Explore chapters and articles related to this topic
Transient Receptor Potential Channels and Itch
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Mahar Fatima, Jingyi Liu, Bo Duan
TRPA1 is suggested to be critically involved in cholestatic itch—a type of systemic itch caused by liver dysfunction. Increased bile acid levels can cause excessive itch through the activation of G-protein–coupled bile acid receptor 1 TGR5. TGR5 is co-expressed with TRPA1 in a subset of the TRPA1 population of sensory neurons. Deletion or blocking of TRPA1 receptors abolishes bile acid- or TGR5-evoked scratching (77). Lysophosphatidic acid (LPA) is another itch mediator found in cholestatic itch patients (35). LPA-induced itch is dependent on activation of TRPA1 and TRPV1 channels in the DRG. Extracellular LPA activates the LPA5 receptor and membrane lipids are metabolized mainly by Phospholipase D (PLD). Activity of PLD and calcium-independent phospholipase A2 (iPLA2) leads to intracellular LPA production, which results in the activation of TRPA1 and TRPV1 channels.
Luminally Active Therapies
Published in John K. DiBaise, Carol Rees Parrish, Jon S. Thompson, Short Bowel Syndrome Practical Approach to Management, 2017
The implications of recent research identifying diverse and far-reaching roles for bile acids as signaling molecules for the pathophysiology and management of SBS are yet to be delineated. In addition to the signaling pathways described previously related to bile acid homeostasis, it is now abundantly evident that bile acids exert diverse endocrine and metabolic actions by activating G protein-coupled bile acid receptor 1 (also referred to as TGR5), a membrane G protein-coupled receptor that is expressed in enteroendocrine cells. Activation of TGR5 on enteroendocrine cells stimulates secretion of glucagon-like peptides-1 and -2 (GLP-1 and GLP-2). GLP-1 operates as the major incretin hormone involved in glucose homeostasis [16]. These effects have led to the clinical investigation of FXR agonists, such as obeticholic acid, in nonalcoholic fatty liver disease [21] and may have relevance to steatosis in IFALD. Meanwhile, GLP-2 is a key trophic hormone in relation to the process of intestinal adaptation and growth in response to food ingestion; these effects may explain the experimental observation that dietary bile acid supplementation promoted intestinal integrity (decreased apoptosis) and improved survival in a murine intestinal injury model [22].
Diabetes in Older Adults and Its Management
Published in K. Rao Poduri, Geriatric Rehabilitation, 2017
Susanne U. Miedlich, Steven D. Wittlin
Bile acid sequestrants are nonabsorbable resins that bind and sequester bile acids in the intestine, thus diverting them from the enterohepatic cycle. As a consequence, low-density lipoprotein (LDL) delivery to the liver is increased to compensate for the reduction of the bile acid pool (reviewed in Reference 123). These events translate into a 10%–15% reduction of LDL levels and led to the approval of bile acid sequestrants for the therapy of hypercholesterolemias (reviewed in Reference 123). The first evidence of a glucose-lowering effect of bile aid sequestrants, in particular cholestyramine, dates back to 1994 (124). Colesevelam was later approved for diabetes therapy. The exact mechanisms of the hypoglycemic actions of bile acid sequestrants are not entirely understood but may involve the bile acid receptor FXR (nuclear farnesoid X receptor) and FGF19 pathway (fibroblast growth factor 19), stimulation of incretin secretion through TGR5 (also known as GPBAR1 or G protein-coupled bile acid receptor 1), and possibly modulation of gut microbiota composition (reviewed in Reference 123).
Gut microbiota and hypertension: association, mechanisms and treatment
Published in Clinical and Experimental Hypertension, 2023
Zhihua Yang, Qingchun Wang, Yangxi Liu, Lin Wang, Zhao Ge, Zhenzhen Li, Shaoling Feng, Chongming Wu
The most important feature of endothelial dysfunction is the impair of vasomotor regulation. BA receptors such as nuclear receptor farnesoid X receptor (FXR) and membrane receptor G protein-coupled bile acid receptor-1 (GPBAR1) play important roles in regulating endothelial function (78,79). As endogenous vasodilators, BAs promote the production of NO and inhibit the release of Endothelin-1 (ET-1), thus regulating vasomotion and blood pressure (80). Renal-humor feedback is the main mechanism of long-term regulation of blood pressure. Abnormal renal function is a key factor in the pathogenesis of hypertension. In mice, deletion of FXR- or TGR5-related genes is associated with reduced expression of AQP-2 and impaired urine concentration (81), which impacts the development of hypertension. FXR and TGR5 are endogenous renal receptors. BAs can regulate renal pathophysiology by activating FXR, TGR5, and genes involved in inflammation and renal fibrosis (82). Furthermore, BA metabolism is closely related to the TMAO pathway. FXR regulates the activity of FMO3 (83). After entering the liver through the portal circulation, TMA will be oxidized into TMAO by liver FMO3. Afterward, TMAO enters the systemic circulation and promotes hypertension by altering lipid metabolism, platelet activity, and vascular promotion of AS (71). BAs can regulate lipid metabolism by activating FXR (84). Activation of TGR5 can reduce inflammation (85), promote insulin secretion, and improve insulin resistance, which in turn regulates the occurrence of hypertension (86).
Deoxycholic acid induces gastric intestinal metaplasia by activating STAT3 signaling and disturbing gastric bile acids metabolism and microbiota
Published in Gut Microbes, 2022
Duochen Jin, Keting Huang, Miao Xu, Hongjin Hua, Feng Ye, Jin Yan, Guoxin Zhang, Yun Wang
It is widely believed that Helicobacter pylori (H. pylori or Hp) eradication can reduce the risk of GC. However, the prevention effect of Hp eradication on IM in the antrum has not been determined, whereas it seems to have no preventive effect on IM in the corpus.7–10 Interestingly, several independent clinical studies have found that high concentrations of bile acids (BAs) in the stomach were associated with elevated risks of IM and GC in cases both with and without Hp infection.11–14 Deoxycholic acid (DCA) is one of the most hydrophobic secondary BAs in the human body15 and the main BA component of duodenogastric reflux (DGR, bile reflux).16 The concentration ratio of DCA to its precursor primary BA cholic acid in gastric juice samples showed an incremental increase during the progression of chronic superficial gastritis into IM and GC.17 G protein-coupled bile acid receptor 1 (GPBAR1, also called TGR5) is expressed in the gastric epithelium and activated by secondary BAs, especially DCA.18 Strong TGR5 staining was not present in normal gastric mucosa but was present in 12% of IM cases (P < .01).19 Therefore, the DCA-TGR5 axis may play a pivotal role in IM initiation.
Sleeve Gastrectomy Surgery Improves Glucose Metabolism by Downregulating the Intestinal Expression of Sodium–Glucose Cotransporter-3
Published in Journal of Investigative Surgery, 2022
Yixing Ren, Zhiming Zhao, Guodong Zhao, Qu Liu, Zizheng Wang, Rong Liu
Sleeve gastrectomy (SG) has the advantage of being a relatively simple surgery with a short learning curve, with no need to reconstruct the digestive tract, and fewer postoperative complications than other forms of bariatric surgery [7,8]. The promotion of glucose homeostasis and energy homeostasis after SG has been demonstrated in many animal models and patient-based studies [9–12]. In studies of the mechanism of SG improving metabolism. Mcgavigan et al. demonstrated that stimulation of the transmembrane G-protein coupled bile acid receptor (TGR5) by increased circulating total bile acid and the changes in the bile acid profile after surgery were beneficial in regulating blood glucose [10]. We and others have found that in mice, SG causes a decrease in food intake after a reduction in the volume of the gastric cavity, which leads to a decreased glucose absorption from the intestine [13]. Adaptive changes in the structure of the villi and decreased expression of the sodium–glucose cotransporter 1 (SGLT1) in the gastrointestinal tract partly explain the reduction in glucose absorption and weight loss, but additional mechanisms remain unexplored.