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

Abstract

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 ( 1 ). The incidence of parenteral nutrition-associated liver disease (PNALD) in infants who Abstract 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% fi sh oil (OV), or a mixture of soybean oil, medium chain triglycerides (MCTs), olive oil, and fi sh 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 7 ␣ -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 (OST ␣ ) 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 This work was supported in part by federal funds from the USDA,, the American Society for Parenteral and Enteral Nutrition, Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSEP, bile salt export pump; CA, cholic acid; CDCA, chenodeoxycholic acid; C4, 7 ␣ -hydroxy-4-cholesten-3-one; CYP8B1, sterol 12-alpha-hydroxylase; CYP7A1, cholesterol 7-hydroxylase; CYP3A29, cytochrome P450 3A29; CYP27A1, sterol 27-hydroxylase; FGF, fi broblast growth factor; FXR, farnesoid X receptor; GGT, gamma glutamyl transferase; MCT, medium chain triglyceride; MRP3, multidrug resistant protein 3; NTCP, Na + / taurocholate cotransporter; OBCA, obeticholic acid; OST ␣ / ␤ , organic solute transporters alpha and beta; PNALD, parenteral nutrition-associated liver disease; TPN, total parenteral nutrition; UDCA, ursodeoxycholic acid . and immediately placed in cages housed at 31°C to 32°C, as described previously ( 12 ). Based on body weight, pigs delivered from each sow were randomly assigned to one of the three TPN treatment groups or to enteral nutrition (ENT). After delivery, pigs were surgically implanted with catheters into the jugular vein and umbilical artery. Pigs in the enteral group also were implanted with an orogastric feeding tube, whereas TPN groups received a sham puncture. Maternal plasma (16 ml/kg intravenously during the fi rst 24 h) was administered for passive immunological protection. During the 14 day study, pigs received antibiotics (enrofl oxacin 5 mg/kg) intrave...

Multi-omic profiles of hepatic metabolism in TPN-fed preterm pigs administered new generation lipid emulsions

“…Soybean-based lipid emulsions are the prevalent lipid emulsion used in the US and are approved by the Food and Drug Administration for clinical use in neonates, but have been associated with PNALD (5). Total PN (TPN) solutions that contain fish oil-based emulsions have been associated with prevention of cholestasis and reversal of cholestasis in some limited studies (6,7), but the basis for these observations is not clear. Some research suggests that phytosterols, a component of soy lipid emulsions, can suppress bile acid synthesis and impact bile acid efflux target genes in the liver through inhibition of the nuclear hormone receptor, farnesoid X receptor.…”

“…A recent report by El Kasmi et al (8) suggests that phytosterols taken up by Kupffer cells mediate an inflammation-induced injury to hepatocytes. However, our recent study in PN-fed piglets showed that a lipid emulsion blend of soy, medium-chain triglycerides (MCTs), olive oil, and fish oil, which contains less than one-half the total phytosterol content as soy-lipid emulsions [207 mg/dl vs. 439 mg/dl (9)], also protects against PNALD (7).…”

“…Sows were obtained from the Texas Department of Criminal Justice (Huntsville, TX) and housed in the Children's Nutrition Research Center. Our surgical protocol has been previously described (7). Briefly, domestic crossbred piglets were delivered 7 days preterm on gestation day 108 by caesarian section.…”

“…The cDNA was generated from RNA extracted from 100 to 150 mg of frozen liver tissue, as described previously (7). Realtime qPCR was performed with SYBR Green chemistry (Applied Biosystems) on a Bio-Rad CFX96.…”

“…In our previous report, we established that new generation lipid emulsions containing fish oil and vitamin E lead to decreased indices of liver damage and lipid accumulation (7). In this report, we have taken a multi-omics approach to examine the effect of those lipid emulsions on whole body metabolism, fatty acid utilization, and lipidomic and metabolomic profiles in the liver and muscle tissue in our PN-fed piglet model.…”