Abstract
Intrahepatic cholestasis of pregnancy is always accompanied by adverse fetal outcomes such as malfunctions of respiration. Farnesoid X receptor (FXR) plays a critical role in the homeostasis of bile acids. Thus, we are determined to explore the effects of farnesoid X receptor (FXR) and five bile acids on respiratory rhythm generation and modulation of neonatal rats. Spontaneous periodic respiratory-related rhythmical discharge activity (RRDA) was recorded from hypoglossal nerves during the perfusion of modified Krebs solution. Group 1–6 was each given GW4064 and five bile acids of chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), cholic acid (CA) as well as ursodeoxycholic acid (UDCA) at different concentrations to identify their specific functions on respiratory rhythm modulations. Group 7 was applied to receive FXR blocker Z-guggulsterone and Z-guggulsterone with the above bile acids separately to explore the role of FXR in the respiratory rhythm modulation. Group 8 was given dimethyl sulfoxide (DMSO) as controls. Apart from UDCA, CDCA, DCA LCA and CA all exerted effects on RRDA recorded from hypoglossal nerves in a concentration-dependent manner. Respiratory cycle (RC), Inspiratory time (TI), Expiratory Time (TE) and Integral Amplitude (IA) were influenced and such effects could be reversed by Z-guggulsterone. FXR may contribute to the effects on the modulation of respiratory rhythm exerted by bile acids.
Highlights
Conversion of cholesterol to bile acids plays an important role in the cholesterol homeostasis and serves as the main pathway for cholesterol catabolism [1]
Effects of Bile Acids and GW4064 on farnesoid X receptor (FXR)-small heterodimer partner (SHP) Pathway Bile acids are acknowledged as physiological ligands of FXR
All four bile acids (CDCA, cholic acid (CA), deoxycholic acid (DCA) and lithocholic acid (LCA)) and GW4064 except ursodeoxycholic acid (UDCA) were able to increase the mRNA of FXR
Summary
Conversion of cholesterol to bile acids plays an important role in the cholesterol homeostasis and serves as the main pathway for cholesterol catabolism [1]. Bile acids are normally produced in the liver cells and secreted into the intestines. Bile acids are known as signaling molecules that activate the farnesoid X receptor (FXR) [4]. As the target genes of FXR like bile salt export pump (BSEP) and small heterodimer partner (SHP), FXR is able to maintain the homeostasis of cholesterol and bile acids via regulating their expressions by binding to the FXR response element (FXRE) located on the promoters of these genes [5]. FXR antagonists such as guggulsterone are able to stimulate the conversion of cholesterol to bile acids. Guggulsterone is reported to inhibit FXR induction of ileal bile acid binding protein (IBABP) and SHP expression and is used to lower serum levels of cholesterol and triglyceride [9]. Taking the abilities of inhibiting FXR-mediated effects into consideration, FXR antagonists may have therapeutic potential
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