Spexin Acts as Novel Regulator for Bile Acid Synthesis

Cheng-Yuan Lin,Linda L D Zhong,Zong-Wei Cai,Anderson O L Wong,Tao Huang,Ling Zhao,Mahjabin Khan,Jie Liu,Lin Lu,Bao-Min Fan,Zhao-Xiang Bian

doi:10.3389/fphys.2018.00378

Abstract

Spexin is a novel hormone involved in obesity and diabetes while its biofunctional significance in lipid metabolism is still to be comprehended. Global metabolomic analysis in the present study revealed multiple metabolic pathways altered by spexin intraperitoneal (i.p.) injection in rat serum, which are highlighted by the changes in several bile acid metabolites. In rats, spexin (300 μg/kg) could dramatically reduce hepatic and circulating total bile acids (TBA) level compared with the controls. Correspondingly, treatment with spexin by i.p. injection for 28 days led to significant decrease in serum TBA and gallbladder weight in C57BL/6J mice. In enterohepatic circulation system, spexin effectively reduced TBA levels in mouse liver and gallbladder but not the intestine. Hepatic cholesterol 7α-hydroxylase 1 (CYP7A1) expression, unsurprisingly, was suppressed by spexin injection. Both GALR2 and GALR3 antagonists reversed the inhibitory effects of spexin on concentrations of serum TBA and 7 α-hydroxy-4-cholesten-3-one (C4), and hepatic CYP7A1 expression. Finally, negative correlations were observed between serum spexin and total cholesterol (TC), total bile acid (TBA), tauro-chenodeoxycholate (TCDCA), as well as glycochenodeoxycholate (GCDCA) in 91 healthy volunteers. These findings illuminate the intrinsic importance of spexin in the regulation of bile acid synthesis and metabolism.

Highlights

Spexin, an endogenous peptide discovered using bioinformatics tools (Mirabeau et al, 2007; Sonmez et al, 2009), has been found to activate both galanin receptor 2 (GALR2) and galanin receptor 3 (GALR3) (Kim et al, 2014)
Metabolite set enrichment analysis (MSEA) for those changed signatures revealed that bile acid biosynthesis topped in enriched pathways (Figure 1C)
Consistent with observations in rats (Porzionato et al, 2010), intense cytoplasmic staining of spexin was found in the hepatocytes of mice, with co-localization with GALR2 and GALR3 receptors (Figure 6A). This suggests spexin may play biofunctions in the liver via the two receptors, GALR2 and GALR3. We found that both GALR2 antagonist and GALR3 inhibitor could effectively attenuate the inhibitory effect of spexin on hepatic total bile acids (TBA) level (Figure 6B) and reverse the suppressed cholesterol 7α-hydroxylase 1 (CYP7A1) expression by spexin injection (Figure 6C)

Summary

Introduction

An endogenous peptide discovered using bioinformatics tools (Mirabeau et al, 2007; Sonmez et al, 2009), has been found to activate both galanin receptor 2 (GALR2) and galanin receptor 3 (GALR3) (Kim et al, 2014). Spexin Inhibit Bile Acid Synthesis blood glucose in type 2 diabetes mellitus (T2DM) patients (Gu et al, 2015) and body weight in obese children (Kumar et al, 2016). Spexin treatment effectively suppressed hepatic lipids and long-chain fatty acid (LCFA) uptake, contributing to loss in body weight (Ge et al, 2016). These findings imply that spexin may be an intrinsic regulator of glucose and lipid metabolism in obesity and T2DM condition

Methods

Results

Conclusion