title: Cinnamamides, Novel Liver X Receptor Antagonists that Inhibit Ligand-Induced Lipogenesis and Fatty Liver.
abstract: Liver X receptor (LXR) is a member of the nuclear receptor superfamily, and it regulates various biologic processes, including de novo lipogenesis, cholesterol metabolism, and inflammation. Selective inhibition of LXR may aid the treatment of nonalcoholic fatty liver diseases. In the present study, we evaluated the effects of three cinnamamide derivatives on ligand-induced LXRα activation and explored whether these derivatives could attenuate steatosis in mice. N-(4-trifluoromethylphenyl) 3,4-dimethoxycinnamamide (TFCA) decreased the luciferase activity in LXRE-tk-Luc-transfected cells and also suppressed ligand-induced lipid accumulation and expression of the lipogenic genes in murine hepatocytes. Furthermore, it significantly attenuated hepatic neutral lipid accumulation in a ligand-induced fatty liver mouse system. Modeling study indicated that TFCA inhibited activation of the LXRα ligand-binding domain by hydrogen bonding to Arg305 in the H5 region of that domain. It regulated the transcriptional control exerted by LXRα by influencing coregulator exchange; this process involves dissociation of the thyroid hormone receptor-associated proteins (TRAP)/DRIP coactivator and recruitment of the nuclear receptor corepressor. These results show that TFCA has the potential to attenuate ligand-induced lipogenesis and fatty liver by selectively inhibiting LXRα in the liver.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (W.C.S., D.G.K., K.J.L., You-Jin C., J.W.K., W.K.O., B.H.L.); College of Pharmacy, The Catholic University, Republic of Korea (Yeon-Jae C., K.J.S.); Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea (D.W.J.); School of Pharmacy, Sungkyunkwan University, Jangan-gu, Republic of Korea (S.J.P., H.J.P.).
authors.forename: Woo-Cheol
authors.initials: WC
authors.lastname: Sim
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (W.C.S., D.G.K., K.J.L., You-Jin C., J.W.K., W.K.O., B.H.L.); College of Pharmacy, The Catholic University, Republic of Korea (Yeon-Jae C., K.J.S.); Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea (D.W.J.); School of Pharmacy, Sungkyunkwan University, Jangan-gu, Republic of Korea (S.J.P., H.J.P.).
authors.forename: Dong Gwang
authors.initials: DG
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (W.C.S., D.G.K., K.J.L., You-Jin C., J.W.K., W.K.O., B.H.L.); College of Pharmacy, The Catholic University, Republic of Korea (Yeon-Jae C., K.J.S.); Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea (D.W.J.); School of Pharmacy, Sungkyunkwan University, Jangan-gu, Republic of Korea (S.J.P., H.J.P.).
authors.forename: Kyeong Jin
authors.initials: KJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (W.C.S., D.G.K., K.J.L., You-Jin C., J.W.K., W.K.O., B.H.L.); College of Pharmacy, The Catholic University, Republic of Korea (Yeon-Jae C., K.J.S.); Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea (D.W.J.); School of Pharmacy, Sungkyunkwan University, Jangan-gu, Republic of Korea (S.J.P., H.J.P.).
authors.forename: You-Jin
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (W.C.S., D.G.K., K.J.L., You-Jin C., J.W.K., W.K.O., B.H.L.); College of Pharmacy, The Catholic University, Republic of Korea (Yeon-Jae C., K.J.S.); Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea (D.W.J.); School of Pharmacy, Sungkyunkwan University, Jangan-gu, Republic of Korea (S.J.P., H.J.P.).
authors.forename: Yeon Jae
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (W.C.S., D.G.K., K.J.L., You-Jin C., J.W.K., W.K.O., B.H.L.); College of Pharmacy, The Catholic University, Republic of Korea (Yeon-Jae C., K.J.S.); Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea (D.W.J.); School of Pharmacy, Sungkyunkwan University, Jangan-gu, Republic of Korea (S.J.P., H.J.P.).
authors.forename: Kye Jung
authors.initials: KJ
authors.lastname: Shin
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (W.C.S., D.G.K., K.J.L., You-Jin C., J.W.K., W.K.O., B.H.L.); College of Pharmacy, The Catholic University, Republic of Korea (Yeon-Jae C., K.J.S.); Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea (D.W.J.); School of Pharmacy, Sungkyunkwan University, Jangan-gu, Republic of Korea (S.J.P., H.J.P.).
authors.forename: Dae Won
authors.initials: DW
authors.lastname: Jun
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (W.C.S., D.G.K., K.J.L., You-Jin C., J.W.K., W.K.O., B.H.L.); College of Pharmacy, The Catholic University, Republic of Korea (Yeon-Jae C., K.J.S.); Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea (D.W.J.); School of Pharmacy, Sungkyunkwan University, Jangan-gu, Republic of Korea (S.J.P., H.J.P.).
authors.forename: So-Jung
authors.initials: SJ
authors.lastname: Park
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (W.C.S., D.G.K., K.J.L., You-Jin C., J.W.K., W.K.O., B.H.L.); College of Pharmacy, The Catholic University, Republic of Korea (Yeon-Jae C., K.J.S.); Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea (D.W.J.); School of Pharmacy, Sungkyunkwan University, Jangan-gu, Republic of Korea (S.J.P., H.J.P.).
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Park
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (W.C.S., D.G.K., K.J.L., You-Jin C., J.W.K., W.K.O., B.H.L.); College of Pharmacy, The Catholic University, Republic of Korea (Yeon-Jae C., K.J.S.); Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea (D.W.J.); School of Pharmacy, Sungkyunkwan University, Jangan-gu, Republic of Korea (S.J.P., H.J.P.).
authors.forename: Jiwon
authors.initials: J
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (W.C.S., D.G.K., K.J.L., You-Jin C., J.W.K., W.K.O., B.H.L.); College of Pharmacy, The Catholic University, Republic of Korea (Yeon-Jae C., K.J.S.); Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea (D.W.J.); School of Pharmacy, Sungkyunkwan University, Jangan-gu, Republic of Korea (S.J.P., H.J.P.).
authors.forename: Won Keun
authors.initials: WK
authors.lastname: Oh
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (W.C.S., D.G.K., K.J.L., You-Jin C., J.W.K., W.K.O., B.H.L.); College of Pharmacy, The Catholic University, Republic of Korea (Yeon-Jae C., K.J.S.); Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea (D.W.J.); School of Pharmacy, Sungkyunkwan University, Jangan-gu, Republic of Korea (S.J.P., H.J.P.) lee@snu.ac.kr.
authors.forename: Byung-Hoon
authors.initials: BH
authors.lastname: Lee
mesh_terms: D000135:Acid Phosphatase / Q000235:genetics / Q000378:metabolism; D050156:Adipogenesis; D000818:Animals; D002460:Cell Line; D002934:Cinnamates / Q000494:pharmacology*; D005234:Fatty Liver / Q000517:prevention & control*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D050356:Lipid Metabolism / Q000187:drug effects; D050155:Lipogenesis / Q000187:drug effects*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors*; D000071681:Tartrate-Resistant Acid Phosphatase; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism
chemical_list: D002934:Cinnamates; D007527:Isoenzymes; D008024:Ligands; D000071518:Liver X Receptors; C000604692:N-(4-trifluoromethylphenyl) 3,4-dimethoxycinnamamide; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D014280:Triglycerides; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase; C411088:cinnamamide