title: A combination of dietary N-3 fatty acids and a cyclooxygenase-1 inhibitor attenuates nonalcoholic fatty liver disease in mice.
abstract: We sought to determine whether a combination of purified n-3 fatty acids (n-3) and SC-560 (SC), a cyclooxygenase-1-specific inhibitor, is effective in ameliorating nonalcoholic fatty liver disease in obesity. Female wild-type mice were fed a high-fat and high-cholesterol diet (HF) supplemented with n-3 in the presence or absence of SC. Mice treated with SC alone exhibited no change in liver lipids, whereas n-3-fed mice tended to have lower hepatic lipids. Mice given n-3+SC had significantly lower liver lipids compared with HF controls indicating enhanced lipid clearance. Total and sulfated bile acids were significantly higher only in n-3+SC-treated mice compared with chow diet (CD) controls. Regarding mechanisms, the level of pregnane X receptor (PXR), a nuclear receptor regulating drug/bile detoxification, was significantly higher in mice given n-3 or n-3+SC. Studies in precision-cut liver slices and in cultured hepatoma cells showed that n-3+SC enhanced not only the expression/activation of PXR and its target genes but also the expression of farnesoid X receptor (FXR), another regulator of bile synthesis/clearance, indicating that n-3+SC can induce both PXR and FXR. The mRNA level of FGFR4 which inhibits bile formation showed a significant reduction in Huh 7 cells upon n-3 and n-3+SC treatment. PXR overexpression in hepatoma cells confirmed that n-3 or SC each induced the expression of PXR target genes and in combination had an enhanced effect. Our findings suggest that combining SC with n-3 potentiates its lipid-lowering effect, in part, by enhanced PXR and/or altered FXR/FGFR4 signaling.
authors.affiliation: Department of Internal Medicine, Division of Diabetes, Endocrinology, and Metabolism, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address: s.viswanathan@unmc.edu.
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Saraswathi
authors.affiliation: Department of Internal Medicine, Division of Diabetes, Endocrinology, and Metabolism, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Curtis
authors.initials: C
authors.lastname: Perriotte-Olson
authors.affiliation: Department of Internal Medicine, Division of Diabetes, Endocrinology, and Metabolism, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Murali
authors.initials: M
authors.lastname: Ganesan
authors.affiliation: Department of Internal Medicine, Division of Diabetes, Endocrinology, and Metabolism, University of Nebraska Medical Center, Omaha, NE, USA; VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA.
authors.forename: Cyrus V
authors.initials: CV
authors.lastname: Desouza
authors.affiliation: Department of Pharmaceutical Science, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Yazen
authors.initials: Y
authors.lastname: Alnouti
authors.affiliation: Department of Internal Medicine, Division of Rheumatology and Immunology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Duryee
authors.affiliation: Department of Pharmaceutical Science, University of Nebraska Medical Center, Omaha, NE, USA; VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA.
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Thiele
authors.affiliation: Department of Internal Medicine, Division of Pulmonary, Critical Care, Sleep, and Allergy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Tara M
authors.initials: TM
authors.lastname: Nordgren
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE, USA; VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA.
authors.forename: Dahn L
authors.initials: DL
authors.lastname: Clemens
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002784:Cholesterol / Q000009:adverse effects; D051545:Cyclooxygenase 1; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D059305:Diet, High-Fat / Q000009:adverse effects; D019587:Dietary Supplements; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D005260:Female; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008103:Liver Cirrhosis / Q000178:diet therapy / Q000188:drug therapy; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000178:diet therapy* / Q000188:drug therapy* / Q000209:etiology; D000077297:Pregnane X Receptor; D011720:Pyrazoles / Q000494:pharmacology; D011987:Receptors, Steroid / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D016861:Cyclooxygenase Inhibitors; D015525:Fatty Acids, Omega-3; D008565:Membrane Proteins; D000077297:Pregnane X Receptor; D011720:Pyrazoles; D011987:Receptors, Steroid; C115461:SC 560; D002784:Cholesterol; D051545:Cyclooxygenase 1; C496512:Ptgs1 protein, mouse
keywords: Bile; Fish oil; Nonalcoholic fatty liver disease; Omega-3 fatty acids; PXR