ω‐3 Fatty Acids Prevent Hepatic Steatosis,Independent of PPAR‐α Activity,in a Murine Model of Parenteral Nutrition–Associated Liver Disease |
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Authors: | Esther Prince MD Farrah B Lazare DO William R Treem MD Jiliu Xu MD Jahangir Iqbal PhD Xiaoyue Pan PhD Joby Josekutty PhD Meghan Walsh BA Virginia Anderson MD M Mahmood Hussain PhD Steven M Schwarz MD |
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Institution: | 1. Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, State University of New York Downstate Medical Center, Brooklyn, New York;2. Department of Pediatrics, Winthrop University Medical Center, Mineola, New York;3. Johnson & Johnson Pharmaceutical Research and Development, LLC, Titusville, New Jersey;4. Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York;5. Department of Pathology, State University of New York Downstate Medical Center, Brooklyn, New York |
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Abstract: | Objectives: 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. |
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Keywords: | microsomal triglyceride transfer protein ω ‐3‐fatty acids parenteral nutrition– associated liver disease peroxisome proliferator‐activated receptor– α steatosis |
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