Dissociation of Intestinal and Hepatic Activities of FXR and LXRα Supports Metabolic Effects of Terminal Ileum Interposition in Rodents
- Andrea Mencarelli1,
- Barbara Renga1⇑,
- Claudio D’Amore1,
- Chiara Santorelli2,
- Luigina Graziosi2,
- Angela Bruno1,
- Maria Chiara Monti3,
- Eleonora Distrutti4,
- Sabrina Cipriani1,
- Annibale Donini2 and
- Stefano Fiorucci1
- 1Department of Experimental and Clinical Medicine, University of Perugia, Perugia, Italy
- 2Department of Surgical, Radiological and Odontostomatological Sciences, University of Perugia, Perugia, Italy
- 3Department of Biomedical and Pharmaceutical Sciences, University of Salerno, Salerno, Italy
- 4Hospital of Perugia Santa Maria della Misericordia, Perugia, Italy.
- Corresponding author: Barbara Renga, .
A.M. and B.R. contributed equally to this work
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0299/-/DC1.
- Received February 21, 2013.
- Accepted June 21, 2013.
- © 2013 by the American Diabetes Association.
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