A Novel Mechanism for Decreasing Plasma Lipid Level from Imidazoline I-1 Receptor Activation in High Fat Diet-fed Mice

Abstract

The imidazoline I-1 receptor (I-1 R) agonists are widely used to lower blood pressure, but their effects on hyperlipidemia are still obscure. The present study is aimed to evaluate the possible mechanism(s) of I-1 R in the regulation of lipid homeostasis. Farnesoid X receptor (FXR) plays an important role in blood lipid homeostasis; however, the role of FXR in rilmenidine-induced blood lipid lowering action is still unknown. Thus, we administered rilmenidine, a selective agonist of I-1 R, into high fat diet-fed (HFD) mice showing hypertriglyceridemia and hypercholesterolemia. Rilmenidine significantly ameliorated hyperlipidemia in HFD mice after 7 days of administration. Pretreatment with efaroxan, at a dose sufficient to inhibit I-1 R activation, blocked the effects of rilmenidine. Also, in cultured HepG2 cells, rilmenidine dose-dependently induced the expression of farnesoid X receptor (FXR). The rilmenidine-induced FXR expression and FXR-related genes were blocked by efaroxan. However, rilmenidine treatment did not affect the expression of enzymes related to β-oxidation. In conclusion, activation of I-1 R may activate FXR to lower plasma lipids, suggesting I-1 R as a new target for the treatment of hyperlipidemia.

Rilmenidine improves hepatic steatosis through p38-dependent pathway to higher the expression of farnesoid X receptor

“…In the study, we found that an activation of imidazoline I-1 receptor by the specific agonist rilmenidine significantly improved high-fat diet-induced hepatic steatosis at the effective dose as described previously (Niu et al 2011). Also, this action of rilmenidine was reversed by pretreatment of the I-1 receptor antagonist, implying the role of I-1 receptor in the regulation of lipid homeostasis.…”

“…Although Hep G2 cells are hard to show the same as normal human hepatocytes totally, this cell line is introduced to offer an alternative and reliable model for studies on liver lipid metabolism (Wang et al 1988). Similar to the changes in primary culture of mouse hepatocytes (Niu et al 2011), oleic acid-induced lipid accumulation in Hep G2 cells that also improved by rilmenidine (Fig. 2).…”

“…It has been indicated that activation of I-1 receptor increases the expression of FXR (Niu et al 2011), while activation of FXR may improve hepatic steatosis (Claudel et al 2005). In the previous study (Niu et al 2011), rilmenidine dose dependently induced the increase of FXR expression in Hep G2 cells to lower plasma lipid. In the present study, rilmenidine at the same effective dose also improved hepatic steatosis (Fig.…”

“…The first group was intraperitoneally (i.p.) injected with rilmenidine (Tocris Bioscience, Ellisville, MO, USA) at 1 mg/kg daily following our previous method (Niu et al 2011). In the second group, 1 mg/kg efaroxan (Tocris Bioscience, Ellisville, MO, USA), one specific antagonist of imidazoline I-1 receptor, was also i.p.…”

“…Activation of I-3 receptor stimulates insulin secretion from pancreatic β-cells to regulate blood glucose (Raasch et al 2001). The recent study indicated that activation of I-1 receptor by rilmenidine regulates blood lipid through an increase of FXR expression (Niu et al 2011). However, the potential signals for this increase of FXR by rilmenidine remained obscure.…”