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Cells
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The Molecular Mechanisms of Bile Acids in Diseases
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The Molecular Mechanisms of Bile Acids in Diseases

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (30 April 2024) | Viewed by 19015

Special Issue Editors

Prof. Dr. Grace Guo

E-Mail Website
Guest Editor
Ernest Mario School of Pharmacy, Rutgers University, Rutgers, NJ, USA
Interests: bile acids; liver diseases; metabolism; gut-liver crosstalk
Prof. Dr. Huiping Zhou

E-Mail Website
Guest Editor
Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
Interests: bile acids; sphingolipids; liver diseases; lipid metabolism

Special Issue Information

Dear Colleagues,

Bile acids are important in physiology and pathology. The research over the last few decades has positioned bile acids into the central stage in maintaining novel liver and gut physiology and the development of chronic liver diseases. The unique regulatory pathways and endocrine axis involved in bile acid homeostasis present interesting investigatory opportunities at molecular and pharmacological levels.

In this Special Issue of Cells, we invite you to contribute, either in the form of original research articles, reviews, or shorter perspective articles on all aspects related to the theme of “The Molecular Mechanisms of Bile Acids in Diseases”. Expert articles describing mechanistic, functional, cellular, biochemical, or general aspects of bile acids are highly welcome. Relevant topics include, but are not limited to

  • Bile acid metabolism
  • Lipid metabolism
  • Energy metabolism
  • In vitro and in vivo models
  • Cholestatic liver injury
  • Hepatic fibrosis
  • Inflammation
  • Fibrosis
  • NASH/NAFLD
  • Alcoholic liver disease
  • Microbiota
  • Drug development 

Prof. Dr. Grace Guo
Prof. Dr. Huiping Zhou
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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Published Papers (6 papers)

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Research

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14 pages, 6694 KiB  
Article
Glycine-β-Muricholic Acid Improves Liver Fibrosis and Gut Barrier Function by Reducing Bile Acid Pool Size and Hydrophobicity in Male Cyp2c70 Knockout Mice
by Mohammad Nazmul Hasan, Jianglei Chen, Huaiwen Wang, Yanhong Du, Yung Dai Clayton, Lijie Gu and Tiangang Li
Cells 2023, 12(10), 1371; https://doi.org/10.3390/cells12101371 - 12 May 2023
Cited by 5 | Viewed by 2306
Abstract
Cyp2c70 knockout mice lack the enzyme that produces muricholic acids and show a “human-like” hydrophobic bile acid pool-induced hepatobiliary injury. In this study, we investigated the potential anti-cholestasis effect of glycine-conjugated β muricholic acid (G-β-MCA) in male Cyp2c70 KO mice based on its [...] Read more.
Cyp2c70 knockout mice lack the enzyme that produces muricholic acids and show a “human-like” hydrophobic bile acid pool-induced hepatobiliary injury. In this study, we investigated the potential anti-cholestasis effect of glycine-conjugated β muricholic acid (G-β-MCA) in male Cyp2c70 KO mice based on its hydrophilic physiochemical property and signaling property as an farnesoid X receptor (FXR) antagonist. Our results showed that G-β-MCA treatment for 5 weeks alleviated ductular reaction and liver fibrosis and improved gut barrier function. Analysis of bile acid metabolism suggested that exogenously administered G-β-MCA was poorly absorbed in the small intestine and mostly deconjugated in the large intestine and converted to taurine-conjugated MCA (T-MCA) in the liver, leading to T-MCA enrichment in the bile and small intestine. These changes decreased the biliary and intestine bile acid hydrophobicity index. Furthermore, G-β-MCA treatment decreased intestine bile acid absorption via unknown mechanisms, resulting in increased fecal bile acid excretion and a reduction in total bile acid pool size. In conclusion, G-β-MCA treatment reduces the bile acid pool size and hydrophobicity and improves liver fibrosis and gut barrier function in Cyp2c70 KO mice. Full article
(This article belongs to the Special Issue The Molecular Mechanisms of Bile Acids in Diseases)
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24 pages, 3716 KiB  
Article
Conjugated Bile Acids Promote Lymphangiogenesis by Modulation of the Reactive Oxygen Species–p90RSK–Vascular Endothelial Growth Factor Receptor 3 Pathway
by Priyanka Banerjee, Subhashree Kumaravel, Sukanya Roy, Niyanshi Gaddam, Johnny Odeh, Kayla J. Bayless, Shannon Glaser and Sanjukta Chakraborty
Cells 2023, 12(4), 526; https://doi.org/10.3390/cells12040526 - 6 Feb 2023
Cited by 3 | Viewed by 2517
Abstract
Conjugated bile acids (BA) are significantly elevated in several liver pathologies and in the metastatic lymph node (LN). However, the effects of BAs on pathological lymphangiogenesis remains unknown. The current study explores the effects of BAs on lymphangiogenesis. BA levels were elevated in [...] Read more.
Conjugated bile acids (BA) are significantly elevated in several liver pathologies and in the metastatic lymph node (LN). However, the effects of BAs on pathological lymphangiogenesis remains unknown. The current study explores the effects of BAs on lymphangiogenesis. BA levels were elevated in the LN and serum of Mdr2−/− mice (model of sclerosing cholangitis) compared to control mice. Liver and LN tissue sections showed a clear expansion of the lymphatic network in Mdr2−/− mice, indicating activated lymphangiogenic pathways. Human lymphatic endothelial cells (LECs) expressed BA receptors and a direct treatment with conjugated BAs enhanced invasion, migration, and tube formation. BAs also altered the LEC metabolism and upregulated key metabolic genes. Further, BAs induced the production of reactive oxygen species (ROS), that in turn phosphorylated the redox-sensitive kinase p90RSK, an essential regulator of endothelial cell dysfunction and oxidative stress. Activated p90RSK increased the SUMOylation of the Prox1 transcription factor and enhanced VEGFR3 expression and 3-D LEC invasion. BA-induced ROS in the LECs, which led to increased levels of Yes-associated protein (YAP), a lymphangiogenesis regulator. The suppression of cellular YAP inhibited BA-induced VEGFR3 upregulation and lymphangiogenic mechanism. Overall, our data shows the expansion of the lymphatic network in presclerotic liver disease and establishes a novel mechanism whereby BAs promote lymphangiogenesis. Full article
(This article belongs to the Special Issue The Molecular Mechanisms of Bile Acids in Diseases)
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Review

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13 pages, 944 KiB  
Review
Bile Acids in Autoimmune Liver Disease: Unveiling the Nexus of Inflammation, Inflammatory Cells, and Treatment Strategies
by Tianhao Zhou, AbdiGhani Ismail and Heather Francis
Cells 2023, 12(23), 2725; https://doi.org/10.3390/cells12232725 - 29 Nov 2023
Cited by 3 | Viewed by 1865
Abstract
As bile acids not solely play an essential role in nutrition absorption, but also in regulating metabolic functions as well as immune response, bile acids and their signaling pathways are increasingly acknowledged as potential therapeutic targets in the context of chronic liver diseases. [...] Read more.
As bile acids not solely play an essential role in nutrition absorption, but also in regulating metabolic functions as well as immune response, bile acids and their signaling pathways are increasingly acknowledged as potential therapeutic targets in the context of chronic liver diseases. Bile acid receptors such as G protein bile acid-activated receptor 1 and farnesoid X receptor are expressed in different immune cells engaged in innate immunity. Recently, a series of studies have revealed distinct functions of bile acids and bile acid receptors within the adaptive immune system. In addition, a variety of molecules targeting bile acid receptors and transporters are currently in advanced stages of clinical development. Autoimmune liver diseases including conditions like primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis can lead to chronic inflammation, fibrosis, and even cirrhosis and liver failure. In this review, we focus on the role of bile acids in the inflammatory aspects of autoimmune liver diseases. Full article
(This article belongs to the Special Issue The Molecular Mechanisms of Bile Acids in Diseases)
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16 pages, 1055 KiB  
Review
Bile Acids, Intestinal Barrier Dysfunction, and Related Diseases
by Linsen Shi, Lihua Jin and Wendong Huang
Cells 2023, 12(14), 1888; https://doi.org/10.3390/cells12141888 - 19 Jul 2023
Cited by 27 | Viewed by 4660
Abstract
The intestinal barrier is a precisely regulated semi-permeable physiological structure that absorbs nutrients and protects the internal environment from infiltration of pathological molecules and microorganisms. Bile acids are small molecules synthesized from cholesterol in the liver, secreted into the duodenum, and transformed to [...] Read more.
The intestinal barrier is a precisely regulated semi-permeable physiological structure that absorbs nutrients and protects the internal environment from infiltration of pathological molecules and microorganisms. Bile acids are small molecules synthesized from cholesterol in the liver, secreted into the duodenum, and transformed to secondary or tertiary bile acids by the gut microbiota. Bile acids interact with bile acid receptors (BARs) or gut microbiota, which plays a key role in maintaining the homeostasis of the intestinal barrier. In this review, we summarize and discuss the recent studies on bile acid disorder associated with intestinal barrier dysfunction and related diseases. We focus on the roles of bile acids, BARs, and gut microbiota in triggering intestinal barrier dysfunction. Insights for the future prevention and treatment of intestinal barrier dysfunction and related diseases are provided. Full article
(This article belongs to the Special Issue The Molecular Mechanisms of Bile Acids in Diseases)
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22 pages, 1332 KiB  
Review
Mitochondrial Cholesterol Metabolites in a Bile Acid Synthetic Pathway Drive Nonalcoholic Fatty Liver Disease: A Revised “Two-Hit” Hypothesis
by Genta Kakiyama, Daniel Rodriguez-Agudo and William M. Pandak
Cells 2023, 12(10), 1434; https://doi.org/10.3390/cells12101434 - 20 May 2023
Cited by 9 | Viewed by 3823
Abstract
The rising prevalence of nonalcoholic fatty liver disease (NAFLD)-related cirrhosis highlights the need for a better understanding of the molecular mechanisms responsible for driving the transition of hepatic steatosis (fatty liver; NAFL) to steatohepatitis (NASH) and fibrosis/cirrhosis. Obesity-related insulin resistance (IR) is a [...] Read more.
The rising prevalence of nonalcoholic fatty liver disease (NAFLD)-related cirrhosis highlights the need for a better understanding of the molecular mechanisms responsible for driving the transition of hepatic steatosis (fatty liver; NAFL) to steatohepatitis (NASH) and fibrosis/cirrhosis. Obesity-related insulin resistance (IR) is a well-known hallmark of early NAFLD progression, yet the mechanism linking aberrant insulin signaling to hepatocyte inflammation has remained unclear. Recently, as a function of more distinctly defining the regulation of mechanistic pathways, hepatocyte toxicity as mediated by hepatic free cholesterol and its metabolites has emerged as fundamental to the subsequent necroinflammation/fibrosis characteristics of NASH. More specifically, aberrant hepatocyte insulin signaling, as found with IR, leads to dysregulation in bile acid biosynthetic pathways with the subsequent intracellular accumulation of mitochondrial CYP27A1-derived cholesterol metabolites, (25R)26-hydroxycholesterol and 3β-Hydroxy-5-cholesten-(25R)26-oic acid, which appear to be responsible for driving hepatocyte toxicity. These findings bring forth a “two-hit” interpretation as to how NAFL progresses to NAFLD: abnormal hepatocyte insulin signaling, as occurs with IR, develops as a “first hit” that sequentially drives the accumulation of toxic CYP27A1-driven cholesterol metabolites as the “second hit”. In the following review, we examine the mechanistic pathway by which mitochondria-derived cholesterol metabolites drive the development of NASH. Insights into mechanistic approaches for effective NASH intervention are provided. Full article
(This article belongs to the Special Issue The Molecular Mechanisms of Bile Acids in Diseases)
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19 pages, 2426 KiB  
Review
Bile Acids and Biliary Fibrosis
by Sayed Obaidullah Aseem, Phillip B. Hylemon and Huiping Zhou
Cells 2023, 12(5), 792; https://doi.org/10.3390/cells12050792 - 2 Mar 2023
Cited by 7 | Viewed by 2603
Abstract
Biliary fibrosis is the driving pathological process in cholangiopathies such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Cholangiopathies are also associated with cholestasis, which is the retention of biliary components, including bile acids, in the liver and blood. Cholestasis may [...] Read more.
Biliary fibrosis is the driving pathological process in cholangiopathies such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Cholangiopathies are also associated with cholestasis, which is the retention of biliary components, including bile acids, in the liver and blood. Cholestasis may worsen with biliary fibrosis. Furthermore, bile acid levels, composition and homeostasis are dysregulated in PBC and PSC. In fact, mounting data from animal models and human cholangiopathies suggest that bile acids play a crucial role in the pathogenesis and progression of biliary fibrosis. The identification of bile acid receptors has advanced our understanding of various signaling pathways involved in regulating cholangiocyte functions and the potential impact on biliary fibrosis. We will also briefly review recent findings linking these receptors with epigenetic regulatory mechanisms. Further detailed understanding of bile acid signaling in the pathogenesis of biliary fibrosis will uncover additional therapeutic avenues for cholangiopathies. Full article
(This article belongs to the Special Issue The Molecular Mechanisms of Bile Acids in Diseases)
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