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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.

ABSTRACT: 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 ?-tocopherol and phytosterol content. Soybean oil is rich in phytosterols and contains little ?-tocopherol. Fish oil contains abundant ?-tocopherol and little phytosterols. This study tested whether ?-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 ?-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 (PPAR?), was increased in animals administered SO. ACC and PPAR? levels were comparable to chow-fed controls in animals receiving SO+AT, FO, and FO+P. This study suggests a hepatoprotective role for ?-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.

SUBMITTER: Fell GL

PROVIDER: S-EPMC6622470 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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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.

Fell Gillian L GL Anez-Bustillos Lorenzo L Dao Duy T DT Baker Meredith A MA Nandivada Prathima P Cho Bennet S BS Pan Amy A O'Loughlin Alison A AA Nose Vania V Gura Kathleen M KM Puder Mark M

PloS one 20190711 7

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. F ...[more]

PMID: 31295333

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Project description:BackgroundParenteral (intravenous) nutrition is lifesaving for patients with intestinal failure, but long-term use of parenteral nutrition often leads to liver disease. SEFA-6179 is a synthetic medium-chain fatty acid analogue designed to target multiple fatty acid receptors regulating metabolic and inflammatory pathways. We hypothesized that SEFA-6179 would prevent hepatosteatosis and lipotoxicity in a murine model of parenteral nutrition-induced hepatosteatosis.MethodsTwo in vivo experiments were conducted. In the first experiment, six-week-old male mice were provided an ad lib fat-free high carbohydrate diet (HCD) for 19 days with orogastric gavage of either fish oil, medium-chain triglycerides, or SEFA-6179 at a low (0.3mmol/kg) or high dose (0.6mmol/kg). In the second experiment, six-week-old mice were provided an ad lib fat-free high carbohydrate diet for 19 days with every other day tail vein injection of saline, soybean oil lipid emulsion, or fish oil lipid emulsion. Mice then received every other day orogastric gavage of medium-chain triglyceride vehicle or SEFA-6179 (0.6mmol/kg). Hepatosteatosis was assessed by a blinded pathologist using an established rodent steatosis score. Hepatic lipid metabolites were assessed using ultra-high-performance liquid chromatography-mass spectrometry. Effects of SEFA-6179 on fatty acid oxidation, lipogenesis, and fatty acid uptake in human liver cells were assessed in vitro.ResultsIn the first experiment, mice receiving the HCD with either saline or medium-chain triglyceride treatment developed macrovesicular steatosis, while mice receiving fish oil or SEFA-6179 retained normal liver histology. In the second experiment, mice receiving a high carbohydrate diet with intravenous saline or soybean oil lipid emulsion, along with medium chain triglyceride vehicle treatment, developed macrovescular steatosis. Treatment with SEFA-6179 prevented steatosis. In each experiment, SEFA-6179 treatment decreased arachidonic acid metabolites as well as key molecules (diacylglycerol, ceramides) involved in lipotoxicity. SEFA-6179 increased both β- and complete fatty oxidation in human liver cells, while having no impact on lipogenesis or fatty acid uptake.ConclusionsSEFA-6179 treatment prevented hepatosteatosis and decreased toxic lipid metabolites in a murine model of parenteral nutrition-induced hepatosteatosis. An increase in both β- and complete hepatic fatty acid oxidation may underlie the reduction in steatosis.

Project description:BACKGROUND:Fish oil (FO) intravenous lipid emulsions (ILEs) are used as a monotherapy to treat parenteral nutrition (PN)-associated liver disease and provide essential fatty acids (EFAs) needed to sustain growth and prevent EFA deficiency (EFAD). Studies have suggested that medium-chain triglycerides (MCTs) and ?-tocopherol have anti-inflammatory properties. OBJECTIVE:The purpose of this study was to test whether FO-ILEs containing MCTs and/or additional ?-tocopherol decrease the inflammatory response to an endotoxin challenge compared with FO-ILE alone and preserve the ability to prevent PN-induced liver injury in mice. METHODS:A murine model of PN-induced hepatosteatosis was used to compare the effects of ILEs formulated in the laboratory containing varying ratios of FO and MCTs, and subsequently FO- and 50:50 FO:MCT-ILE plus 500 mg/L ?-tocopherol (FO + AT and 50:50 + AT, respectively). C57BL/6 mice receiving unpurified diet (UPD), PN-equivalent diet (PN) + saline, and PN + soybean oil (SO)-ILE served as controls. After 19 d, mice received an intraperitoneal saline or endotoxin challenge 4 h before being killed. Serum and livers were harvested for histologic analysis, fatty acid profiling, and measurement of systemic inflammatory markers (tumor necrosis factor-?, interleukin-6). RESULTS:All ILEs were well tolerated and prevented biochemical EFAD. Livers of mice that received saline and SO developed steatosis. Mice that received 30:70 FO:MCT developed mild hepatosteatosis. All other FO-containing ILEs preserved normal hepatic architecture. Mice that received FO- or SO-ILE had significantly elevated systemic inflammatory markers after endotoxin challenge compared with UPD-fed controls, whereas 50:50 FO:MCT, 30:70 FO:MCT, FO + AT, and 50:50 + AT groups had significantly lower inflammatory markers similar to those seen in UPD-fed controls. CONCLUSIONS:Mixed FO/MCT and the addition of ?-tocopherol to FO improved the inflammatory response to endotoxin challenge compared with FO-ILE alone while still preventing PN-induced liver injury and EFAD in mice. There was no synergistic relation between ?-tocopherol and MCTs.

Project description:Background and aimsDespite enteral nutrition (EN) is the preferred route of nutrition in patients with critical illness, EN is not always able to provide optimal nutrient provision and parenteral nutrition (PN) is needed. This is strongly associated with gastrointestinal (GI) complications, a feature of gastrointestinal dysfunction and disease severity. The aim of the present study was to investigate factors associated with the need of PN after start of EN, together with the use and complications associated with EN.MethodsAdult patients admitted to 38 Spanish intensive care units (ICUs) between April and July 2018, who needed EN therapy were included in a prospective observational study. The characteristics of EN-treated patients and those who required PN after start EN were analyzed (i.e., clinical, laboratory and scores).ResultsOf a total of 443 patients, 43 (9.7%) received PN. One-third (29.3%) of patients presented GI complications, which were more frequent among those needing PN (26% vs. 60%, p = 0.001). No differences regarding mean energy and protein delivery were found between patients treated only with EN (n = 400) and those needing supplementary or total PN (n = 43). Abnormalities in lipid profile, blood proteins, and inflammatory markers, such as C-Reactive Protein, were shown in those patients needing PN. Sequential Organ Failure Assessment (SOFA) on ICU admission (Hazard ratio [HR]:1.161, 95% confidence interval [CI]:1.053-1.281, p = 0.003) and modified Nutrition Risk in Critically Ill (mNUTRIC) score (HR:1.311, 95% CI:1.098-1.565, p = 0.003) were higher among those who needed PN. In the multivariate analysis, higher SOFA score (HR:1.221, 95% CI:1.057-1.410, p = 0.007) and higher triglyceride levels on ICU admission (HR:1.004, 95% CI:1.001-1.007, p = 0.003) were associated with an increased risk for the need of PN, whereas higher albumin levels on ICU admission (HR:0.424, 95% CI:0.210-0.687, p = 0.016) was associated with lower need of PN.ConclusionA higher SOFA and nutrition-related laboratory parameters on ICU admission may be associated with the need of PN after starting EN therapy. This may be related with a higher occurrence of GI complications, a feature of GI dysfunction.Clinical trial registrationClinicalTrials.gov: NCT03634943.

Dataset Information

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.

Publications

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.

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