Dissociation of Intestinal and Hepatic Activities of FXR and LXRα Supports Metabolic Effects of Terminal Ileum Interposition in Rodents

Abstract

The farnesoid X receptor (FXR) and the liver x receptors (LXRs) are bile acid–activated receptors that are highly expressed in the enterohepatic tissues. The mechanisms that support the beneficial effects of bariatric surgery are only partially defined. We have investigated the effects of ileal interposition (IT), a surgical relocation of the distal ileum into the proximal jejunum, on FXR and LXRs in rats. Seven months after surgery, blood concentrations of total bile acids, taurocholic acid, an FXR ligand, and taurohyocholic acid, an LXRα ligand, were significantly increased by IT (P < 0.05). In contrast, liver and intestinal concentrations of conjugated and nonconjugated bile acids were decreased (P < 0.05). These changes were associated with a robust induction of FXR and FXR-regulated genes in the intestine, including Fgf15, a negative regulator of bile acid synthesis. IT repressed the liver expression of glucose-6-phosphatase (G6PC) and phosphoenolpyruvate carboxykinase (Pepck), two gluconeogenetic genes, along with the expression of LXRα and its target genes sterol regulatory element-binding protein (Srebp) 1c and fatty acid synthase (Fas) in the liver. Treating IT rats with chenodeoxycholic acid ameliorated insulin signaling in the liver. Whether confirmed in human settings, these results support the association of pharmacological therapies with bariatric surgeries to exploit the selective activation of intestinal nuclear receptors.

Targeting Bile Acid Receptors: Discovery of a Potent and Selective Farnesoid X Receptor Agonist as a New Lead in the Pharmacological Approach to Liver Diseases

“…The tune page parameters were automatically optimized injecting taurocholic acid at 1 μM as standard. The MS/MS detection was operated in MRM mode using a collision energy of 20 (arbitrary units) and the observed transitions are reported in Mencarelli et al, 2013.…”

“…In addition, FXR plays a crucial beneficial role in triglyceride and cholesterol homeostasis, as well as in glucose metabolism (Fiorucci et al, 2004, 2007, 2009, 2010a,c; Cariou et al, 2006; Zhang et al, 2006; Cipriani et al, 2010; Mencarelli et al, 2013; Swanson et al, 2013). …”

Modification on Ursodeoxycholic Acid (UDCA) Scaffold. Discovery of Bile Acid Derivatives As Selective Agonists of Cell-Surface G-Protein Coupled Bile Acid Receptor 1 (GP-BAR1)

“…34 After centrifugation at 16000g for 10 min, the clear supernatant was transferred to a new vial, snap frozen, and lyophilized. The samples were then redissolved in methanol−water (2:1, v/v) for tauroconjugated bile acids determination.…”

Obesity and Diabetes

“…In a seminal study, Dr. Koopmans demonstrated that transposition of 5, 10, or 20 cm of the ileum to the duodenum produced a lengthdependent reduction in food intake and body weight, with the effects more robust in rats made obese with lesions in the ventromedial hypothalamus . Others studies in rats have since reported that IT surgery either produces a significant reduction in intake and weight gain (Atkinson et al 1982;Boozer et al 1990;Chen et al 1990;Chelikani et al 2010;Grueneberger et al 2013;Koopmans et al , 1984Ramzy et al 2014;Strader et al 2005;Wang et al 2008), or no effect on these parameters (Cummings et al 2010;Patriti et al 2007;Mencarelli et al 2013). These inconsistencies are likely due to varying lengths of transposed ileal segments and animal models.…”