title: Fish oil and indomethacin in combination potently reduce dyslipidemia and hepatic steatosis in LDLR(-/-) mice.
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, 6 mg/l 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 with control. The mRNA and/or protein expression of pregnane X receptor (PXR) and cytochrome P450 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 cytochrome P450.
authors: Division of Diabetes, Endocrinology and Metabolism, University of Nebraska Medical Center and the VA Nebraska Western Iowa Health Care System, Omaha, NE.
authors: Ganesan
authors: G
authors: Murali
authors: Department of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN.
authors: Ginger L
authors: GL
authors: Milne
authors: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN; and.
authors: Corey D
authors: CD
authors: Webb
authors: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN; and.
authors: Ann B
authors: AB
authors: Stewart
authors: Department of Human Nutrition, Foods, and Exercise and The Virginia Tech Metabolic Phenotyping Core, Virginia Polytechnic Institute and State University, Blacksburg, VA.
authors: Ryan P
authors: RP
authors: McMillan
authors: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN; and.
authors: Brandon C
authors: BC
authors: Lyle
authors: Department of Human Nutrition, Foods, and Exercise and The Virginia Tech Metabolic Phenotyping Core, Virginia Polytechnic Institute and State University, Blacksburg, VA.
authors: Matthew W
authors: MW
authors: Hulver
authors: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN; and. Electronic address: s.viswanathan@unmc.edu.
authors: Viswanathan
authors: V
authors: Saraswathi
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D050171:Dyslipidemias / Q000188:drug therapy / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism*; D005260:Female; D005395:Fish Oils / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D005395:Fish Oils; D000960:Hypolipidemic Agents; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011973:Receptors, LDL; D011987:Receptors, Steroid; D003577:Cytochrome P-450 Enzyme System; D007213:Indomethacin