Google Scholar). The incidence of parenteral nutrition-associated liver disease (PNALD) in infants who receive parenteral nutrition for at least 2 months can be as high as 50% (2Carter B.A. Shulman R.J. Mechanisms of disease: update on the molecular etiology and fundamentals of parenteral nutrition associated cholestasis.Nat. Clin. Pract. Gastroenterol. Hepatol. 2007; 4: 277-287Crossref PubMed Scopus (137) Google Scholar). Risk factors associated with PNALD are multifactorial and include immature hepatic function, lack of enteral feeding, sepsis or infection, toxin exposure, or nutrient deficiencies. Currently, there is much interest in the role of lipid emulsions in the development of PNALD. Soybean oil-based emulsions, rich in PUFAs, are the most common form of lipid emulsion administered to preterm infants in the world (3Waitzberg D.L. Torrinhas R.S. Jacintho T.M. New parenteral lipid emulsions for clinical use.JPEN J. Parenter. Enteral Nutr. 2006; 30: 351-367Crossref PubMed Scopus (178) Google Scholar). However, an excess intake of n-6 PUFA in parenteral nutrition is associated with an unbalanced fatty acid pattern and increased harmful lipid peroxidation (3Waitzberg D.L. Torrinhas R.S. Jacintho T.M. New parenteral lipid emulsions for clinical use.JPEN J. Parenter. Enteral Nutr. 2006; 30: 351-367Crossref PubMed Scopus (178) Google Scholar). Other studies have shown that phytosterols present in soybean oil are associated with phytosterolemia and the severity of cholestasis (4Clayton P.T. Bowron A. Mills K.A. Massoud A. Casteels M. Milla P.J. Phytosterolemia in children with parenteral nutrition-associated cholestatic liver disease.Gastroenterology. 1993; 105: 1806-1813Abstract Full Text PDF PubMed Scopus (196) Google Scholar). The cholestatic effect of phytosterols is thought to be mediated by their antagonism of the farnesoid X receptor (FXR), the dominant bile acid sensor involved in bile acid homeostasis, as shown in cultured hepatocytes (5Carter B.A. Taylor O.A. Prendergast D.R. Zimmerman T.L. Von Furstenberg R. Moore D.D. Karpen S.J. Stigmasterol, a soy lipid-derived phytosterol, is an antagonist of the bile acid nuclear receptor FXR.Pediatr. Res. 2007; 62: 301-306Crossref PubMed Scopus (225) Google Scholar). The cholestatic effect of lipid emulsions has also been shown to be closely associated with the lipid dose itself (6Colomb V. Jobert-Giraud A. Lacaille F. Goulet O. Fournet J.C. Ricour C. Role of lipid emulsions in cholestasis associated with long-term parenteral nutrition in children.JPEN J. Parenter. Enteral Nutr. 2000; 24: 345-350Crossref PubMed Scopus (282) Google Scholar, 7Cober M.P. Killu G. Brattain A. Welch K.B. Kunisaki S.M. Teitelbaum D.H. Intravenous fat emulsions reduction for patients with parenteral nutrition-associated liver disease.J. Pediatr. 2012; 160: 421-427Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar). New lipid emulsions have emerged that contain either only fish oil or a mixture of soybean oil, medium chain triglycerides (MCTs), olive oil, and fish oil. Several small trials with these emulsions have shown good tolerance; in infants and children with PNALD, fish oil emulsions in low doses reduced serum triglyceride and and liver function, and in of these fish oil PNALD M. Fish oil-based lipid emulsions prevent and reverse parenteral nutrition-associated liver disease: the J. Parenter. Enteral Nutr. PubMed Scopus Google Scholar, C. J. C. and of a fat emulsion in the treatment of parenteral nutrition-associated liver PubMed Scopus Google Scholar, A. the for the treatment of liver in Pediatr. Gastroenterol. Nutr. PubMed Scopus Google Scholar). However, it is unknown if fish lipid emulsions can prevent the development of PNALD. We that parenteral lipid emulsions fish oil or a mixture of soybean oil, olive oil, and fish oil can prevent hepatic cholestasis with a soybean oil-based lipid emulsion given to TPN-fed preterm pigs. We and have the as an of the and preterm to the of parenteral and enteral nutrition P.T. M. J. G. the to parenteral and enteral nutrition in Nutr. PubMed Scopus Google Scholar, D.L. A. A. A. parenteral nutrition hepatic and in Nutr. PubMed Scopus Google Scholar, P.J. C. parenteral and enteral nutrition metabolic in J. Parenter. Enteral Nutr. 2012; PubMed Scopus Google Scholar, to nutrition in Clin. Nutr. PubMed Scopus Google Scholar). first was to fish emulsions with soybean oil emulsions can prevent the development of PNALD in TPN-fed pigs. was to the presence of and hepatic phytosterolemia in preterm TPN-fed pigs and the of phytosterols on The was by the and of of and was in with the for the and of were the of were in the and were given and day were days preterm by and in at to as D.L. A. A. A. parenteral nutrition hepatic and in Nutr. PubMed Scopus Google Scholar). on pigs were to one of the TPN treatment groups or to enteral nutrition (ENT). pigs were with the and in the enteral group also were with an TPN groups a plasma the first was administered for the 14 day pigs on TPN of an a nutrient mixture of and and a parenteral lipid emulsion, was in the TPN groups one of the lipid 100% soybean oil 100% fish oil or a mixture of soybean oil, olive oil, and fish oil lipid emulsions were by ENT pigs were fed a formula at in TPN was at and increased to ENT pigs also TPN with IL but to be fed enterally the day and were TPN by day day TPN and enterally fed pigs of nutrition 14 and as D.L. A. A. A. parenteral nutrition hepatic and in Nutr. PubMed Scopus Google Scholar). were and were and on days and after the was on day the were with and with of were and were in and at also were in for were in and at at for and were at for serum were at for and at for serum was at was for gamma glutamyl transferase (GGT), and and triglyceride and were as D.L. A. A. A. parenteral nutrition hepatic and in Nutr. PubMed Scopus Google Scholar). plasma was for a is a protein in and were in plasma and and lipid and formula as their by after and as J.C. R.J. of bile acids and bile in patients the of acid PubMed Scopus Google Scholar). was on a with a and were in total and phytosterols were by with the and with were as Total plasma bile acid was a total bile acid bile acid in plasma and liver were by and by as A. R.J. of bile acids in plasma for of PubMed Scopus Google Scholar, M. R.J. M. of bile acid and in and protein and Full Text Full Text PDF PubMed Scopus Google Scholar, R. C. A. 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Role of bile acids and bile acid in metabolic PubMed Scopus Google was in TPN bile acid the increased plasma bile acid concentrations, is a bile acid transporter with that is by and is to bile acid export the F. F. Role of bile acids and bile acid in metabolic PubMed Scopus Google Scholar). We an in the expression of in the IL yet the OV and SL groups were to the ENT group. In the expression of bile was in TPN that hepatocytes in IL pigs bile in a bile acid the are bile the and and and a PubMed Scopus Google and the expression in the TPN groups but was the ENT group. We the expression in of and gene as an on hepatic CYP7A1 In the expression of to be in TPN yet was only in IL versus ENT pigs. the expression of was in ENT and but in OV and SL pigs versus studies Moore D.D. Enteral bile acid treatment parenteral liver disease and in J. 2012; PubMed Scopus Google that plasma in ENT pigs was in but OV or SL pigs. the bile and as as studies that phytosterols in hepatocytes, their in We expression as a direct that an role in bile acid (5Carter B.A. Taylor O.A. Prendergast D.R. Zimmerman T.L. Von Furstenberg R. Moore D.D. Karpen S.J. Stigmasterol, a soy lipid-derived phytosterol, is an antagonist of the bile acid nuclear receptor FXR.Pediatr. Res. 2007; 62: 301-306Crossref PubMed Scopus (225) Google Scholar). We first that expression increased dose in to the and We expression after treatment with of the phytosterols and and as as IL and OV We it is a R. G. E. A. T.M. C. A. acid as of the farnesoid X and of a of and chain of PubMed Scopus Google Scholar). expression was by phytosterols at and as as IL and an to that was after to The that a in was with of either or but also to in a with but was TPN the of PNALD, in preterm infants. However, studies have shown that to fish oil emulsions can reverse PNALD in infants given soybean oil lipid emulsions M. Fish oil-based lipid emulsions prevent and reverse parenteral nutrition-associated liver disease: the J. Parenter. Enteral Nutr. PubMed Scopus Google Scholar, C. J. C. and of a fat emulsion in the treatment of parenteral nutrition-associated liver PubMed Scopus Google Scholar). for the effect of fish oil emulsions include reduction of lipid phytosterol PUFA fatty acid of and direct of bile (3Waitzberg D.L. Torrinhas R.S. Jacintho T.M. New parenteral lipid emulsions for clinical use.JPEN J. Parenter. Enteral Nutr. 2006; 30: 351-367Crossref PubMed Scopus (178) Google Scholar, for associated liver Pediatr. PubMed Scopus Google Scholar). has emerged in the lipid in fish oil emulsions is itself the PNALD, the differences in the of the of the lipid itself has been shown to reverse cholestasis (6Colomb V. Jobert-Giraud A. Lacaille F. Goulet O. Fournet J.C. Ricour C. Role of lipid emulsions in cholestasis associated with long-term parenteral nutrition in children.JPEN J. Parenter. Enteral Nutr. 2000; 24: 345-350Crossref PubMed Scopus (282) Google Scholar, 7Cober M.P. Killu G. Brattain A. Welch K.B. Kunisaki S.M. Teitelbaum D.H. Intravenous fat emulsions reduction for patients with parenteral nutrition-associated liver disease.J. Pediatr. 2012; 160: 421-427Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar). We to these preterm by the of cholestatic liver disease in to treatment with soybean and fish lipid emulsions administered at lipid We also that phytosterols in soybean oil emulsions, but in fish oil emulsions, are a in the development of PNALD. of TPN in preterm pigs in differences in of hepatic cholestasis and injury among the TPN of cholestasis were increased in TPN but ENT pigs days and direct and total were to in in IL versus ENT pigs at day was highest in the IL group and the OV and ENT that and were both increased in treatment groups after 14 yet were in the TPN-fed to the ENT group. in liver a pattern of that the plasma bile acid was highest in the IL pigs and in OV and SL pigs. The plasma bile acids were and and was increased in IL versus that of bile acid is associated with of the liver in TPN groups with enteral formula feeding, with (4Clayton P.T. Bowron A. Mills K.A. Massoud A. Casteels M. Milla P.J. Phytosterolemia in children with parenteral nutrition-associated cholestatic liver disease.Gastroenterology. 1993; 105: 1806-1813Abstract Full Text PDF PubMed Scopus (196) Google Scholar, A. R.J. M.P. of long-term parenteral nutrition on serum cholesterol and liver in Pediatr. Gastroenterol. Nutr. PubMed Scopus Google Scholar). TPN pigs of and However, the that the injury and were highest among the IL versus lipid emulsion of cholestasis have shown with fish oil A. R.J. M.P. of long-term parenteral nutrition on serum cholesterol and liver in Pediatr. Gastroenterol. Nutr. PubMed Scopus Google Scholar, M. C. J. C. fish oil in patients with parenteral nutrition-associated liver PubMed Scopus Google Scholar). these that fish emulsions prevent the development of PNALD in TPN-fed pigs. was to the presence of and hepatic phytosterolemia in preterm TPN-fed pigs and be associated with of cholestasis and liver injury among the lipid emulsion Soybean IL is in fish OV is of SL is a of soybean oil, olive oil, and fish oil and The on phytosterols their with bile acids and of phytosterolemia associated with PNALD in TPN-fed patients (4Clayton P.T. Bowron A. Mills K.A. Massoud A. Casteels M. Milla P.J. Phytosterolemia in children with parenteral nutrition-associated cholestatic liver disease.Gastroenterology. 1993; 105: 1806-1813Abstract Full Text PDF PubMed Scopus (196) Google Scholar, A. R.J. M.P. of long-term parenteral nutrition on serum cholesterol and liver in Pediatr. Gastroenterol. Nutr. PubMed Scopus Google Scholar, A. M. M. and liver disease in Pediatr. Gastroenterol. Nutr. 2012; PubMed Scopus Google Scholar). 2 the differences in phytosterol intake among the groups were in both the plasma and liver phytosterol concentrations, with the highest and phytosterol in IL and OV pigs, of phytosterol among that they were in liver that the in plasma and liver phytosterol were weakly correlated with of cholestasis and liver injury among lipid emulsion to the presence of phytosterols in the SL the that phytosterolemia to hepatic cholestasis and We the molecular phytosterolemia with of hepatic expression of and show that TPN groups had expression with ENT pigs. that CYP7A1 expression was in TPN groups versus the ENT with the in both the OV and SL with CYP7A1 also that the of plasma an in bile acid was also in TPN groups versus the ENT group. In the CYP7A1 protein abundance on that the IL group was to the ENT group and the OV and SL expression and protein abundance of CYP7A1 be by a that is either protein or protein The expression of bile acid and was among We also that expression of and was in TPN a of expression in IL versus OV and SL pigs. that TPN suppressed both bile acid and export and to bile acid in IL pigs, a of expression and increased of bile acid the The of hepatic bile acids in IL versus OV and SL groups of bile acid and export that OV and SL of bile acid as or The in hepatic and gene expression among the lipid emulsion groups were also closely correlated with the liver phytosterol a molecular of bile acid is the to as a to hepatic bile acid We that TPN in reduced in TPN-fed with enterally fed Moore D.D. Enteral bile acid treatment parenteral liver disease and in J. 2012; PubMed Scopus Google Scholar). In the with preterm also a plasma in IL versus ENT pigs, but in the OV or SL The in plasma to the in expression for the TPN but the ENT had the the in and plasma were related to hepatic CYP7A1 and plasma as be on in of bile acid However, these of protein and are in to a in and that the plasma in or hepatic CYP7A1 A. M. G. G. protein in the in the or hepatic CYP7A1 Res. Full Text Full Text PDF PubMed Scopus Google Scholar). that is to in in to TPN versus enteral or to in direct of bile acid We also the of phytosterols to in We of in to both and the with that expression was with the of of the with and the direct effect of studied their effect in a had and the the of antagonism of in hepatocytes (5Carter B.A. Taylor O.A. Prendergast D.R. Zimmerman T.L. Von Furstenberg R. Moore D.D. Karpen S.J. Stigmasterol, a soy lipid-derived phytosterol, is an antagonist of the bile acid nuclear receptor FXR.Pediatr. Res. 2007; 62: 301-306Crossref PubMed Scopus (225) Google and of liver injury in TPN-fed Karpen S.J. R.J. liver injury and in parenteral nutrition-associated liver PubMed Scopus Google it is with in vivo in the of cholestasis and gene expression among the lipid groups in TPN-fed In that fish oil and a lipid emulsion fish oil PNALD in preterm TPN-fed pigs. The for the that the of the lipid emulsion is a of PNALD the lipid is the that lipid also to PNALD. in but in the that phytosterols are strongly associated with PNALD and antagonism of hepatic with the that phytosterols liver injury and is by the that of phytosterol, yet is that the of these lipid emulsions are by lipid emulsion that are to be present in among these lipid emulsions, as PUFA and E. PUFA and have been shown to be in of liver disease and A. A. G. D.H. of by fatty by fatty Res. Full Text Full Text PDF PubMed Scopus Google Scholar, A. B.A. J. A. or for J. PubMed Scopus Google Scholar, V. J. J. M. A. fatty acid hepatic steatosis in a of fatty liver Res. PubMed Scopus Google Scholar). are in with studies in infants and children with PNALD in the soybean oil-based emulsions to the of fish oil-based emulsions as also in of serum of liver injury (6Colomb V. Jobert-Giraud A. Lacaille F. Goulet O. Fournet J.C. Ricour C. Role of lipid emulsions in cholestasis associated with long-term parenteral nutrition in children.JPEN J. Parenter. Enteral Nutr. 2000; 24: 345-350Crossref PubMed Scopus (282) Google Scholar, M. Fish oil-based lipid emulsions prevent and reverse parenteral nutrition-associated liver disease: the J. Parenter. Enteral Nutr. PubMed Scopus Google Scholar, A. the for the treatment of liver in Pediatr. Gastroenterol. Nutr. PubMed Scopus Google Scholar, M. C. J. C. fish oil in patients with parenteral nutrition-associated liver PubMed Scopus Google Scholar). The a to the clinical and metabolic of lipid emulsions to their and in infants. The to and the of the for and The for the of bile salt export pump acid acid 7α-hydroxy-4-cholesten-3-one cholesterol 7-hydroxylase farnesoid X receptor gamma glutamyl transferase medium chain triglyceride protein acid solute alpha and parenteral nutrition-associated liver disease total parenteral nutrition acid

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