title: Rilmenidine improves hepatic steatosis through p38-dependent pathway to higher the expression of farnesoid X receptor.
abstract: The nuclear receptor farnesoid X receptor (FXR) regulates pathways in lipid, glucose, and energy metabolism. Activation of FXR in mice significantly improved high-fat diet-induced hepatic steatosis. It has been reported that activation of imidazoline I-1 receptor by rilmenidine increases the expression of FXR in human hepatoma cell line, Hep G2 cell, to regulate the target genes relating to lipid metabolism; activation of FXR by rilmenidine exerts an antihyperlipidemic action. However, signals for this action of rilmenidine are still unknown. In the present study, hepatic steatosis induced in mice by high-fat diet was improved by rilmenidine after intraperitoneal injection at 1 mg/kg daily for 12 weeks. Also, mediation of I-1 receptors was identified using the specific antagonist efaroxan. Moreover, rilmenidine decreased the oleic acid-induced lipid accumulation in Hep G2 cells. Otherwise, rilmenidine increased the phosphorylation of p38 to increase the expression of FXR. Deletion of calcium ions by BAPTA-AM reversed the rilmenidine-induced p38 phosphorylation. In conclusion, we suggest that rilmenidine activates I-1 receptor to increase intracellular calcium ions that may enhance the phosphorylation of p38 to higher the expression of FXR for improvement of hepatic steatosis in both animals and cells.
authors.affiliation: Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Li-Nong Street, Taipei, Taiwan.
authors.forename: Po-Sheng
authors.initials: PS
authors.lastname: Yang
authors.forename: Hung-Tsung
authors.initials: HT
authors.lastname: Wu
authors.forename: Hsien-Hui
authors.initials: HH
authors.lastname: Chung
authors.forename: Chun-Ta
authors.initials: CT
authors.lastname: Chen
authors.forename: Chin-Wen
authors.initials: CW
authors.lastname: Chi
authors.forename: Ching-Hua
authors.initials: CH
authors.lastname: Yeh
authors.forename: Juei-Tang
authors.initials: JT
authors.lastname: Cheng
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D059305:Diet, High-Fat / Q000009:adverse effects; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D005234:Fatty Liver / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D006801:Humans; D054755:Imidazoline Receptors / Q000819:agonists* / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019301:Oleic Acid / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis*; D000077769:Rilmenidine; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002118:Calcium; D004533:Egtazic Acid; D054755:Imidazoline Receptors; D019301:Oleic Acid; D010080:Oxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D000077769:Rilmenidine; D000099150:Receptor, Farnesoid X-Activated; C410887:imidazoline I1 receptors; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester