Vitamin E in New‐Generation Lipid Emulsions Protects Against Parenteral Nutrition–Associated Liver Disease in Parenteral Nutrition–Fed Preterm Pigs

Abstract

Introduction Parenteral nutrition (PN) in preterm infants leads to PN-associated liver disease (PNALD). PNALD has been linked to serum accumulation of phytosterols that are abundant in plant oil but absent in fish oil emulsions. Hypothesis Whether modifying the phytosterol and vitamin E composition of soy and fish oil lipid emulsions affects development of PNALD in preterm pigs. Methods We measured markers of PNALD in preterm pigs that received 14 days of PN that included 1 of the following: (1) Intralipid (IL, 100% soybean oil), (2) Intralipid + vitamin E (ILE, d-α-tocopherol), (3) Omegaven (OV, 100% fish oil), or (4) Omegaven + phytosterols (PS, β-sitosterol, campesterol, and stigmasterol). Results Serum levels of direct bilirubin, gamma glutamyl transferase, serum triglyceride, low-density lipoprotein, and hepatic triglyceride content were significantly lower (P < .05) in the ILE, OV, and PS compared to IL. Hepatic cholesterol 7-hydroxylase and organic solute transporter–α expression was lower (P < .05) and portal plasma FGF19 higher in the ILE, OV, and PS vs IL. Hepatic expression of mitochondrial carnitine palmitoyltransferase 1A and microsomal cytochrome P450 2E1 fatty acid oxidation genes was higher in ILE, OV, and PS vs IL. In vivo 13C-CDCA clearance and expression of pregnane X receptor target genes, cytochrome P450 3A29 and multidrug resistance-associated protein 2, were higher in ILE, OV, and PS vs IL. Conclusions α-tocopherol in Omegaven and added to Intralipid prevented serum and liver increases in biliary and lipidemic markers of PNALD in preterm piglets. The addition of phytosterols to Omegaven did not produce evidence of PNALD.

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

“…The vitamin E concentration in IL was insufficient to maintain plasma levels similar to that seen in piglets on the ENT diet. In accordance with our previous study (32), the IL group had a considerable hepatic concentration of -tocopherol, whereas -tocopherol was not detectable in the liver of other groups, or in plasma. The contribution of -tocopherol and the stereoisomer composition of -tocopherol in plasma and liver tissue in the IL versus OV and SL probably reflected the difference in the chemical forms of vitamin E in the emulsions.…”

“…The concentration of -tocopherol per mole percent total unsaturated fatty acids was three times higher in OV and 2.3 times higher in SL compared with IL. At the same lipid dose of 5 g/(kg·d), we recently showed prevention of cholestasis in preterm piglets by supplementing IL with vitamin E to a concentration equivalent to that present in OV (32). However, a recent publication in term piglets administered IL supplemented with vitamin E at 10 g/(kg·d) failed to show any effect on treatment (50).…”

“…OAs were analyzed by Trace Ultra GC coupled to a Trace DSQ mass spectrometer using a stable isotope dilution method described previously (31,32). For analysis of long-chain ACs, chloroacetaldehyde was added to the homogenate and samples were separated by HPLC and then detection of individual ACs was done fluorometrically (33).…”

Intestinal Microbiota, Lipids, and the Pathogenesis of Intestinal Failure–Associated Liver Disease

“…33 The authors suggested that other lipid components present in SMOF-based and FO-based ILE, such as vitamin E or ω-3 PUFA, may be protective against PNALD. 33, 34 In subsequent experiments, the, addition of α-tocopherol to SO-ILE prevented the increase in serum and hepatic markers of PNALD, as compared with PN solution containing SO-ILE alone. 34 Furthermore, addition of phytosterols to 100% FO-ILE did not reproduce evidence of PNALD.…”

Intravenous Lipid Emulsions in Parenteral Nutrition

“…In vitro, fish oil suppresses the lipopolysaccharide-induced inflammatory response in cultured monocytes as well as TGF-b1-induced epithelial-to-mesenchymal transition that characterizes fibrosis in cultured liver epithelial cells (87). A recent study in PN-administered preterm pigs showed that adding 251 mg/L a-tocopherol to a parenterally administered soybean oil lipid emulsion attenuates soybean oil-mediated biochemical evidence of liver injury and reduction in bile acid clearance, thus suggesting a hepatoprotective role for antioxidants in fish oil emulsions (88). Similar to our understanding of parenteral soybean oil hepatotoxicity, our understanding of parenteral fish oil hepatoprotection in the setting of PNALD remains incomplete but is likely multifactorial.…”