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.

Stimulatory Effect of Allantoin on Imidazoline I1 Receptors in Animal and Cell Line

“…1 ), which is consistent with the previous report [ 23 ] . We further investigated the potential mechanisms of the hypolipidemic action of allantoin using HepG2 cells.…”

Imidazoline Receptor System: The Past, the Present, and the Future

“…This effect appears to be due to an increase in intracellular calcium and an increase in p38 phosphorylation. An improvement in hepatic steatosis was also observed in vivo in mice treated with rilmenidine (Yang et al, 2012). I 1 receptor activation negatively regulates the progression of fibrosis through a Nrf2-dependent pathway in hepatic stellate cells.…”

Emerging Roles of Impaired Autophagy in Fatty Liver Disease and Hepatocellular Carcinoma

“…Administration of rilmenidine, an investigational small molecule, reduced levels of the mutant Huntingtin fragment in a mouse disease model [157] and also reduced cAMP levels in cellular models of the disease [158]. The role of rilmenidine in the reduction of hepatic steatosis was previously reported [159]. Rilmenidine modulates intracellular calcium ions by activation of the imidazoline I-1 receptor, increasing phosphorylation of p38 and the expression of nuclear receptor farnesoid X receptor (FXR), leading to reduced levels of hepatic steatosis in mice and cell steatosis in HepG2 HCC cells [159].…”

“…The role of rilmenidine in the reduction of hepatic steatosis was previously reported [159]. Rilmenidine modulates intracellular calcium ions by activation of the imidazoline I-1 receptor, increasing phosphorylation of p38 and the expression of nuclear receptor farnesoid X receptor (FXR), leading to reduced levels of hepatic steatosis in mice and cell steatosis in HepG2 HCC cells [159]. The testing of rilmenidine in FLD and HCC clinical trials has not yet been carried out.…”