Intestinal transport and metabolism of bile acids Dawson, Paul A.; Karpen, Saul J.
Journal of lipid research,
June 2015, 2015-Jun, 2015-06-00, 20150601, 2015-06-01, Volume:
56, Issue:
6
Journal Article
Peer reviewed
Open access
In addition to their classical roles as detergents to aid in the process of digestion, bile acids have been identified as important signaling molecules that function through various nuclear and G ...protein-coupled receptors to regulate a myriad of cellular and molecular functions across both metabolic and nonmetabolic pathways. Signaling via these pathways will vary depending on the tissue and the concentration and chemical structure of the bile acid species. Important determinants of the size and composition of the bile acid pool are their efficient enterohepatic recirculation, their host and microbial metabolism, and the homeostatic feedback mechanisms connecting hepatocytes, enterocytes, and the luminal microbiota. This review focuses on the mammalian intestine, discussing the physiology of bile acid transport, the metabolism of bile acids in the gut, and new developments in our understanding of how intestinal metabolism, particularly by the gut microbiota, affects bile acid signaling.
Animal models to study bile acid metabolism Li, Jianing; Dawson, Paul A.
Biochimica et biophysica acta. Molecular basis of disease,
05/2019, Volume:
1865, Issue:
5
Journal Article
Peer reviewed
Open access
The use of animal models, particularly genetically modified mice, continues to play a critical role in studying the relationship between bile acid metabolism and human liver disease. Over the past ...20 years, these studies have been instrumental in elucidating the major pathways responsible for bile acid biosynthesis and enterohepatic cycling, and the molecular mechanisms regulating those pathways. This work also revealed bile acid differences between species, particularly in the composition, physicochemical properties, and signaling potential of the bile acid pool. These species differences may limit the ability to translate findings regarding bile acid-related disease processes from mice to humans. In this review, we focus primarily on mouse models and also briefly discuss dietary or surgical models commonly used to study the basic mechanisms underlying bile acid metabolism. Important phenotypic species differences in bile acid metabolism between mice and humans are highlighted.
•Mouse models have been used to elucidate the core pathways controlling bile acid homeostasis•Important species differences may limit “translatability” of the findings to humans•Mouse models with “humanized” bile acid compositions may offer new insights to the role of bile acids in liver disease
Dysregulation of the epigenome drives aberrant transcriptional programmes that promote cancer onset and progression. Although defective gene regulation often affects oncogenic and tumour-suppressor ...networks, tumour immunogenicity and immune cells involved in antitumour responses may also be affected by epigenomic alterations. This could have important implications for the development and application of both epigenetic therapies and cancer immunotherapies, and combinations thereof. Here, we review the role of key aberrant epigenetic processes - DNA methylation and post-translational modification of histones - in tumour immunogenicity, as well as the effects of epigenetic modulation on antitumour immune cell function. We emphasize opportunities for small-molecule inhibitors of epigenetic regulators to enhance antitumour immune responses, and discuss the challenges of exploiting the complex interplay between cancer epigenetics and cancer immunology to develop treatment regimens combining epigenetic therapies with immunotherapies.
Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem worldwide and an important risk factor for both hepatic and cardiometabolic mortality. The rapidly increasing prevalence of ...this disease and of its aggressive form nonalcoholic steatohepatitis (NASH) will require novel therapeutic approaches to prevent disease progression to advanced fibrosis or cirrhosis and cancer. In recent years, bile acids have emerged as relevant signaling molecules that act at both hepatic and extrahepatic tissues to regulate lipid and carbohydrate metabolic pathways as well as energy homeostasis. Activation or modulation of bile acid receptors, such as the farnesoid X receptor and TGR5, and transporters, such as the ileal apical sodium‐dependent bile acid transporter, appear to affect both insulin sensitivity and NAFLD/NASH pathogenesis at multiple levels, and these approaches hold promise as novel therapies. In the present review, we summarize current available data on the relationships of bile acids to NAFLD and the potential for therapeutically targeting bile‐acid‐related pathways to address this growing world‐wide disease. (Hepatology 2017;65:350‐362)
Bile acid transporters Dawson, Paul A.; Lan, Tian; Rao, Anuradha
Journal of lipid research,
December 2009, 2009-Dec, 2009-12-00, 20091201, 2009-12-01, Volume:
50, Issue:
12
Journal Article
Peer reviewed
Open access
In liver and intestine, transporters play a critical role in maintaining the enterohepatic circulation and bile acid homeostasis. Over the past two decades, there has been significant progress toward ...identifying the individual membrane transporters and unraveling their complex regulation. In the liver, bile acids are efficiently transported across the sinusoidal membrane by the Na+ taurocholate cotransporting polypeptide with assistance by members of the organic anion transporting polypeptide family. The bile acids are then secreted in an ATP-dependent fashion across the canalicular membrane by the bile salt export pump. Following their movement with bile into the lumen of the small intestine, bile acids are almost quantitatively reclaimed in the ileum by the apical sodium-dependent bile acid transporter. The bile acids are shuttled across the enterocyte to the basolateral membrane and effluxed into the portal circulation by the recently indentified heteromeric organic solute transporter, OSTα-OSTβ. In addition to the hepatocyte and enterocyte, subgroups of these bile acid transporters are expressed by the biliary, renal, and colonic epithelium where they contribute to maintaining bile acid homeostasis and play important cytoprotective roles. This article will review our current understanding of the physiological role and regulation of these important carriers.
Membrane transporters expressed by the hepatocyte and enterocyte play critical roles in maintaining the enterohepatic circulation of bile acids, an effective recycling and conservation mechanism that ...largely restricts these potentially cytotoxic detergents to the intestinal and hepatobiliary compartments. In doing so, the hepatic and enterocyte transport systems ensure a continuous supply of bile acids to be used repeatedly during the digestion of multiple meals throughout the day. Absorption of bile acids from the intestinal lumen and export into the portal circulation is mediated by a series of transporters expressed on the enterocyte apical and basolateral membranes. The ileal apical sodium-dependent bile acid cotransporter (abbreviated ASBT; gene symbol, SLC10A2) is responsible for the initial uptake of bile acids across the enterocyte brush border membrane. The bile acids are then efficiently shuttled across the cell and exported across the basolateral membrane by the heteromeric Organic Solute Transporter, OSTα-OSTβ. This chapter briefly reviews the tissue expression, physiology, genetics, pathophysiology, and transport properties of the ASBT and OSTα-OSTβ. In addition, the chapter discusses the relationship between the intestinal bile acid transporters and drug metabolism, including development of ASBT inhibitors as novel hypocholesterolemic or hepatoprotective agents, prodrug targeting of the ASBT to increase oral bioavailability, and involvement of the intestinal bile acid transporters in drug absorption and drug-drug interactions.
Cancer cells exploit the expression of the programmed death-1 (PD-1) ligand 1 (PD-L1) to subvert T-cell-mediated immunosurveillance. The success of therapies that disrupt PD-L1-mediated tumour ...tolerance has highlighted the need to understand the molecular regulation of PD-L1 expression. Here we identify the uncharacterized protein CMTM6 as a critical regulator of PD-L1 in a broad range of cancer cells, by using a genome-wide CRISPR-Cas9 screen. CMTM6 is a ubiquitously expressed protein that binds PD-L1 and maintains its cell surface expression. CMTM6 is not required for PD-L1 maturation but co-localizes with PD-L1 at the plasma membrane and in recycling endosomes, where it prevents PD-L1 from being targeted for lysosome-mediated degradation. Using a quantitative approach to profile the entire plasma membrane proteome, we find that CMTM6 displays specificity for PD-L1. Notably, CMTM6 depletion decreases PD-L1 without compromising cell surface expression of MHC class I. CMTM6 depletion, via the reduction of PD-L1, significantly alleviates the suppression of tumour-specific T cell activity in vitro and in vivo. These findings provide insights into the biology of PD-L1 regulation, identify a previously unrecognized master regulator of this critical immune checkpoint and highlight a potential therapeutic target to overcome immune evasion by tumour cells.
Richly illustrated and packed with numerous examples, this unique global perspective introduces wetland ecology from basic principles to advanced applications. Thoroughly revised and reorganised, ...this new edition of this prize-winning textbook begins with underlying causal factors, before moving on to more advanced concepts that add depth and context. Each chapter begins with an explanation of the basic principles covered, illustrated with clear examples. More difficult concepts and exceptions are introduced only once the general principle is well-established. Key principles are now discussed at the beginning of the book, and in order of relative importance, enabling students to understand the most important material without wading through complex theory. New chapters on wetland restoration and wetland services draw upon practical examples from around the world, providing a global context, and a new chapter on research will be particularly relevant to the advanced student planning their own studies.
The liver can substantially regenerate after injury, with both main epithelial cell types, hepatocytes and biliary epithelial cells (BECs), playing important roles in parenchymal regeneration. Beyond ...metabolic functions, BECs exhibit substantial plasticity and in some contexts can drive hepatic repopulation. Here, we performed single-cell RNA sequencing to examine BEC and hepatocyte heterogeneity during homeostasis and after injury. Instead of evidence for a transcriptionally defined progenitor-like BEC cell, we found significant homeostatic BEC heterogeneity that reflects fluctuating activation of a YAP-dependent program. This transcriptional signature defines a dynamic cellular state during homeostasis and is highly responsive to injury. YAP signaling is induced by physiological bile acids (BAs), required for BEC survival in response to BA exposure, and is necessary for hepatocyte reprogramming into biliary progenitors upon injury. Together, these findings uncover molecular heterogeneity within the ductal epithelium and reveal YAP as a protective rheostat and regenerative regulator in the mammalian liver.
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•scRNA-seq of the healthy and injured liver epithelium reveals dynamic heterogeneity•Transcriptional heterogeneity is driven by fluctuating activation of YAP signaling•YAP is essential for adult biliary cell survival under homeostatic conditions•YAP is required in hepatocytes for the ductular response during regeneration
The transcriptional landscape of the epithelium in healthy and regenerating murine livers was investigated, revealing a dynamically fluctuating and heterogeneous YAP transcriptional program. Further analysis uncovered YAP signaling dualism: it is essential in biliary epithelial cells for homeostatic maintenance and in hepatocytes for the regenerative response to injury.
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