A Physiology-Based Model of Bile Acid Distribution and Metabolism Under Healthy and Pathologic Conditions in Human Beings

Voronova, Veronika; Соколов, В. В.; Al-Khaifi, Amani; Straniero, Sara; Kumar, Chanchal; Peskov, Kirill; Helmlinger, Gabriel; Rudling, Mats; Angelin, Bo

doi:10.1016/j.jcmgh.2020.02.005

Cited by 33 publications

(26 citation statements)

References 55 publications

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“…Unconjugated BAs are reabsorbed into intestinal enterocytes via passive diffusion in the jejunum and colon, whereas conjugated BAs, bile salts, are reabsorbed through a sodium-dependent BA transporter (ASBT) in the jejunum [ 27 , 31 ]. While 95% of BAs are reabsorbed and return to the liver via the portal circulation, the remaining 5% do not get reabsorbed at the intestinal lumen and are excreted in feces [ 14 , 32 ]. This mechanism puts a constant demand on the liver to continue BA synthesis.…”

Section: Bile Acid Physiology and Metabolismmentioning

confidence: 99%

Pharmacological and Metabolic Significance of Bile Acids in Retinal Diseases

et al. 2021

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Bile acids (BAs) are amphipathic sterols primarily synthesized from cholesterol in the liver and released in the intestinal lumen upon food intake. BAs play important roles in micellination of dietary lipids, stimulating bile flow, promoting biliary phospholipid secretion, and regulating cholesterol synthesis and elimination. Emerging evidence, however, suggests that, aside from their conventional biological function, BAs are also important signaling molecules and therapeutic tools. In the last decade, the therapeutic applications of BAs in the treatment of ocular diseases have gained great interest. Despite the identification of BA synthesis, metabolism, and recycling in ocular tissues, much remains unknown with regards to their biological significance in the eye. Additionally, as gut microbiota directly affects the quality of circulating BAs, their analysis could derive important information on changes occurring in this microenvironment. This review aims at providing an overview of BA metabolism and biological function with a focus on their potential therapeutic and diagnostic use for retinal diseases.

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Section: Bile Acid Physiology and Metabolismmentioning

confidence: 99%

Pharmacological and Metabolic Significance of Bile Acids in Retinal Diseases

et al. 2021

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“…Their work was stimulated by a similar effort nearly 40 years ago by Molino and Hofmann together with colleagues from the Politechnico University in Torino, Italy. 1,2 The effort of Voronova et al 1 extends the earlier work, however, by also including the pharmacodynamic effects resulting from activation of the nuclear receptor Farnesoid X receptor by bile acids. Their model also includes changes in the plasma level of C4, an early intermediate in bile acid biosynthesis, whose plasma level correlates linearly with the rate of bile acid synthesis.…”

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confidence: 99%

“…In the past decade, bile acids have had renewed interest because of the discovery of their signaling properties as well as the marketing of a modified bile acid (obeticholic acid) for the treatment of primary biliary cholangitis. In this issue of Cellular and Molecular Gastroenterology and Hepatology, a physiology-based pharmacokinetic (PBPK) model of bile acid metabolism in health and in certain disease conditions is described by Voronova et al 1 She has led a consortium of investigators from Russia, Oman, and Sweden, coming from both industry and academia, whose aim was to develop the most complete PBPK description of bile acid metabolism in human beings that is currently available. Their work was stimulated by a similar effort nearly 40 years ago by Molino and Hofmann together with colleagues from the Politechnico University in Torino, Italy.…”

mentioning

confidence: 99%

“…These, in turn, may be absorbed, join the circulating primary bile acids, and undergo further metabolism. Voronova et al 1 included deoxycholic acid in their simulation, which is reasonable because it is a major bile acid in human beings. Lithocholic acid, which is formed by bacterial 7-dehydroxylation of chenodeoxycholic acid, was not included in their model because it is esterified with sulfate (at C3) in the liver after absorption from the colon; sulfated lithocholate does not undergo intestinal absorption and rapidly is lost from the circulating bile acids.…”

mentioning

confidence: 99%

“…Investigators whose research is concerned with bile acids should be grateful for the comprehensive PBPK model of bile acid metabolism in human beings by Voronova et al 1 that substantially advances our understanding of human hepatobiliary physiology.…”

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confidence: 99%

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Mathematical models of cystic fibrosis as a systemic disease

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et al. 2023

WIREs Mechanisms of Disease

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Cystic fibrosis (CF) is widely known as a disease of the lung, even though it is in truth a systemic disease, whose symptoms typically manifest in gastrointestinal dysfunction first. CF ultimately impairs not only the pancreas and intestine but also the lungs, gonads, liver, kidneys, bones, and the cardiovascular system. It is caused by one of several mutations in the gene of the epithelial ion channel protein CFTR. Intense research and improved antimicrobial treatments during the past eight decades have steadily increased the predicted life expectancy of a person with CF (pwCF) from a few weeks to over 50 years. Moreover, several drugs ameliorating the sequelae of the disease have become available in recent years, and notable treatments of the root cause of the disease have recently generated substantial improvements in health for some but not all pwCF. Yet, numerous fundamental questions remain unanswered. Complicating CF, for instance in the lung, is the fact that the associated insufficient chloride secretion typically perturbs the electrochemical balance across epithelia and, in the airways, leads to the accumulation of thick, viscous mucus and mucus plaques that cannot be cleared effectively and provide a rich breeding ground for a spectrum of bacterial and fungal communities. The subsequent infections often become chronic and respond poorly to antibiotic treatments, with outcomes sometimes only weakly correlated with the drug susceptibility of the target pathogen. Furthermore, in contrast to rapidly resolved acute infections with a single target pathogen, chronic infections commonly involve multi‐species bacterial communities, called “infection microbiomes,” that develop their own ecological and evolutionary dynamics. It is presently impossible to devise mathematical models of CF in its entirety, but it is feasible to design models for many of the distinct drivers of the disease. Building upon these growing yet isolated modeling efforts, we discuss in the following the feasibility of a multi‐scale modeling framework, known as template‐and‐anchor modeling, that allows the gradual integration of refined sub‐models with different granularity. The article first reviews the most important biomedical aspects of CF and subsequently describes mathematical modeling approaches that already exist or have the potential to deepen our understanding of the multitude aspects of the disease and their interrelationships. The conceptual ideas behind the approaches proposed here do not only pertain to CF but are translatable to other systemic diseases.This article is categorized under: Congenital Diseases > Computational Models

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A Physiology-Based Model of Bile Acid Distribution and Metabolism Under Healthy and Pathologic Conditions in Human Beings

Cited by 33 publications

References 55 publications

Pharmacological and Metabolic Significance of Bile Acids in Retinal Diseases

Pharmacological and Metabolic Significance of Bile Acids in Retinal Diseases

Quantifying the Complexities of Bile Acid Metabolism in Man: Continued Progress

Mathematical models of cystic fibrosis as a systemic disease

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