title: Ω-3 fatty acids prevent hepatic steatosis, independent of PPAR-α activity, in a murine model of parenteral nutrition-associated liver disease.
abstract: OBJECTIVE
  ω-3 Fatty acids (FAs), natural ligands for the peroxisome proliferator-activated receptor-α (PPAR-α), attenuate parenteral nutrition-associated liver disease (PNALD). However, the mechanisms underlying the protective role of ω-3 FAs are still unknown. The aim of this study was to determine the effects of ω-3 FAs on hepatic triglyceride (TG) accumulation in a murine model of PNALD and to investigate the role of PPAR-α and microsomal triglyceride transfer protein (MTP) in this experimental setting.
  
  
  METHODS
  129S1/SvImJ wild-type or 129S4/SvJaePparatm/Gonz/J PPAR-α knockout mice were fed chow and water (controls); oral, fat-free PN solution only (PN-O); PN-O plus intraperitoneal (IP) ω-6 FA-predominant supplements (PN-ω-6); or PN-O plus IP ω-3 FA (PN-ω-3). Control and PN-O groups received sham IP injections of 0.9% NaCl. Hepatic histology, TG and cholesterol, MTP activity, and PPAR-α messenger RNA were assessed after 19 days.
  
  
  RESULTS
  In all experimental groups, PN feeding increased hepatic TG and MTP activity compared with controls. Both PN-O and PN-ω-6 groups accumulated significantly greater amounts of TG when compared with PN-ω-3 mice. Studies in PPAR-α null animals showed that PN feeding increases hepatic TG as in wild-type mice. PPAR-α null mice in the PN-O and PN-ω-6 groups demonstrated variable degrees of hepatic steatosis, whereas no evidence of hepatic fat accumulation was found after 19 days of oral PN plus IP ω-3 FAs.
  
  
  CONCLUSIONS
  PN induces TG accumulation (steatosis) in wild-type and PPAR-α null mice. In PN-fed wild-type and PPAR-α null mice given IP ω-3 FAs, reduced hepatic TG accumulation and absent steatosis are found. Prevention of steatosis by ω-3 FAs results from PPAR-α-independent pathways.
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, State University of New York Downstate Medical Center, Brooklyn, New York.
authors.forename: Esther
authors.initials: E
authors.lastname: Prince
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, State University of New York Downstate Medical Center, Brooklyn, New York Department of Pediatrics, Winthrop University Medical Center, Mineola, New York.
authors.forename: Farrah B
authors.initials: FB
authors.lastname: Lazare
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, State University of New York Downstate Medical Center, Brooklyn, New York Johnson & Johnson Pharmaceutical Research and Development, LLC, Titusville, New Jersey.
authors.forename: William R
authors.initials: WR
authors.lastname: Treem
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, State University of New York Downstate Medical Center, Brooklyn, New York.
authors.forename: Jiliu
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York.
authors.forename: Jahangir
authors.initials: J
authors.lastname: Iqbal
authors.affiliation: Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York.
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Pan
authors.affiliation: Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York.
authors.forename: Joby
authors.initials: J
authors.lastname: Josekutty
authors.affiliation: Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York.
authors.forename: Meghan
authors.initials: M
authors.lastname: Walsh
authors.affiliation: Department of Pathology, State University of New York Downstate Medical Center, Brooklyn, New York.
authors.forename: Virginia
authors.initials: V
authors.lastname: Anderson
authors.affiliation: Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York.
authors.forename: M Mahmood
authors.initials: MM
authors.lastname: Hussain
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, State University of New York Downstate Medical Center, Brooklyn, New York steven.schwarz@downstate.edu.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Schwarz
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage / Q000494:pharmacology*; D005234:Fatty Liver / Q000178:diet therapy* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D047493:PPAR alpha / Q000172:deficiency* / Q000235:genetics; D010288:Parenteral Nutrition; D016896:Treatment Outcome; D014280:Triglycerides / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D015525:Fatty Acids, Omega-3; D047493:PPAR alpha; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; D002784:Cholesterol
keywords: microsomal triglyceride transfer protein; parenteral nutrition–associated liver disease; peroxisome proliferator-activated receptor–α; steatosis; ω-3-fatty acids