omega-3 Fatty Acids Prevent Hepatic Steatosis, Independent of PPAR-alpha Activity, in a Murine Model of Parenteral Nutrition-Associated Liver Disease

摘要

Objectives: omega-3 Fatty acids (FAs), natural ligands for the peroxisome proliferator-activated receptor-alpha (PPAR-alpha), attenuate parenteral nutrition-associated liver disease (PNALD). However, the mechanisms underlying the protective role of omega-3 FAs are still unknown. The aim of this study was to determine the effects of omega-3 FAs on hepatic triglyceride (TG) accumulation in a murine model of PNALD and to investigate the role of PPAR-alpha and microsomal triglyceride transfer protein (MTP) in this experimental setting. Methods: 129S1/SvImJ wild-type or 129S4/SvJaePparatm/Gonz/J PPAR-alpha knockout mice were fed chow and water (controls); oral, fat-free PN solution only (PN-O); PN-O plus intraperitoneal (IP) omega-6 FA-predominant supplements (PN-omega-6); or PN-O plus IP omega-3 FA (PN-omega-3). Control and PN-O groups received sham IP injections of 0.9% NaCl. Hepatic histology, TG and cholesterol, MTP activity, and PPAR-alpha 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-omega-6 groups accumulated significantly greater amounts of TG when compared with PN-omega-3 mice. Studies in PPAR-alpha null animals showed that PN feeding increases hepatic TG as in wild-type mice. PPAR-alpha null mice in the PN-O and PN-omega-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 omega-3 FAs. Conclusions: PN induces TG accumulation (steatosis) in wild-type and PPAR-alpha null mice. In PN-fed wild-type and PPAR-alpha null mice given IP omega-3 FAs, reduced hepatic TG accumulation and absent steatosis are found. Prevention of steatosis by omega-3 FAs results from PPAR-alpha-independent pathways.