scholarly journals Bile acids in glucose metabolism in health and disease

2018 ◽  
Vol 215 (2) ◽  
pp. 383-396 ◽  
Author(s):  
Hagit Shapiro ◽  
Aleksandra A. Kolodziejczyk ◽  
Daniel Halstuch ◽  
Eran Elinav
Keyword(s):  
Glucose Metabolism ◽  
Bile Acids ◽  
Glycogen Synthesis ◽  
Dietary Lipids ◽  
Farnesoid X Receptor ◽  
Morbidly Obese ◽  
Glycemic Response ◽  
Multiple Organs ◽  
Health And Disease ◽  
The Impact

Bile acids (BAs) are cholesterol-derived metabolites that facilitate the intestinal absorption and transport of dietary lipids. Recently, BAs also emerged as pivotal signaling molecules controlling glucose, lipid, and energy metabolism by binding to the nuclear hormone farnesoid X receptor (FXR) and Takeda G protein receptor 5 (TGR5) in multiple organs, leading to regulation of intestinal incretin secretion, hepatic gluconeogenesis, glycogen synthesis, energy expenditure, inflammation, and gut microbiome configuration. Alterations in BA metabolism and signaling are associated with obesity and type 2 diabetes mellitus (T2DM), whereas treatment of T2DM patients with BA sequestrants, or bariatric surgery in morbidly obese patients, results in a significant improvement in glycemic response that is associated with changes in the BA profile and signaling. Herein, we review the roles of BAs in glucose metabolism in health and disease; highlight the limitations, unknowns, and challenges in understanding the impact of BAs on the glycemic response; and discuss how this knowledge may be harnessed to develop innovative therapeutic approaches for the treatment of hyperglycemia and diabetes.

scholarly journals Role of Bile Acids in the Regulation of Food Intake, and Their Dysregulation in Metabolic Disease

Nutrients ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 1104
Author(s):  
Cong Xie ◽  
Weikun Huang ◽  
Richard L. Young ◽  
Karen L. Jones ◽  
Michael Horowitz ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Peptide Yy ◽  
Glycogen Synthesis ◽  
Hormone Secretion ◽  
Gastrointestinal Hormones ◽  
Farnesoid X Receptor ◽  
Gastrointestinal Hormone ◽  
Bile Acid Sequestrants

Bile acids are cholesterol-derived metabolites with a well-established role in the digestion and absorption of dietary fat. More recently, the discovery of bile acids as natural ligands for the nuclear farnesoid X receptor (FXR) and membrane Takeda G-protein-coupled receptor 5 (TGR5), and the recognition of the effects of FXR and TGR5 signaling have led to a paradigm shift in knowledge regarding bile acid physiology and metabolic health. Bile acids are now recognized as signaling molecules that orchestrate blood glucose, lipid and energy metabolism. Changes in FXR and/or TGR5 signaling modulates the secretion of gastrointestinal hormones including glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), hepatic gluconeogenesis, glycogen synthesis, energy expenditure, and the composition of the gut microbiome. These effects may contribute to the metabolic benefits of bile acid sequestrants, metformin, and bariatric surgery. This review focuses on the role of bile acids in energy intake and body weight, particularly their effects on gastrointestinal hormone secretion, the changes in obesity and T2D, and their potential relevance to the management of metabolic disorders.

scholarly journals Impact of Global Mean Normalization on Regional Glucose Metabolism in the Human Brain

2018 ◽  
Vol 2018 ◽  
pp. 1-16 ◽  
Author(s):  
Kristian N. Mortensen ◽  
Albert Gjedde ◽  
Garth J. Thompson ◽  
Peter Herman ◽  
Maxime J. Parent ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Human Brain ◽  
Disease Biomarkers ◽  
Eyes Closed ◽  
Positron Emission ◽  
Congenitally Blind ◽  
Eyes Open ◽  
Health And Disease ◽  
The Impact ◽  
Global Mean

Because the human brain consumes a disproportionate fraction of the resting body’s energy, positron emission tomography (PET) measurements of absolute glucose metabolism (CMRglc) can serve as disease biomarkers. Global mean normalization (GMN) of PET data reveals disease-based differences from healthy individuals as fractional changes across regions relative to a global mean. To assess the impact of GMN applied to metabolic data, we compared CMRglc with and without GMN in healthy awake volunteers with eyes closed (i.e., control) against specific physiological/clinical states, including healthy/awake with eyes open, healthy/awake but congenitally blind, healthy/sedated with anesthetics, and patients with disorders of consciousness. Without GMN, global CMRglc alterations compared to control were detected in all conditions except in congenitally blind where regional CMRglc variations were detected in the visual cortex. However, GMN introduced regional and bidirectional CMRglc changes at smaller fractions of the quantitative delocalized changes. While global information was lost with GMN, the quantitative approach (i.e., a validated method for quantitative baseline metabolic activity without GMN) not only preserved global CMRglc alterations induced by opening eyes, sedation, and varying consciousness but also detected regional CMRglc variations in the congenitally blind. These results caution the use of GMN upon PET-measured CMRglc data in health and disease.

scholarly journals Systemic bile acids induce insulin resistance in a TGR5-independent manner

2019 ◽  
Vol 316 (5) ◽  
pp. E782-E793 ◽  
Author(s):  
Kristen E. Syring ◽  
Travis J. Cyphert ◽  
Thomas C. Beck ◽  
Charles R. Flynn ◽  
Nicholas A. Mignemi ◽  
...  
Keyword(s):  
Bile Acid ◽  
Insulin Sensitivity ◽  
Bile Acids ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Farnesoid X Receptor ◽  
Serum Bile Acid ◽  
Hepatic Insulin Sensitivity ◽  
Hepatic Glucose ◽  
The Impact

Bile acids are involved in the emulsification and absorption of dietary fats, as well as acting as signaling molecules. Recently, bile acid signaling through farnesoid X receptor and G protein-coupled bile acid receptor (TGR5) has been reported to elicit changes in not only bile acid synthesis but also metabolic processes, including the alteration of gluconeogenic gene expression and energy expenditure. A role for bile acids in glucose metabolism is also supported by a correlation between changes in the metabolic state of patients (i.e., obesity or postbariatric surgery) and altered serum bile acid levels. However, despite evidence for a role for bile acids during metabolically challenging settings, the direct effect of elevated bile acids on insulin action in the absence of metabolic disease has yet to be investigated. The present study examines the impact of acutely elevated plasma bile acid levels on insulin sensitivity using hyperinsulinemic-euglycemic clamps. In wild-type mice, elevated bile acids impair hepatic insulin sensitivity by blunting the insulin suppression of hepatic glucose production. The impaired hepatic insulin sensitivity could not be attributed to TGR5 signaling, as TGR5 knockout mice exhibited a similar inhibition of insulin suppression of hepatic glucose production. Canonical insulin signaling pathways, such as hepatic PKB (or Akt) activation, were not perturbed in these animals. Interestingly, bile acid infusion directly into the portal vein did not result in an impairment in hepatic insulin sensitivity. Overall, the data indicate that acute increases in circulating bile acids in lean mice impair hepatic insulin sensitivity via an indirect mechanism.

scholarly journals The Biosynthesis, Signaling, and Neurological Functions of Bile Acids

Biomolecules ◽  
2019 ◽  
Vol 9 (6) ◽  
pp. 232 ◽  
Author(s):  
Yoshimitsu Kiriyama ◽  
Hiromi Nochi
Keyword(s):  
Bile Acids ◽  
Muscarinic Acetylcholine Receptor ◽  
Dietary Lipids ◽  
Farnesoid X Receptor ◽  
Na Channel ◽  
Peripheral Tissues ◽  
Surface Receptors ◽  
Glucose And Lipid Metabolism ◽  
Protein Receptor ◽  
The Central Nervous System

Bile acids (BA) are amphipathic steroid acids synthesized from cholesterol in the liver. They act as detergents to expedite the digestion and absorption of dietary lipids and lipophilic vitamins. BA are also considered to be signaling molecules, being ligands of nuclear and cell-surface receptors, including farnesoid X receptor and Takeda G-protein receptor 5. Moreover, BA also activate ion channels, including the bile acid-sensitive ion channel and epithelial Na+ channel. BA regulate glucose and lipid metabolism by activating these receptors in peripheral tissues, such as the liver and brown and white adipose tissue. Recently, 20 different BA have been identified in the central nervous system. Furthermore, BA affect the function of neurotransmitter receptors, such as the muscarinic acetylcholine receptor and γ-aminobutyric acid receptor. BA are also known to be protective against neurodegeneration. Here, we review recent findings regarding the biosynthesis, signaling, and neurological functions of BA.

P729The functional relevance of bile acids in the improvement of HDL-mediated endothelial protection after bariatric surgery

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Jomard ◽  
O Chavez-Talavera ◽  
A Tailleux ◽  
M Bueter ◽  
A Taheri ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Bile Acids ◽  
Ex Vivo ◽  
Function Analysis ◽  
Farnesoid X Receptor ◽  
High Density Lipoproteins ◽  
Morbidly Obese ◽  
No Production ◽  
Obese Patients ◽  
Aortic Endothelial Cells

Abstract Introduction Roux-en-Y gastric bypass (RYGB) reduces cardiovascular mortality. We showed that high density lipoproteins (HDL)-mediated vasoprotection is improved early after RYGB. Circulating BAs increase upon RYGB and contribute to the weight-loss independent metabolic improvements after surgery. Bile acids (BA) are signaling molecules increasingly recognized as regulators of cardiometabolic homeostasis. BAs circulate in the blood either free or bound to albumin and HDL. The signaling role of HDL-bound BAs (HDL-BAs) is unknown. Indeed, HDL may facilitate BA delivery directly to endothelial cells where BA may synergize with HDL to promote vasoprotection. Purpose We studied whether RYGB changes the composition of HDL-BA and whether HDL functional properties may be modulated by specific BA bound to HDL. Methods HDL were isolated by ultracentrifugation from 29 morbidly obese patients before and 1 year after RYGB. The HDL-BA composition was determined by liquid chromatography-mass spectrometry (LC/MS-MS) and HDL vasoprotective properties were evaluated ex-vivo in human aortic endothelial cells (HAEC). The size and abundance of HDL particles were determined by NMR spectroscopy in plasma. Results The increase in total BA concentrations observed in plasma 1 year after RYGB also translated into higher concentrations (up to 25%) of BA bound to HDL. Moreover, obesity-induced HDL dysfunction was reversed after surgery, as shown by improved HDL-mediated endothelial NO production, anti-apoptotic effects and cholesterol efflux capacity. The size function analyses showed a post-operative shift towards larger HDL. After RYGB there was a remodeling of BA bound to HDL, which are either agonists of the endothelial nuclear farnesoid X receptor (FXR), e.g. chenodeoxy-CA (CDCA), cholic acid (CA) or for the membrane TGR5 receptor, e.g. deoxy-CA (DCA). The composition-function analysis revealed that among all BA subclasses, the specific enrichment in CA and in CDCA bound to HDL correlated with an improved endothelial anti-apoptotic capacity of HDL (R −0.52, p=0.006 for CA-HDL and R −0.35, p=0.07 for CDCA-HDL). Further, the exogenous loading of CA onto healthy native HDL isolated from human serum significantly enhanced their endothelial anti-apoptotic function. In the case of obese, dysfunctional, pro-apoptotic HDL, exogenous CA loading was able to restore HDL anti-apoptotic function. Conclusion Exogenous loading of CA restored HDL anti-apoptotic function of HDL from obese patients mimicking the beneficial remodeling of BA bound to HDL observed after RYGB. These results suggest a crucial interaction between endothelial cells and BA in the improvement of HDL's vasoprotective properties. Acknowledgement/Funding Swiss national Science Foundation Ambizione and PRIMA grant to EO

scholarly journals Type 2 Diabetes and Dietary Carbohydrate Intake of Adolescents and Young Adults: What Is the Impact of Different Choices?

Nutrients ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 3344
Author(s):  
Luisa Bonsembiante ◽  
Giovanni Targher ◽  
Claudio Maffeis
Keyword(s):  
Type 2 Diabetes ◽  
Glucose Metabolism ◽  
Harmful Effect ◽  
Current Evidence ◽  
Single Individual ◽  
Glycemic Response ◽  
Dietary Carbohydrates ◽  
High Consumption ◽  
The Impact

Type 2 diabetes mellitus has a high prevalence worldwide, with a rapidly increasing incidence even in youth. Nutrition, dietary macronutrient composition, and in particular dietary carbohydrates play a major role in the development of type 2 diabetes. The aim of this narrative review is to discuss the current evidence on the role of dietary carbohydrates in the prevention and management of type 2 diabetes. The digestibility or availability of carbohydrates and their glycemic index (and glycemic load) markedly influence the glycemic response. High consumption of dietary fiber is beneficial for management of type 2 diabetes, whereas high consumption of both glycemic starch and sugars may have a harmful effect on glucose metabolism, thereby increasing the risk of developing type 2 diabetes in the presence of genetic predisposition or making its glycemic control more difficult to achieve in people with established T2D. Therefore, the same dietary macronutrient may have harmful or beneficial effects on type 2 diabetes mainly depending on the subtypes consumed. Some other factors are involved in glucose metabolism, such as meal composition, gut microbiota and genetics. For this reason, the glycemic response after carbohydrate consumption is not easy to predict in the single individual. Nutrition suggested to subjects with known type 2 diabetes should be always person-centered, considering the individual features of each subject.

scholarly journals Role of Organic Solute Transporter Alpha/Beta in Hepatotoxic Bile Acid Transport and Drug Interactions

2020 ◽  
Vol 176 (1) ◽  
pp. 34-45 ◽  
Author(s):  
James J Beaudoin ◽  
Jacqueline Bezençon ◽  
Noora Sjöstedt ◽  
John K Fallon ◽  
Kim L R Brouwer
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Farnesoid X Receptor ◽  
Acid Transport ◽  
Bile Acid Transport ◽  
Organic Solute Transporter ◽  
Organic Solute ◽  
The Impact ◽  
Solute Transporter

Abstract Organic solute transporter (OST) α/β is a key bile acid transporter expressed in various organs, including the liver under cholestatic conditions. However, little is known about the involvement of OSTα/β in bile acid-mediated drug-induced liver injury (DILI), a major safety concern in drug development. This study investigated whether OSTα/β preferentially transports more hepatotoxic, conjugated, primary bile acids and to what extent xenobiotics inhibit this transport. Kinetic studies with OSTα/β-overexpressing cells revealed that OSTα/β preferentially transported bile acids in the following order: taurochenodeoxycholate > glycochenodeoxycholate > taurocholate > glycocholate. The apparent half-maximal inhibitory concentrations for OSTα/β-mediated bile acid (5 µM) transport inhibition by fidaxomicin, troglitazone sulfate, and ethinyl estradiol were: 210, 334, and 1050 µM, respectively, for taurochenodeoxycholate; 97.6, 333, and 337 µM, respectively, for glycochenodeoxycholate; 140, 265, and 527 µM, respectively, for taurocholate; 59.8, 102, and 117 µM, respectively, for glycocholate. The potential role of OSTα/β in hepatocellular glycine-conjugated bile acid accumulation and cholestatic DILI was evaluated using sandwich-cultured human hepatocytes (SCHH). Treatment of SCHH with the farnesoid X receptor agonist chenodeoxycholate (100 µM) resulted in substantial OSTα/β induction, among other proteomic alterations, reducing glycochenodeoxycholate and glycocholate accumulation in cells+bile 4.0- and 4.5-fold, respectively. Treatment of SCHH with troglitazone and fidaxomicin together under cholestatic conditions resulted in increased hepatocellular toxicity compared with either compound alone, suggesting that OSTα/β inhibition may accentuate DILI. In conclusion, this study provides insights into the role of OSTα/β in preferential disposition of bile acids associated with hepatotoxicity, the impact of xenobiotics on OSTα/β-mediated bile acid transport, and the role of this transporter in SCHH and cholestatic DILI.

Drug Induced Changes in Cell Organelles

1968 ◽  
Vol 26 ◽  
pp. 110-111
Author(s):  
Sarah A. Luse
Keyword(s):  
Clinical Medicine ◽  
Cell Organelles ◽  
Riboflavin Deficiency ◽  
Drug Induced ◽  
New Era ◽  
Health And Disease ◽  
In The Beginning ◽  
Cellular Pathology ◽  
Induced Changes ◽  
The Impact

In the mid-nineteenth century Virchow revolutionized pathology by introduction of the concept of “cellular pathology”. Today, a century later, this term has increasing significance in health and disease. We now are in the beginning of a new era in pathology, one which might well be termed “organelle pathology” or “subcellular pathology”. The impact of lysosomal diseases on clinical medicine exemplifies this role of pathology of organelles in elucidation of disease today.Another aspect of cell organelles of prime importance is their pathologic alteration by drugs, toxins, hormones and malnutrition. The sensitivity of cell organelles to minute alterations in their environment offers an accurate evaluation of the site of action of drugs in the study of both function and toxicity. Examples of mitochondrial lesions include the effect of DDD on the adrenal cortex, riboflavin deficiency on liver cells, elevated blood ammonia on the neuron and some 8-aminoquinolines on myocardium.

The Laryngeal Epithelium in Reflux

2011 ◽  
Vol 21 (3) ◽  
pp. 112-117 ◽  
Author(s):  
Elizabeth Erickson-Levendoski ◽  
Mahalakshmi Sivasankar
Keyword(s):  
Laryngopharyngeal Reflux ◽  
Critical Role ◽  
Structure And Function ◽  
Laryngeal Disease ◽  
Health And Disease ◽  
And Function ◽  
The Impact

The epithelium plays a critical role in the maintenance of laryngeal health. This is evident in that laryngeal disease may result when the integrity of the epithelium is compromised by insults such as laryngopharyngeal reflux. In this article, we will review the structure and function of the laryngeal epithelium and summarize the impact of laryngopharyngeal reflux on the epithelium. Research investigating the ramifications of reflux on the epithelium has improved our understanding of laryngeal disease associated with laryngopharyngeal reflux. It further highlights the need for continued research on the laryngeal epithelium in health and disease.

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