PPARα-UGT axis activation represses intestinal FXR-FGF15 feedback signalling and exacerbates experimental colitis

Abstract

Bile acids play a pivotal role in the pathological development of inflammatory bowel disease (IBD). However, the mechanism of bile acid dysregulation in IBD remains unanswered. Here we show that intestinal peroxisome proliferator-activated receptor α (PPARα)-UDP-glucuronosyltransferases (UGTs) signalling is an important determinant of bile acid homeostasis. Dextran sulphate sodium (DSS)-induced colitis leads to accumulation of bile acids in inflamed colon tissues via activation of the intestinal peroxisome PPARα-UGTs pathway. UGTs accelerate the metabolic elimination of bile acids, and thereby decrease their intracellular levels in the small intestine. Reduced intracellular bile acids results in repressed farnesoid X receptor (FXR)-FGF15 signalling, leading to upregulation of hepatic CYP7A1, thus promoting the de novo bile acid synthesis. Both knockout of PPARα and treatment with recombinant FGF19 markedly attenuate DSS-induced colitis. Thus, we propose that intestinal PPARα-UGTs and downstream FXR-FGF15 signalling play vital roles in control of bile acid homeostasis and the pathological development of colitis.

Intestinal transport and metabolism of bile acids

“…Similarly in the small intestine and colon, evidence suggests that glucuronidation of native unconjugated bile acids is limited in normal physiology (123)(124)(125). However, under pathophysiological conditions such as colitis, very recent evidence suggests that activation of intestinal UGT gene expression and increased glucuronidation of bile acids plays an important role in altering bile acid signaling and homeostasis and exacerbating bile acid injury in the colon ( 126 ). Bile acids that undergo glucuronidation in the enterocyte or colonocyte can be exported by MRP2 ( ABCC2 ) or the breast cancer resistance protein (BCRP) ( ABCG2 ) across the apical membrane back into the gut lumen ( 127 ) or by MRP3 across the basolateral membrane into the blood to undergo renal fi ltration and elimination ( 128 ).…”

“…The emerging consensus from this work is that these transformations are important contributors to bile acid signaling and gut microbiota-induced changes in whole body physiology ( 26,126,212 ). For example, microbiota effects upon body weight, adiposity, lipid metabolism, liver disease, intestinal mucosal function, colon carcinogenesis, and cardiovascular function have recently been linked to luminal bile acid metabolism and modulation of bile acid signaling ( 26, 213-218 ).…”

Mechanism-Based Inhibitory and Peroxisome Proliferator-Activated Receptor α–Dependent Modulating Effects of Silybin on Principal Hepatic Drug-Metabolizing Enzymes

“…It is largely unclear, in addition to its direct enzyme activity-inhibitory effect, whether silybin could regulate the mRNA and protein expression of DMEs. In addition, DMEs are under the control of multiple nuclear receptors, such as Pregnane X Receptor (PXR) and peroxisome proliferator-activated receptor (PPAR)a (Buckley and Klaassen, 2009;Runge-Morris and Kocarek, 2009;Zhou et al, 2014). More recently, silybin was identified as a potential antagonist of PXR that is a master regulator of CYP3A4 and other P450s (Mooiman et al, 2013).…”

“…Silybin and isosilybin were recently identified as novel PXR antagonists, which could inhibit PXR agonist-induced CYP3A4 expression (Mooiman et al, 2013). Considering that PPARa is a master regulator of UGTs (Zhou et al, 2014) and that silybin has a high affinity with UGT isozymes, we asked whether silybin could regulate the function of PPARa. All of the evidence collected from the targeting gene analysis, reporter gene assay, and molecular docking assay support that silybin per se is a weak PPARa agonist.…”

Ginsenosides Regulate PXR/NF-κB Signaling and Attenuate Dextran Sulfate Sodium–Induced Colitis

“…Several investigations have revealed that the inhibition of NF-kB activity ameliorated the severity of intestinal inflammation (Neurath et al, 1996;Atreya et al, 2008). In consideration of the well validated important roles of PXR and NF-kB in IBD and their mutual repressive relationship, it is reasonable to expect that restoration of the balance between PXR and NF-kB would be a promising strategy for the therapy of IBD, a disease with complicated causes and poor therapeutic means (Zhou et al, 2014).…”