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The role of bile acid receptor fxr and hdl in intestinal inflammation


Attinkara, Ragam. The role of bile acid receptor fxr and hdl in intestinal inflammation. 2012, University of Zurich, Faculty of Science.

Abstract

Inflammatory bowel disease (IBD) characterizes chronic gastrointestinal inflammation manifested by abdominal pain, diarrhea, malabsorbtion and bleeding, of which two phenotypes, Crohn’s disease (CD) and ulcerative colitis (UC) have been described [1-3]. It affects about 1.4 million people in the USA and 2.2 million people in Europe [4, 5]. The nuclear receptor farnesoid X receptor senses intracellular bile acid levels. In response to elevated levels of intracellular bile acids, activated FXR induces gene expression of bile acid efflux transporters whereas the expression of bile acid uptake transporters are down regulated, thus protecting against bile acid toxicity in the liver and intestine. FXR regulates several genes that can protect against intestinal inflammation and bacterial overgrowth. FXR-deficient mice have increased ileal concentrations of gut bacteria and exhibit defects in the integrity of the intestinal epithelial barrier. Furthermore, in rodent models of colitis and in CD patients, it has been reported that reduced expression of FXR is associated with colon inflammation [6]. The fact that FXR thus appears to play a role in the protection of the integrity of the intestinal epithelial barrier and its inverse correlation with the level of intestinal inflammation suggest a potential connection between FXR and the molecular pathogenesis of IBD. In the first chapter of this thesis, we have investigated five FXR single nucleotide polymorphisms - two common SNPs and three rare variants - which have been previously studied in the context of human disease, in a well sized IBD vs non-IBD cohort, and report that two of these genetic variants are associated with IBD. NF-κB activity is upregulated in patients with IBD, characterized by high circulatory levels of cytokines especially tumor necrosis factor (TNF). Low plasma concentration of high density lipoprotein (HDL) cholesterol is a marker and considered as a risk factor for coronary heart disease, diabetes mellitus, and several cancers including colorectal cancers [7-9]. The intestine plays a crucial role in HDL metabolism. In addition, the classical anti-atherogenic function of HDL, the mediation of reverse transport of excess cholesterol from macrophages of the arterial wall to the liver is completed by biliary excretion of cholesterol into the intestine. Intestinal dysfunction and inflammation leads to decrease in serum levels of HDL cholesterol and ApoA1 [10-13]. Consistent with this, clinical studies show significantly lower HDL-cholesterol levels in patients with active IBD [14]. Traditionally, the low HDL cholesterol in IBD patients is interpreted as the consequence of IBD. The association of low HDL-cholesterol with IBD together with the many anti-inflammatory properties of HDL however raises the question of whether HDL and its protein and lipid components have any causal impact on intestinal inflammation in IBD patients. In the second chapter of the thesis, we approached this question and investigated the effect of HDL and ApoA1 on intestinal inflammation both in vitro and in vivo. Autophagy, a catabolic process involving intracellular degradation of organelles and proteins, has been shown to be compromised in many human diseases including IBD. Autophagy malfunction has been attributed to defective clearance of pathogens and dysfunction of paneth and goblet cells, which are relevant for pathogenesis of IBD. In the third chapter of the thesis, we put forward autophagy as a mechanism by which HDL suppress intestinal inflammation.

Abstract

Inflammatory bowel disease (IBD) characterizes chronic gastrointestinal inflammation manifested by abdominal pain, diarrhea, malabsorbtion and bleeding, of which two phenotypes, Crohn’s disease (CD) and ulcerative colitis (UC) have been described [1-3]. It affects about 1.4 million people in the USA and 2.2 million people in Europe [4, 5]. The nuclear receptor farnesoid X receptor senses intracellular bile acid levels. In response to elevated levels of intracellular bile acids, activated FXR induces gene expression of bile acid efflux transporters whereas the expression of bile acid uptake transporters are down regulated, thus protecting against bile acid toxicity in the liver and intestine. FXR regulates several genes that can protect against intestinal inflammation and bacterial overgrowth. FXR-deficient mice have increased ileal concentrations of gut bacteria and exhibit defects in the integrity of the intestinal epithelial barrier. Furthermore, in rodent models of colitis and in CD patients, it has been reported that reduced expression of FXR is associated with colon inflammation [6]. The fact that FXR thus appears to play a role in the protection of the integrity of the intestinal epithelial barrier and its inverse correlation with the level of intestinal inflammation suggest a potential connection between FXR and the molecular pathogenesis of IBD. In the first chapter of this thesis, we have investigated five FXR single nucleotide polymorphisms - two common SNPs and three rare variants - which have been previously studied in the context of human disease, in a well sized IBD vs non-IBD cohort, and report that two of these genetic variants are associated with IBD. NF-κB activity is upregulated in patients with IBD, characterized by high circulatory levels of cytokines especially tumor necrosis factor (TNF). Low plasma concentration of high density lipoprotein (HDL) cholesterol is a marker and considered as a risk factor for coronary heart disease, diabetes mellitus, and several cancers including colorectal cancers [7-9]. The intestine plays a crucial role in HDL metabolism. In addition, the classical anti-atherogenic function of HDL, the mediation of reverse transport of excess cholesterol from macrophages of the arterial wall to the liver is completed by biliary excretion of cholesterol into the intestine. Intestinal dysfunction and inflammation leads to decrease in serum levels of HDL cholesterol and ApoA1 [10-13]. Consistent with this, clinical studies show significantly lower HDL-cholesterol levels in patients with active IBD [14]. Traditionally, the low HDL cholesterol in IBD patients is interpreted as the consequence of IBD. The association of low HDL-cholesterol with IBD together with the many anti-inflammatory properties of HDL however raises the question of whether HDL and its protein and lipid components have any causal impact on intestinal inflammation in IBD patients. In the second chapter of the thesis, we approached this question and investigated the effect of HDL and ApoA1 on intestinal inflammation both in vitro and in vivo. Autophagy, a catabolic process involving intracellular degradation of organelles and proteins, has been shown to be compromised in many human diseases including IBD. Autophagy malfunction has been attributed to defective clearance of pathogens and dysfunction of paneth and goblet cells, which are relevant for pathogenesis of IBD. In the third chapter of the thesis, we put forward autophagy as a mechanism by which HDL suppress intestinal inflammation.

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Additional indexing

Item Type:Dissertation
Referees:Wenger RH, Rogler Gerhard , Jyrki Eloranta, Boecker Ulrich
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2012
Deposited On:17 Jan 2013 16:13
Last Modified:05 Apr 2016 16:21

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