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    • aminopeptidase inhibitor Conjugated BAs via S PR also activa

    2022-05-18

    Conjugated BAs via S1PR2 also activate ERK1/2- and AKT-signaling pathways leading to the growth and invasion of cholangiocarcinoma cells. The role of conjugated BAs via S1PR2 to regulate apoptosis or cancer progression remains to be dissected. Nevertheless, there is no doubt that the composition of free and conjugated BAs has an impact on regulating BA receptor activity.
    Conclusions and perspectives BA receptors can be found in many types of cells within and outside the digestive tract. By activating G protein-coupled membrane receptors, i.e., TGR5, S1PR2, and muscarinic receptor, BAs exert their effects without crossing the cell membrane. Similarly, those receptors are readily accessible to enzymes that regulate methylation, acetylation, glycosylation, etc. Thus, in addition to transcriptional regulation, it is important to study post-transcriptional modification of those receptors. It is likely that due to transcriptional and post-transcriptional modification, those receptors exert various biological effects ranging across metabolism, energy homeostasis in skeletal muscle and adipose tissue, inflammatory signaling in macrophages, muscle relaxation, hormonal secretion, as well as cell proliferation and apoptosis, etc. The current knowledge limits to acetylation and methylation of a few receptors. More research should be done to understand the mechanism that influences their expression, modification, and biological effects.
    Authors' contributions
    Conflict of interest
    Acknowledgments The authors thank Kyle Mcneil from University of California, Davis, for editing the manuscript. This study was supported by grants funded by the USA National Institutes of Health (NIH) U01CA179582 and R01 CA222490.
    Introduction Cystic fibrosis (CF), caused by a mutation in the gene encoding the CF transmembrane conductance regulator (CFTR), results in production of abnormally thick, viscous mucus in various organ systems [1]. Aside from pulmonary problems, CF patients often suffer from GI disorders, hepatobiliary problems and cystic fibrosis related diabetes (CFRD). A specific GI feature common among CF patients is impaired bile aminopeptidase inhibitor (BA) homeostasis manifesting via BA malabsorption and subsequent increased fecal excretion [2]. Recent studies show the interrelation of BA homeostasis with various other intestinal, hepatic and metabolic parameters. In this review we discuss the role of impaired BA homeostasis in CF, explaining its potential role in other GI and metabolic complications and as a therapeutic target.
    Gastrointestinal complications of cystic fibrosis A functional GI system is essential for maintaining adequate nutritional status and whole body homeostasis. Similar to pulmonary complications, viscous mucus, as a consequence of deficient surface fluid and bicarbonate flux is an important underlying factor in the GI phenotype of CF [3]. Exocrine pancreatic insufficiency (EPI) is used as a marker for severity of the CF phenotype. However, other manifestations of the GI phenotype of CF are often highly variable and do not strongly correlated to allelic CFTR variation [4]. Patients experience various symptoms including malabsorption, fatty stools (steatorrhea), abdominal pain, nausea, anorexia, bloating, gastro-esophageal reflux, constipation, distal intestinal obstruction syndrome (DIOS) and flatulence. Although most of the GI complications are interrelated, they can be subdivided in pancreatic, hepatobiliary and intestinal-luminal categories. A severe CFTR gene mutation in both alleles results in little or no CFTR Cl− channel activity and destruction of the exocrine pancreas [5]. EPI is an early sign of CF and can present at birth or develop in the first months of life [6]. Ultimately, around 85% of CF patients develop EPI and these patients are prone to nutritional deficiencies, severe malnutrition and growth retardation [7]. Fortunately, EPI can be successfully treated with pancreatic enzyme replacement therapy (PERT). However, even with optimal PERT, fat malabsorption and GI complaints are often not fully corrected [[8], [9], [10]]. Mice with targeted mutations in the Cftr gene do not display EPI but nevertheless have a lower bodyweight upon ad libitum feeding, possibly due to bacterial overgrowth or from impaired epithelial absorption of nutrients [11]. This suggests that, in addition to EPI, there are other changes in the intestinal tract in CF that have important effects on nutrient absorption and growth.