Ω-3 fatty acids prevent hepatic steatosis, independent of PPAR-α activity, in a murine model of parenteral nutrition-associated liver disease.

Objectives: omega-3 Fatty acids (FAs), natural ligands for the peroxisome proliferator-activated receptor-a (PPAR-a), 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-a and microsomal triglyceride transfer protein (MTP) in this experimental setting. Methods: 129S1/SvImJ wildtype or 129S4/SvJaePparatm/Gonz/J PPAR-a knockout mice were fed chow and water (controls); oral, fat-free PN solution only (PN-O); PN-O plus intraperitoneal (IP).-6 FA-predominant supplements (PN-.-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-a 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-.-6 groups accumulated significantly greater amounts of TG when compared with PN-omega-3 mice. Studies in PPAR-a null animals showed that PN feeding increases hepatic TG as in wild-type mice. PPAR-a null mice in the PN-O and PN-.-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-a null mice. In PN-fed wild-type and PPAR-a 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-a-independent pathways.