Fish Oil and Indomethacin in Combination Potently Reduce Dyslipidemia and Hepatic Steatosis in LDLR-/- Mice

Authors

• Ganesan Murali, University of Nebraska Medical Center
• Ginger L. Milne, Vanderbilt University Medical Center
• Corey Webb, Vanderbilt University Medical Center
• Ann B. Stewart, Vanderbilt University Medical Center
• Ryan P. McMillan, The Virginia Tech Metabolic Phenotyping Core
• Brandon C. Lyle, Vanderbilt University Medical Center
• Matthew W. Hulver, The Virginia Tech Metabolic Phenotyping Core
• Viswanathan Saraswathi, University of Nebraska Medical CenterFollow

Date of this Version

2012

Citation

J. Lipid Res., 29 July 2012, 10.1194/jlr.M029843

Abstract

Fish oil (FO) is a potent anti-inflammatory and lipid-lowering agent. Because inflammation can modulate lipid metabolism and vice versa, we hypothesized that combining FO with cyclooxygenase inhibitors (COXIBs), well-known anti-inflammatory drugs, can enhance the anti-inflammatory and lipid-lowering effect of FO. LDLR-/- mice were fed a high fat diet supplemented with 6% olive oil or FO for 12 wk in the presence or absence of indomethacin (Indo, 6mg/liter drinking water). FO reduced plasma total cholesterol by 30% but in combination with Indo, exerted a greater decrease (44%). The reduction of liver cholesterol ester (CE) and triglycerides (TG) by FO (63% and 41%, respectively) was enhanced by Indo (80% in CE and 64% in TG). FO + Indo greatly increased the expression of genes modulating lipid metabolism and reduced the expression of inflammatory genes compared to control. The mRNA and/or protein expression of pregnane X receptor (PXR) and cytochrome P450 (CYP 450) isoforms that alter inflammation and/or lipid metabolism are increased to a greater extent in mice that received FO + Indo. Moroever, the nuclear level of PXR is significantly increased in FO + Indo group. Combining FO with COXIBs may exert their beneficial effects on inflammation and lipid metabolism via PXR and CYP 450s.