Research Article: Alpha-tocopherol in intravenous lipid emulsions imparts hepatic protection in a murine model of hepatosteatosis induced by the enteral administration of a parenteral nutrition solution

Date Published: July 11, 2019

Publisher: Public Library of Science

Author(s): Gillian L. Fell, Lorenzo Anez-Bustillos, Duy T. Dao, Meredith A. Baker, Prathima Nandivada, Bennet S. Cho, Amy Pan, Alison A. O’Loughlin, Vania Nose, Kathleen M. Gura, Mark Puder, Wolf-Hagen Schunck.


Intestinal failure-associated liver disease (IFALD) is a risk of parenteral nutrition (PN)-dependence. Intravenous soybean oil-based parenteral fat can exacerbate the risk of IFALD while intravenous fish oil can minimize its progression, yet the mechanisms by which soybean oil harms and fish oil protects the liver are uncertain. Properties that differentiate soybean and fish oils include α-tocopherol and phytosterol content. Soybean oil is rich in phytosterols and contains little α-tocopherol. Fish oil contains abundant α-tocopherol and little phytosterols. This study tested whether α-tocopherol confers hepatoprotective properties while phytosterols confer hepatotoxicity to intravenous fat emulsions. Utilizing emulsions formulated in the laboratory, a soybean oil emulsion (SO) failed to protect from hepatosteatosis in mice administered a PN solution enterally. An emulsion of soybean oil containing α-tocopherol (SO+AT) preserved normal hepatic architecture. A fish oil emulsion (FO) and an emulsion of fish oil containing phytosterols (FO+P) protected from steatosis in this model. Expression of hepatic acetyl CoA carboxylase (ACC) and peroxisome proliferator-activated receptor gamma (PPARγ), was increased in animals administered SO. ACC and PPARγ levels were comparable to chow-fed controls in animals receiving SO+AT, FO, and FO+P. This study suggests a hepatoprotective role for α-tocopherol in liver injury induced by the enteral administration of a parenteral nutrition solution. Phytosterols do not appear to compromise the hepatoprotective effects of fish oil.

Partial Text

Parenteral nutrition (PN) is the intravenous administration of macronutrients and micronutrients, including carbohydrates, protein in the form of amino acids, lipids, vitamins, and trace elements. PN is a critical component of therapy for patients with intestinal failure (IF) who are unable to absorb sufficient nutrients ingested orally due to inadequate intestinal length or intestinal malfunction. Although PN is life sustaining for IF patients, there are complications associated with its administration. One such complication is the development of intestinal failure-associated liver disease (IFALD), which is characterized by cholestatic liver disease that can progress to cirrhosis and end-stage liver disease necessitating liver transplantation. Traditionally, the progression of IFALD could only be stopped if patients could wean off PN and achieve enteral autonomy. More recently, it has been demonstrated that use of fish oil as a parenteral fat source can prevent PN-induced liver injury in animal models [1,2] and reverse cholestasis and stop or slow the progression of liver disease in patients with IFALD [3–9].

The role of phytosterols and α-tocopherol in modulating the effects of intravenous fat emulsions on the liver has been debated. Serum and hepatic phytosterol levels are higher in PN-dependent patients receiving soybean oil-containing intravenous lipid emulsions than in patients who have been weaned off PN [26]. Furthermore, among PN-dependent patients, levels of serum and liver phytosterols positively correlate with the degree of deranged liver enzymes as well as the degree of portal inflammation and hepatic fibrosis on histologic analysis [26]. In neonatal PN-dependent patients, serum phytosterol levels are higher in patients who meet biochemical criteria for IFALD than in those without IFALD [27]. In vitro studies have shown that stigmasterol, one of the principal phytosterols in SO [16], inhibits the expression of target genes of the bile acid-responsive nuclear receptor FXR [17]. In contrast, Ng et al found no adverse effects on bile acid clearance with the addition of beta-sitosterol and stigmasterol to commercial FO in a preterm piglet model of IFALD [21]. This group did show that SO-mediated deficits in bile acid clearance were ameliorated by adding α-tocopherol to a commercial SO [21]. However, similar studies performed by Muto et al in a neonatal piglet model of IFALD showed no improvements in bile flow, serum bile acid concentration, or serum direct bilirubin levels with the addition of α-tocopherol to a commercially available SO emulsion [28].




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