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Roussis IM, Pearton DJ, Niazi U, Tsaknakis G, Papadopoulos GL, Cook R, Saqi M, Ragoussis J, Strouboulis J. A novel role for Friend of GATA1 (FOG-1) in regulating cholesterol transport in murine erythropoiesis. PLoS Genet 2025; 21:e1011617. [PMID: 40048486 PMCID: PMC11913303 DOI: 10.1371/journal.pgen.1011617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 03/17/2025] [Accepted: 02/12/2025] [Indexed: 03/18/2025] Open
Abstract
Friend of GATA1 (FOG-1) is an essential transcriptional co-factor of the master erythroid transcription factor GATA1. The knockout of the Zfpm1 gene, coding for FOG-1, results in early embryonic lethality due to anemia in mice, similar to the embryonic lethal phenotype of the Gata1 gene knockout. However, a detailed molecular analysis of the Zfpm1 knockout phenotype in erythropoiesis is presently incomplete. To this end, we used CRISPR/Cas9 to knockout Zfpm1 in mouse erythroleukemic (MEL) cells. Phenotypic characterization of DMSO-induced terminal erythroid differentiation showed that the Zfpm1 knockout MEL cells did not progress past the proerythroblast stage of differentiation. Expression profiling of the Zfpm1 knockout MEL cells by RNAseq showed a lack of up-regulation of erythroid-related gene expression profiles. Bioinformatic analysis highlighted cholesterol transport as a pathway affected in the Zfpm1 knockout cells. Moreover, we show that the cholesterol transporters Abca1 and Ldlr fail to be repressed during erythroid differentiation in Zfpm1 knockout cells, resulting in higher intracellular lipid levels and higher membrane fluidity. We also show that in FOG-1 knockout cells, the nuclear levels of SREBP2, a key transcriptional regulator of cholesterol biosynthesis and transport, are markedly increased. On the basis of these findings we propose that FOG-1 (and, potentially, GATA1) regulate cholesterol homeostasis during erythroid differentiation directly through the down regulation of cholesterol transport genes and indirectly, through the repression of the SREBP2 transcriptional activator of cholesterol homeostasis. Taken together, our work provides a molecular basis for understanding FOG-1 functions in erythropoiesis and reveals a novel role for FOG-1 in cholesterol transport.
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Affiliation(s)
- Ioannis-Marios Roussis
- Red Cell Haematology Lab, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
- Department of Biology, University of Crete, Heraklion, Crete, Greece
| | - David J. Pearton
- Red Cell Haematology Lab, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
| | - Umar Niazi
- Translational Bioinformatics, National Institute for Health Research Biomedical Centre, Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, United Kingdom
| | - Grigorios Tsaknakis
- Institute of Molecular Biology and Biotechnology, Foundation for Research & Technology Hellas, Heraklion, Crete, Greece
| | - Giorgio L. Papadopoulos
- Institute of Molecular Biology and Biotechnology, Foundation for Research & Technology Hellas, Heraklion, Crete, Greece
| | - Riley Cook
- Bone Marrow Failure Group, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
| | - Mansoor Saqi
- Translational Bioinformatics, National Institute for Health Research Biomedical Centre, Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, United Kingdom
| | - Jiannis Ragoussis
- Department of Human Genetics, McGill University and McGill Genome Centre, Montreal, Quebec, Canada
| | - John Strouboulis
- Red Cell Haematology Lab, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
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Bydlowski SP, Levy D. Association of ABCG5 and ABCG8 Transporters with Sitosterolemia. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1440:31-42. [PMID: 38036873 DOI: 10.1007/978-3-031-43883-7_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/02/2023]
Abstract
Sitosterolemia is a rare genetic lipid disorder, mainly characterized by the accumulation of dietary xenosterols in plasma and tissues. It is caused by inactivating mutations in either ABCG5 or ABCG8 subunits, a subfamily-G ATP-binding cassette (ABCG) transporters. ABCG5/G8 encodes a pair of ABC half transporters that form a heterodimer (G5G8). This heterodimeric ATP-binding cassette (ABC) sterol transporter, ABCG5/G8, is responsible for the hepatobiliary and transintestinal secretion of cholesterol and dietary plant sterols to the surface of hepatocytes and enterocytes, promoting the secretion of cholesterol and xenosterols into the bile and the intestinal lumen. In this way, ABCG5/G8 function in the reverse cholesterol transport pathway and mediate the efflux of cholesterol and xenosterols to high-density lipoprotein and bile salt micelles, respectively. Here, we review the biological characteristics and function of ABCG5/G8, and how the mutations of ABCG5/G8 can cause sitosterolemia, a loss-of-function disorder characterized by plant sterol accumulation and premature atherosclerosis, among other features.
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Affiliation(s)
- Sergio Paulo Bydlowski
- Lipids, Oxidation and Cell Biology Team, Laboratory of Immunology (LIM19), Heart Institute (InCor), Faculdade de Medicina, Universidade de São Paulo, Sao Paulo, Brazil.
- National Institute of Science and Technology in Regenerative Medicine (INCT-Regenera) CNPq, Rio de Janeiro, Brazil.
| | - Debora Levy
- Lipids, Oxidation and Cell Biology Team, Laboratory of Immunology (LIM19), Heart Institute (InCor), Faculdade de Medicina, Universidade de São Paulo, Sao Paulo, Brazil
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3
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Gupta K. A modular analysis of bile canalicular function and its implications for cholestasis. Am J Physiol Gastrointest Liver Physiol 2023; 325:G14-G22. [PMID: 37192193 PMCID: PMC10259850 DOI: 10.1152/ajpgi.00165.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 05/03/2023] [Accepted: 05/11/2023] [Indexed: 05/18/2023]
Abstract
Hepatocytes produce bile components and secrete them into a lumen, known as a bile canaliculus, that is formed by the apical membranes of adjoining hepatocytes. Bile canaliculi merge to form tubular structures that subsequently connect to the canal of Hering and larger intra- and extrahepatic bile ducts formed by cholangiocytes, which modify bile and enable flow through the small intestine. The major functional requirements for bile canaliculi are the maintenance of canalicular shape to preserve the blood-bile barrier and regulation of bile flow. These functional requirements are mediated by functional modules, primarily transporters, the cytoskeleton, cell-cell junctions, and mechanosensing proteins. I propose here that bile canaliculi behave as robust machines whereby the functional modules act in a coordinated manner to perform the multistep task of maintaining canalicular shape and bile flow. Cholestasis, the general term for aberrant bile flow, stems from drug/toxin-induced or genetic dysregulation of one or more of the protein components in the functional modules. Here, I discuss the interactions between components of the various functional modules in bile canaliculi and describe how these functional modules regulate canalicular morphology and function. I use this framework to provide a perspective on recent studies of bile canalicular dynamics.
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Affiliation(s)
- Kapish Gupta
- Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Center for Engineering MechanoBiology, The University of Pennsylvania, Philadelphia, Pennsylvania, United States
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4
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Moore JM, Bell EL, Hughes RO, Garfield AS. ABC transporters: human disease and pharmacotherapeutic potential. Trends Mol Med 2023; 29:152-172. [PMID: 36503994 DOI: 10.1016/j.molmed.2022.11.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/24/2022] [Accepted: 11/01/2022] [Indexed: 12/12/2022]
Abstract
Adenosine triphosphate (ATP)-binding cassette (ABC) transporters are a 48-member superfamily of membrane proteins that actively transport a variety of biological substrates across lipid membranes. Their functional diversity defines an expansive involvement in myriad aspects of human biology. At least 21 ABC transporters underlie rare monogenic disorders, with even more implicated in the predisposition to and symptomology of common and complex diseases. Such broad (patho)physiological relevance places this class of proteins at the intersection of disease causation and therapeutic potential, underlining them as promising targets for drug discovery, as exemplified by the transformative CFTR (ABCC7) modulator therapies for cystic fibrosis. This review will explore the growing relevance of ABC transporters to human disease and their potential as small-molecule drug targets.
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Xiao X, Kennelly JP, Ferrari A, Clifford BL, Whang E, Gao Y, Qian K, Sandhu J, Jarrett KE, Brearley-Sholto MC, Nguyen A, Nagari RT, Lee MS, Zhang S, Weston TA, Young SG, Bensinger SJ, Villanueva CJ, de Aguiar Vallim TQ, Tontonoz P. Hepatic nonvesicular cholesterol transport is critical for systemic lipid homeostasis. Nat Metab 2023; 5:165-181. [PMID: 36646756 PMCID: PMC9995220 DOI: 10.1038/s42255-022-00722-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 11/10/2022] [Indexed: 01/18/2023]
Abstract
In cell models, changes in the 'accessible' pool of plasma membrane (PM) cholesterol are linked with the regulation of endoplasmic reticulum sterol synthesis and metabolism by the Aster family of nonvesicular transporters; however, the relevance of such nonvesicular transport mechanisms for lipid homeostasis in vivo has not been defined. Here we reveal two physiological contexts that generate accessible PM cholesterol and engage the Aster pathway in the liver: fasting and reverse cholesterol transport. During fasting, adipose-tissue-derived fatty acids activate hepatocyte sphingomyelinase to liberate sequestered PM cholesterol. Aster-dependent cholesterol transport during fasting facilitates cholesteryl ester formation, cholesterol movement into bile and very low-density lipoprotein production. During reverse cholesterol transport, high-density lipoprotein delivers excess cholesterol to the hepatocyte PM through scavenger receptor class B member 1. Loss of hepatic Asters impairs cholesterol movement into feces, raises plasma cholesterol levels and causes cholesterol accumulation in peripheral tissues. These results reveal fundamental mechanisms by which Aster cholesterol flux contributes to hepatic and systemic lipid homeostasis.
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Affiliation(s)
- Xu Xiao
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA
| | - John Paul Kennelly
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA
| | - Alessandra Ferrari
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA
| | - Bethan L Clifford
- Department of Medicine, Division of Cardiology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Emily Whang
- Pediatric Gastroenterology, Hepatology and Nutrition, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Yajing Gao
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA
| | - Kevin Qian
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA
| | - Jaspreet Sandhu
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA
| | - Kelsey E Jarrett
- Department of Medicine, Division of Cardiology, University of California, Los Angeles, Los Angeles, CA, USA
| | | | - Alexander Nguyen
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Rohith T Nagari
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA
| | - Min Sub Lee
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Sicheng Zhang
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Thomas A Weston
- Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Stephen G Young
- Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA
| | - Steven J Bensinger
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA
| | - Claudio J Villanueva
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Thomas Q de Aguiar Vallim
- Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Medicine, Division of Cardiology, University of California, Los Angeles, Los Angeles, CA, USA
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA
- Jonsson Comprehensive Cancer Center (JCCC), University of California, Los Angeles, Los Angeles, CA, USA
| | - Peter Tontonoz
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
- Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
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Rezaei F, Farhat D, Gursu G, Samnani S, Lee JY. Snapshots of ABCG1 and ABCG5/G8: A Sterol's Journey to Cross the Cellular Membranes. Int J Mol Sci 2022; 24:ijms24010484. [PMID: 36613930 PMCID: PMC9820320 DOI: 10.3390/ijms24010484] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/20/2022] [Accepted: 12/22/2022] [Indexed: 12/29/2022] Open
Abstract
The subfamily-G ATP-binding cassette (ABCG) transporters play important roles in regulating cholesterol homeostasis. Recent progress in the structural data of ABCG1 and ABCG5/G8 disclose putative sterol binding sites that suggest the possible cholesterol translocation pathway. ABCG1 and ABCG5/G8 share high similarity in the overall molecular architecture, and both transporters appear to use several unique structural motifs to facilitate cholesterol transport along this pathway, including the phenylalanine highway and the hydrophobic valve. Interestingly, ABCG5/G8 is known to transport cholesterol and phytosterols, whereas ABCG1 seems to exclusively transport cholesterol. Ligand docking analysis indeed suggests a difference in recruiting sterol molecules to the known sterol-binding sites. Here, we further discuss how the different and shared structural features are relevant to their physiological functions, and finally provide our perspective on future studies in ABCG cholesterol transporters.
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Affiliation(s)
- Fatemeh Rezaei
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Danny Farhat
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Gonca Gursu
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Biochemistry Program, Faculty of Science, University of Ottawa, Ottawa, ON K1H 6N5, Canada
| | - Sabrina Samnani
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Biochemistry Program, Faculty of Science, University of Ottawa, Ottawa, ON K1H 6N5, Canada
| | - Jyh-Yeuan Lee
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Correspondence:
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7
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Guo W, Gao B, Zhang X, Ren Q, Xie D, Liang J, Li H, Wang X, Zhang Y, Liu S, Nie G. Distinct responses from triglyceride and cholesterol metabolism in common carp (Cyprinus carpio) upon environmental cadmium exposure. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2022; 249:106239. [PMID: 35863253 DOI: 10.1016/j.aquatox.2022.106239] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 07/09/2022] [Accepted: 07/11/2022] [Indexed: 06/15/2023]
Abstract
Due to high persistence and bioavailability, Cadmium (Cd) is one of the most prevalent environmental contaminants, posing an elevating threat to the ecosystems. It has been evidenced that high-dose Cd elicits deleterious effects on aquatic organisms, but the potential toxicities of Cd at environmentally relevant concentrations remains underappreciated. In this study, we used common carp to investigate how environmental Cd exposure affects triglyceride (TG) and cholesterol metabolism and underlying mechanisms. The data indicated that Cd resulted in the shift of TG from the liver to blood and the movement of cholesterol in the opposite direction, ultimately giving rise to the storage of crude lipid in liver and muscle, especially hepatic cholesterol retention. Cholesterol, instead of TG, became the principal cause during the progression of hepatic lipid accumulation. Mechanistic investigations at transcriptional and translational levels further substantiated that Cd blocked hepatic biosynthesis of TG and enhanced TG efflux out of the liver and fatty acid β-oxidation, which collectively led to the compromised TG metabolism in the liver and accelerated TG export to the serum. Additionally, strengthened synthesis, retarded export and oxidation of cholesterol detailed the hepatic prominent cholesterol retention. Taken together, our results demonstrated that environmental exposure to Cd perturbed lipid metabolism through triggering distinct responses from hepatic TG and cholesterol homeostasis. These indicated that environmental factors (such as waterborne Cd) could be a potential contributor to the prevalence of non-alcoholic fatty-liver disease in aquaculture and more efforts should be devoted to the ecological risk assessment of pollutants under environmental scenarios.
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Affiliation(s)
- Wenli Guo
- College of Fisheries, Henan Normal University, Xinxiang 453007, China; Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang 453007, China; State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Beibei Gao
- College of Fisheries, Henan Normal University, Xinxiang 453007, China
| | - Xiaoqian Zhang
- College of Fisheries, Henan Normal University, Xinxiang 453007, China
| | - Quanzhong Ren
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Dizhi Xie
- College of Marine Sciences of South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China
| | - Junping Liang
- College of Fisheries, Henan Normal University, Xinxiang 453007, China; Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang 453007, China
| | - Hui Li
- College of Fisheries, Henan Normal University, Xinxiang 453007, China
| | - Xianfeng Wang
- College of Fisheries, Henan Normal University, Xinxiang 453007, China; Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang 453007, China
| | - Yuru Zhang
- College of Fisheries, Henan Normal University, Xinxiang 453007, China; Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang 453007, China
| | - Sijin Liu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Guoxing Nie
- College of Fisheries, Henan Normal University, Xinxiang 453007, China; Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang 453007, China.
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8
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Wang HH, Portincasa P, Liu M, Wang DQH. Genetic Analysis of ABCB4 Mutations and Variants Related to the Pathogenesis and Pathophysiology of Low Phospholipid-Associated Cholelithiasis. Genes (Basel) 2022; 13:1047. [PMID: 35741809 PMCID: PMC9222727 DOI: 10.3390/genes13061047] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 06/08/2022] [Indexed: 12/28/2022] Open
Abstract
Clinical studies have revealed that the ABCB4 gene encodes the phospholipid transporter on the canalicular membrane of hepatocytes, and its mutations and variants are the genetic basis of low phospholipid-associated cholelithiasis (LPAC), a rare type of gallstone disease caused by a single-gene mutation or variation. The main features of LPAC include a reduction or deficiency of phospholipids in bile, symptomatic cholelithiasis at <40 years of age, intrahepatic sludge and microlithiasis, mild chronic cholestasis, a high cholesterol/phospholipid ratio in bile, and recurrence of biliary symptoms after cholecystectomy. Needle-like cholesterol crystals, putatively “anhydrous” cholesterol crystallization at low phospholipid concentrations in model and native bile, are characterized in ABCB4 knockout mice, a unique animal model for LPAC. Gallbladder bile with only trace amounts of phospholipids in these mice is supersaturated with cholesterol, with lipid composition plotting in the left two-phase zone of the ternary phase diagram, consistent with “anhydrous” cholesterol crystallization. In this review, we summarize the molecular biology and physiological functions of ABCB4 and comprehensively discuss the latest advances in the genetic analysis of ABCB4 mutations and variations and their roles in the pathogenesis and pathophysiology of LPAC in humans, based on the results from clinical studies and mouse experiments. To date, approximately 158 distinct LPAC-causing ABCB4 mutations and variants in humans have been reported in the literature, indicating that it is a monogenic risk factor for LPAC. The elucidation of the ABCB4 function in the liver, the identification of ABCB4 mutations and variants in LPAC patients, and the exploration of gene therapy for ABCB4 deficiency in animal models can help us to better understand the cellular, molecular, and genetic mechanisms underlying the onset of the disease, and will pave the way for early diagnosis and prevention of susceptible subjects and effective intervention for LPAC in patients.
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Affiliation(s)
- Helen H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA;
| | - Piero Portincasa
- Department of Biomedical Sciences and Human Oncology, Clinica Medica “A. Murri”, University of Bari Medical School, 70124 Bari, Italy;
| | - Min Liu
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA;
| | - David Q.-H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA;
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9
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Abe RJ, Abe JI, Nguyen MTH, Olmsted-Davis EA, Mamun A, Banerjee P, Cooke JP, Fang L, Pownall H, Le NT. Free Cholesterol Bioavailability and Atherosclerosis. Curr Atheroscler Rep 2022; 24:323-336. [PMID: 35332444 PMCID: PMC9050774 DOI: 10.1007/s11883-022-01011-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/02/2022] [Indexed: 11/30/2022]
Abstract
PURPOSE OF REVIEW As both a cholesterol acceptor and carrier in the reverse cholesterol transport (RCT) pathway, high-density lipoprotein (HDL) is putatively atheroprotective. However, current pharmacological therapies to increase plasma HDL cholesterol (HDL-c) concentration have paradoxically failed to prevent or reduce atherosclerosis and cardiovascular disease (CVD). Given that free cholesterol (FC) transfer between surfaces of lipoproteins and cells is reversible, excess plasma FC can be transferred to the cells of peripheral tissue sites resulting in atherosclerosis. Here, we summarize potential mechanisms contributing to this paradox and highlight the role of excess free cholesterol (FC) bioavailability in atherosclerosis vs. atheroprotection. RECENT FINDINGS Recent findings have established a complex relationship between HDL-c concentration and atherosclerosis. Systemic scavenger receptor class B type 1 (SR-B1) knock out (KO) mice exhibit with increased diet-induced atherosclerosis despite having an elevated plasma HDL-c concentration compared to wild type (WT) mice. The greater bioavailability of HDL-FC in SR-B1 vs. WT mice is associated with a higher FC content in multiple cell types and tissue sites. These results suggest that dysfunctional HDL with high FC bioavailability is atheroprone despite high HDL-c concentration. Past oversimplification of HDL-c involvement in cholesterol transport has led to the failures in HDL targeted therapy. Evidence suggests that FC-mediated functionality of HDL is of higher importance than its quantity; as a result, deciphering the regulatory mechanisms by which HDL-FC bioavailability can induce atherosclerosis can have far-reaching clinical implications.
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Affiliation(s)
- Rei J Abe
- Center for Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA
| | - Jun-Ichi Abe
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Minh T H Nguyen
- Center for Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA
- University of Science and Technology of Hanoi, Vietnam Academy of Science and Technology, Hanoi, Vietnam
| | | | - Abrar Mamun
- Center for Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA
| | - Priyanka Banerjee
- Center for Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA
| | - John P Cooke
- Center for Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA
- Weill Cornell Medicine, New York, NY, USA
| | - Longhou Fang
- Center for Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA
- Weill Cornell Medicine, New York, NY, USA
| | - Henry Pownall
- Weill Cornell Medicine, New York, NY, USA
- Center for Bioenergetics, Department of Medicine, Houston Methodist Research Institute, Houston, TX, USA
| | - Nhat-Tu Le
- Center for Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA.
- Weill Cornell Medicine, New York, NY, USA.
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10
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Sex-specific alterations in hepatic cholesterol metabolism in low birth weight adult guinea pigs. Pediatr Res 2022; 91:1078-1089. [PMID: 34230622 DOI: 10.1038/s41390-021-01491-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 02/19/2021] [Accepted: 02/26/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Intrauterine growth restriction and low birth weight (LBW) have been widely reported as an independent risk factor for adult hypercholesterolaemia and increased hepatic cholesterol in a sex-specific manner. However, the specific impact of uteroplacental insufficiency (UPI), a leading cause of LBW in developed world, on hepatic cholesterol metabolism in later life, is ill defined and is clinically relevant in understanding later life liver metabolic health trajectories. METHODS Hepatic cholesterol, transcriptome, cholesterol homoeostasis regulatory proteins, and antioxidant markers were studied in UPI-induced LBW and normal birth weight (NBW) male and female guinea pigs at 150 days. RESULTS Hepatic free and total cholesterol were increased in LBW versus NBW males. Transcriptome analysis of LBW versus NBW livers revealed that "cholesterol metabolism" was an enriched pathway in LBW males but not in females. Microsomal triglyceride transfer protein and cytochrome P450 7A1 protein, involved in hepatic cholesterol efflux and catabolism, respectively, and catalase activity were decreased in LBW male livers. Superoxide dismutase activity was reduced in LBW males but increased in LBW females. CONCLUSIONS UPI environment is associated with a later life programed hepatic cholesterol accumulation via impaired cholesterol elimination in a sex-specific manner. These programmed alterations could underlie later life cholesterol-induced hepatic lipotoxicity in LBW male offspring. IMPACT Low birth weight (LBW) is a risk factor for increased hepatic cholesterol. Uteroplacental insufficiency (UPI) resulting in LBW increased hepatic cholesterol content, altered hepatic expression of cholesterol metabolism-related genes in young adult guinea pigs. UPI-induced LBW was also associated with markers of a compromised hepatic cholesterol elimination process and failing antioxidant system in young adult guinea pigs. These changes, at the current age studied, were sex-specific, only being observed in LBW males and not in LBW females. These programmed alterations could lead to further hepatic damage and greater predisposition to liver diseases in UPI-induced LBW male offspring as they age.
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Poznyak AV, Kashirskikh DA, Sukhorukov VN, Kalmykov V, Omelchenko AV, Orekhov AN. Cholesterol Transport Dysfunction and Its Involvement in Atherogenesis. Int J Mol Sci 2022; 23:ijms23031332. [PMID: 35163256 PMCID: PMC8836120 DOI: 10.3390/ijms23031332] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/17/2022] [Accepted: 01/23/2022] [Indexed: 12/26/2022] Open
Abstract
Atherosclerosis is the cause of the development of serious cardiovascular disorders, leading to disability and death. Numerous processes are involved in the pathogenesis of atherosclerosis, including inflammation, endothelial dysfunction, oxidative stress, and lipid metabolism disorders. Reverse transport of cholesterol is a mechanism presumably underlying the atheroprotective effect of high-density lipoprotein. In this review, we examined disorders of cholesterol metabolism and their possible effect on atherogenesis. We paid special attention to the reverse transport of cholesterol. Transformed cholesterol metabolism results in dyslipidemia and early atherosclerosis. Reverse cholesterol transport is an endogenous mechanism by which cells export cholesterol and maintain homeostasis. It is known that one of the main factors leading to the formation of atherosclerotic plaques on the walls of blood vessels are multiple modifications of low-density lipoprotein, and the formation of foam cells following them.
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Affiliation(s)
- Anastasia V. Poznyak
- Institute for Atherosclerosis Research, Osennyaya Street 4-1-207, 121609 Moscow, Russia;
- Correspondence: (A.V.P.); (A.N.O.)
| | - Dmitry A. Kashirskikh
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia; (D.A.K.); (V.K.)
| | - Vasily N. Sukhorukov
- AP Avtsyn Research Institute of Human Morphology, 3 Tsyurupa Street, 117418 Moscow, Russia;
| | - Vladislav Kalmykov
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia; (D.A.K.); (V.K.)
- AP Avtsyn Research Institute of Human Morphology, 3 Tsyurupa Street, 117418 Moscow, Russia;
| | - Andrey V. Omelchenko
- Institute for Atherosclerosis Research, Osennyaya Street 4-1-207, 121609 Moscow, Russia;
| | - Alexander N. Orekhov
- Institute for Atherosclerosis Research, Osennyaya Street 4-1-207, 121609 Moscow, Russia;
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia; (D.A.K.); (V.K.)
- AP Avtsyn Research Institute of Human Morphology, 3 Tsyurupa Street, 117418 Moscow, Russia;
- Correspondence: (A.V.P.); (A.N.O.)
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12
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Behl T, Sehgal A, Grover M, Singh S, Sharma N, Bhatia S, Al-Harrasi A, Aleya L, Bungau S. Uncurtaining the pivotal role of ABC transporters in diabetes mellitus. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:41533-41551. [PMID: 34085197 DOI: 10.1007/s11356-021-14675-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 05/27/2021] [Indexed: 06/12/2023]
Abstract
The metabolic disorders are the edge points for the initiation of various diseases. These disorders comprised of several diseases including diabetes, obesity, and cardiovascular complications. Worldwide, the prevalence of these disorders is increasing day by day. The world's population is at higher threat of developing metabolic disease, especially diabetes. Therefore, there is an impregnable necessity of searching for a newer therapeutic target to reduce the burden of these disorders. Diabetes mellitus (DM) is marked with the dysregulated insulin secretion and resistance. The lipid and glucose transporters portray a pivotal role in the metabolism and transport of both of these. The excess production of lipid and glucose and decreased clearance of these leads to the emergence of DM. The ATP-binding cassette transporters (ABCT) are important for the metabolism of glucose and lipid. Various studies suggest the key involvement of ABCT in the pathologic process of different diseases. In addition, the involvement of other pathways, including IGF signaling, P13-Akt/PKC/MAPK signaling, and GLP-1 via regulation of ABCT, may help develop new treatment strategies to cope with insulin resistance dysregulated glucose metabolism, key features in DM.
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Affiliation(s)
- Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Madhuri Grover
- BS Anangpuria Institute of Pharmacy, Faridabad, Haryana, India
| | - Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Neelam Sharma
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Saurabh Bhatia
- Amity Institute of Pharmacy, Amity University, Gurugram, Haryana, India
- Natural & Medical Sciences Research Centre, University of Nizwa, Birkat Al Mauz, Nizwa, Oman
| | - Ahmed Al-Harrasi
- Natural & Medical Sciences Research Centre, University of Nizwa, Birkat Al Mauz, Nizwa, Oman
| | - Lotfi Aleya
- Chrono-Environment Laboratory, UMR CNRS 6249, Bourgogne Franche-Comté University, Besançon, France
| | - Simona Bungau
- Department of Pharmacy, Faculty of Pharmacy, University of Oradea, Oradea, Romania
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13
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Huang J, Wang Q, Chen M, Bi Y, Shi H, Zhou K. Effects of psoralen on hepatic bile acid transporters in rats. Hum Exp Toxicol 2020; 40:1012-1021. [PMID: 33317360 DOI: 10.1177/0960327120979346] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Fructus Psoraleae (FP), widely used in traditional medicine, is increasingly reported to cause serious hepatotoxicity in recent years. However, the main toxic constituents responsible for hepatotoxicity and the underlying mechanisms are poorly understood. In the present study, psoralen, a main and quality-control constituent of FP, was intragastrically administered to Sprague-Dawley rats at a dose of 60 mg/kg for 1, 3 and 7 days. Blood and selected tissue samples were collected and analyzed for biochemistry and histopathology to evaluate hepatotoxicity. The results showed that psoralen could induce hepatotoxicity by enhanced liver-to-body weight ratio and alterations of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total cholesterol after administration for 3 days. In addition, histopathological examinations also indicated the hepatotoxicity induced by psoralen. Furthermore, the mRNA and protein levels of hepatic bile acid transporters were significantly changed, in which MRP4, ABCG5 and ABCG8 were repressed, while the protein level of NTCP tended to increase in the rat liver. Taken together, psoralen caused liver injury possibly through affecting bile acid transporters, leading to the disorder of bile acid transport and accumulation in hepatocytes.
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Affiliation(s)
- Juyang Huang
- School of Integrative Medicine, 58301Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Qin Wang
- Institute of Traditional Chinese Medicine, 58301Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Mengying Chen
- Institute of Traditional Chinese Medicine, 58301Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yanan Bi
- Institute of Traditional Chinese Medicine, 58301Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Hong Shi
- Institute of Traditional Chinese Medicine, 58301Tianjin University of Traditional Chinese Medicine, Tianjin, China.,Tianjin Key Laboratory of Chinese medicine Pharmacology, Tianjin, China
| | - Kun Zhou
- Institute of Traditional Chinese Medicine, 58301Tianjin University of Traditional Chinese Medicine, Tianjin, China.,Tianjin Key Laboratory of Chinese medicine Pharmacology, Tianjin, China
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14
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Mammalian ABCG-transporters, sterols and lipids: To bind perchance to transport? Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1866:158860. [PMID: 33309976 DOI: 10.1016/j.bbalip.2020.158860] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 11/15/2020] [Accepted: 12/08/2020] [Indexed: 02/08/2023]
Abstract
Members of the ATP binding cassette (ABC) transporter family perform a critical function in maintaining lipid homeostasis in cells as well as the transport of drugs. In this review, we provide an update on the ABCG-transporter subfamily member proteins, which include the homodimers ABCG1, ABCG2 and ABCG4 as well as the heterodimeric complex formed between ABCG5 and ABCG8. This review focusses on progress made in this field of research with respect to their function in health and disease and the recognised transporter substrates. We also provide an update on post-translational regulation, including by transporter substrates, and well as the involvement of microRNA as regulators of transporter expression and activity. In addition, we describe progress made in identifying structural elements that have been recognised as important for transport activity. We furthermore discuss the role of lipids such as cholesterol on the transport function of ABCG2, traditionally thought of as a drug transporter, and provide a model of potential cholesterol binding sites for ABCG2.
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15
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Kroll T, Prescher M, Smits SHJ, Schmitt L. Structure and Function of Hepatobiliary ATP Binding Cassette Transporters. Chem Rev 2020; 121:5240-5288. [PMID: 33201677 DOI: 10.1021/acs.chemrev.0c00659] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The liver is beyond any doubt the most important metabolic organ of the human body. This function requires an intensive crosstalk within liver cellular structures, but also with other organs. Membrane transport proteins are therefore of upmost importance as they represent the sensors and mediators that shuttle signals from outside to the inside of liver cells and/or vice versa. In this review, we summarize the known literature of liver transport proteins with a clear emphasis on functional and structural information on ATP binding cassette (ABC) transporters, which are expressed in the human liver. These primary active membrane transporters form one of the largest families of membrane proteins. In the liver, they play an essential role in for example bile formation or xenobiotic export. Our review provides a state of the art and comprehensive summary of the current knowledge of hepatobiliary ABC transporters. Clearly, our knowledge has improved with a breath-taking speed over the last few years and will expand further. Thus, this review will provide the status quo and will lay the foundation for new and exciting avenues in liver membrane transporter research.
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Affiliation(s)
- Tim Kroll
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Martin Prescher
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Sander H J Smits
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.,Center for Structural Studies, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Lutz Schmitt
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
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16
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Abstract
Cholesterol homeostasis and trafficking are critical to the maintenance of the asymmetric plasma membrane of eukaryotic cells. Disruption or dysfunction of cholesterol trafficking leads to numerous human diseases. ATP-binding cassette (ABC) transporters play several critical roles in this process, and mutations in these sterol transporters lead to disorders such as Tangier disease and sitosterolemia. Biochemical and structural information on ABC sterol transporters is beginning to emerge, with published structures of ABCA1 and ABCG5/G8; these two proteins function in the reverse cholesterol transport pathway and mediate the efflux of cholesterol and xenosterols to high-density lipoprotein and bile salt micelles, respectively. Although both of these transporters belong to the ABC family and mediate the efflux of a sterol substrate, they have many distinct differences. Here, we summarize the current understanding of sterol transport driven by ABC transporters, with an emphasis on these two extensively characterized transporters.
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Affiliation(s)
- Ashlee M Plummer
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;
| | - Alan T Culbertson
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;
| | - Maofu Liao
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;
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17
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Trusov NV, Apryatin SA, Shipelin VA, Gmoshinski IV. [Full transcriptome analysis of gene expression in liver of mice in a comparative study of quercetin efficiency on two obesity models]. ACTA ACUST UNITED AC 2020; 66:31-47. [PMID: 33369371 DOI: 10.14341/probl12561] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 09/11/2020] [Accepted: 09/17/2020] [Indexed: 11/06/2022]
Abstract
BACKGROUND Quercetin (Q; 3,3',4',5,7 - pentahydroxyflavone) can help alleviate the pathological effects of nutritional obesity and metabolic syndrome when taken as part of products for special dietary needs and food supplements. The mechanisms of action of Q at the genetic level are not well understood. AIMS To study gene expression in liver tissue of mice with alimentary and genetically determined obesity upon intake of Q with diet. MATERIALS AND METHODS During 46 days of the experiment on 32 male C57Bl/6J mice fed a diet with an excess of fat and fructose and 24 male genetically obese db/db mice the effect of Q in dose of 25 or 100 mg/kg of body weight was studied on differential expression of 39430 genes in mice livers by full transcriptome profiling on microchip according to the Agilent One-Color Microarray-Based Gene Expression Analysis Low Input Quick Amp Labeling protocol (version 6.8). To identify metabolic pathways (KEGGs) that were targets of Q exposure, transcriptomic data were analyzed using bioinformatics methods in an "R" environment. RESULTS Differences were revealed in the nature of Q supplementation action in animals with dietary induced and genetically determined obesity on a number of key metabolic pathways, including the metabolism of lipids and steroids (Saa3, Cidec, Scd1, Apoa4, Acss2, Fabp5, Car3, Acacb, Insig2 genes), amino acids and nitrogen bases (Ngef, Gls2), carbohydrates (G6pdx, Pdk4), regulation of cell growth, apoptosis and proliferation (Btg3, Cgref1, Fst, Nrep Tuba8), neurotransmission (Grin2d, Camk2b), immune system reactions (CD14i, Jchain, Ifi27l2b). CONCLUSIONS The data obtained help to explain the ambiguous effectiveness of Q, like other polyphenols, in the dietary treatment of various forms of obesity in humans, as well as to form a set of sensitive biomarkers that allow us to elucidate the effectiveness of minor biologically active food substances in preclinical trials of new means of metabolic correction of obesity and metabolic syndrome.
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Affiliation(s)
- N V Trusov
- Federal Research Centre of Nutrition, Biotechnology and Food Safety
| | - S A Apryatin
- Federal Research Centre of Nutrition, Biotechnology and Food Safety
| | - V A Shipelin
- Federal Research Centre of Nutrition, Biotechnology and Food Safety; Plekhanov Russian University of Economics
| | - I V Gmoshinski
- Federal Research Centre of Nutrition, Biotechnology and Food Safety
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18
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Bernhard W. Choline in cystic fibrosis: relations to pancreas insufficiency, enterohepatic cycle, PEMT and intestinal microbiota. Eur J Nutr 2020; 60:1737-1759. [PMID: 32797252 DOI: 10.1007/s00394-020-02358-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 08/03/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Cystic Fibrosis (CF) is an autosomal recessive disorder with life-threatening organ manifestations. 87% of CF patients develop exocrine pancreas insufficiency, frequently starting in utero and requiring lifelong pancreatic enzyme substitution. 99% develop progressive lung disease, and 20-60% CF-related liver disease, from mild steatosis to cirrhosis. Characteristically, pancreas, liver and lung are linked by choline metabolism, a critical nutrient in CF. Choline is a tightly regulated tissue component in the form of phosphatidylcholine (Ptd'Cho) and sphingomyelin (SPH) in all membranes and many secretions, particularly of liver (bile, lipoproteins) and lung (surfactant, lipoproteins). Via its downstream metabolites, betaine, dimethylglycine and sarcosine, choline is the major one-carbon donor for methionine regeneration from homocysteine. Methionine is primarily used for essential methylation processes via S-adenosyl-methionine. CLINICAL IMPACT CF patients with exocrine pancreas insufficiency frequently develop choline deficiency, due to loss of bile Ptd'Cho via feces. ~ 50% (11-12 g) of hepatic Ptd'Cho is daily secreted into the duodenum. Its re-uptake requires cleavage to lyso-Ptd'Cho by pancreatic and small intestinal phospholipases requiring alkaline environment. Impaired CFTR-dependent bicarbonate secretion, however, results in low duodenal pH, impaired phospholipase activity, fecal Ptd'Cho loss and choline deficiency. Low plasma choline causes decreased availability for parenchymal Ptd'Cho metabolism, impacting on organ functions. Choline deficiency results in hepatic choline/Ptd'Cho accretion from lung tissue via high density lipoproteins, explaining the link between choline deficiency and lung function. Hepatic Ptd'Cho synthesis from phosphatidylethanolamine by phosphatidylethanolamine-N-methyltransferase (PEMT) partly compensates for choline deficiency, but frequent single nucleotide polymorphisms enhance choline requirement. Additionally, small intestinal bacterial overgrowth (SIBO) frequently causes intraluminal choline degradation in CF patients prior to its absorption. As adequate choline supplementation was clinically effective and adult as well as pediatric CF patients suffer from choline deficiency, choline supplementation in CF patients of all ages should be evaluated.
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Affiliation(s)
- Wolfgang Bernhard
- Department of Neonatology, University Children's Hospital, Faculty of Medicine, Eberhard-Karls-University, Calwer Straße 7, 72076, Tübingen, Germany.
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19
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Roscam Abbing RL, Slijepcevic D, Donkers JM, Havinga R, Duijst S, Paulusma CC, Kuiper J, Kuipers F, Groen AK, Oude Elferink RP, van de Graaf SF. Blocking Sodium-Taurocholate Cotransporting Polypeptide Stimulates Biliary Cholesterol and Phospholipid Secretion in Mice. Hepatology 2020; 71:247-258. [PMID: 31136002 PMCID: PMC7003915 DOI: 10.1002/hep.30792] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 05/13/2019] [Indexed: 12/17/2022]
Abstract
Active secretion of bile salts into the canalicular lumen drives bile formation and promotes biliary cholesterol and phospholipid output. Disrupting hepatic bile salt uptake, by inhibition of sodium-taurocholate cotransporting polypetide (NTCP; Slc10a1) with Myrcludex B, is expected to limit bile salt flux through the liver and thereby to decrease biliary lipid excretion. Here, we show that Myrcludex B-mediated NTCP inhibition actually causes an increase in biliary cholesterol and phospholipid excretion whereas biliary bile salt output and bile salt composition remains unchanged. Increased lysosomal discharge into bile was excluded as a potential contributor to increased biliary lipid secretion. Induction of cholesterol secretion was not a consequence of increased ATP-binding cassette subfamily G member 5/8 activity given that NTCP inhibition still promoted cholesterol excretion in Abcg8-/- mice. Stimulatory effects of NTCP inhibition were maintained in Sr-b1-/- mice, eliminating the possibility that the increase in biliary lipids was derived from enhanced uptake of high-density lipoprotein-derived lipids. NTCP inhibition shifts bile salt uptake, which is generally more periportally restricted, toward pericentral hepatocytes, as was visualized using a fluorescently labeled conjugated bile salt. As a consequence, exposure of the canalicular membrane to bile salts was increased, allowing for more cholesterol and phospholipid molecules to be excreted per bile salt. Conclusion: NTCP inhibition increases biliary lipid secretion, which is independent of alterations in bile salt output, biliary bile salt hydrophobicity, or increased activity of dedicated cholesterol and phospholipid transporters. Instead, NTCP inhibition shifts hepatic bile salt uptake from mainly periportal hepatocytes toward pericentral hepatocytes, thereby increasing exposure of the canalicular membrane to bile salts linking to increased biliary cholesterol secretion. This process provides an additional level of control to biliary cholesterol and phospholipid secretion.
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Affiliation(s)
- Reinout L.P. Roscam Abbing
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and MetabolismAmsterdam UMC, University of AmsterdamAmsterdamThe Netherlands
| | - Davor Slijepcevic
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and MetabolismAmsterdam UMC, University of AmsterdamAmsterdamThe Netherlands
| | - Joanne M. Donkers
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and MetabolismAmsterdam UMC, University of AmsterdamAmsterdamThe Netherlands
| | - Rick Havinga
- Departments of Pediatrics & Laboratory MedicineUniversity Medical Center GroningenGroningenThe Netherlands
| | - Suzanne Duijst
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and MetabolismAmsterdam UMC, University of AmsterdamAmsterdamThe Netherlands
| | - Coen C. Paulusma
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and MetabolismAmsterdam UMC, University of AmsterdamAmsterdamThe Netherlands,Department of Gastroenterology & Hepatology, Amsterdam Gastroenterology and MetabolismAmsterdam UMC, University of AmsterdamAmsterdamThe Netherlands
| | - Johan Kuiper
- Division of Biopharmaceutics, Leiden Academic Centre for Drug ResearchLeiden UniversityLeidenThe Netherlands
| | - Folkert Kuipers
- Departments of Pediatrics & Laboratory MedicineUniversity Medical Center GroningenGroningenThe Netherlands
| | - Albert K. Groen
- Departments of Pediatrics & Laboratory MedicineUniversity Medical Center GroningenGroningenThe Netherlands,Department of Internal and Vascular Medicine, Amsterdam Cardiovascular SciencesAmsterdam UMC, University of AmsterdamAmsterdamThe Netherlands
| | - Ronald P.J. Oude Elferink
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and MetabolismAmsterdam UMC, University of AmsterdamAmsterdamThe Netherlands,Department of Gastroenterology & Hepatology, Amsterdam Gastroenterology and MetabolismAmsterdam UMC, University of AmsterdamAmsterdamThe Netherlands
| | - Stan F.J. van de Graaf
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and MetabolismAmsterdam UMC, University of AmsterdamAmsterdamThe Netherlands,Department of Gastroenterology & Hepatology, Amsterdam Gastroenterology and MetabolismAmsterdam UMC, University of AmsterdamAmsterdamThe Netherlands
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20
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Combined Effect of Diosgenin Along with Ezetimibe or Atorvastatin on the Fate of Labelled Bile Acid and Cholesterol in Hypercholesterolemic Rats. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16040627. [PMID: 30791676 PMCID: PMC6406618 DOI: 10.3390/ijerph16040627] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 02/08/2019] [Accepted: 02/14/2019] [Indexed: 12/19/2022]
Abstract
We analyzed the effect of diosgenin, administered with atorvastatin or ezetimibe, on the fate of 3H(G)-taurocholic acid or 26-14C-cholesterol in hypercholesterolemic rats. Male Wistar rats received a hypercholesterolemic diet (HD), HD + atorvastatin (HD+ATV), HD + ezetimibe (HD+EZT), HD + diosgenin (HD+DG), HD+ATV+EZT, or HD+ATV+DG for 40 days. We also included a control normal group (ND). The labelled compounds were administered on day 30. The animals were placed in metabolic cages for daily feces collection. At day 40 the rats were sacrificed. Lipid extracts from blood, liver, spinal cord, testicles, kidneys, epididymis, intestine, and feces were analyzed for radioactivity. Cholesterol activity was the highest in the liver in HD rats. DG diminished one half of this activity in HD+DG and HD+ATV+DG groups in comparison with the HD group. HD+ATV rats showed four to almost ten-fold cholesterol activity in the spinal cord compared with the ND or HD rats. Fecal elimination of neutral steroids was approximately two-fold higher in the HD+DG and HD+ATV+DG groups. Taurocholic acid activity was four to ten-fold higher in HD+DG intestine as compared to the other experimental groups. Taurocholic activity in the liver of HD and HD+DG groups was two and a half higher than in ND. Our results show that the combination of DG and ATV induced the highest cholesterol reduction in the liver and other tissues.
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21
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Steck TL, Lange Y. Transverse distribution of plasma membrane bilayer cholesterol: Picking sides. Traffic 2018; 19:750-760. [PMID: 29896788 DOI: 10.1111/tra.12586] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 06/04/2018] [Accepted: 06/05/2018] [Indexed: 12/23/2022]
Abstract
The transverse asymmetry (sidedness) of phospholipids in plasma membrane bilayers is well characterized, distinctive, actively maintained and functionally important. In contrast, numerous studies using a variety of techniques have concluded that plasma membrane bilayer cholesterol is either mostly in the outer leaflet or the inner leaflet or is fairly evenly distributed. Sterols might simply partition according to their differing affinities for the asymmetrically disposed phospholipids, but some studies have proposed that it is actively transported to the outer leaflet. Other work suggests that the sterol is enriched in the inner leaflet, driven by either positive interactions with the phosphatidylethanolamine on that side or by its exclusion from the outer leaflet by the long chain sphingomyelin molecules therein. This uncertainty raises three questions: is plasma membrane cholesterol sidedness fixed in a given cell or cell type; is it generally the same among mammalian species; and does it serve specific physiological functions? This review grapples with these issues.
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Affiliation(s)
- Theodore L Steck
- Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois
| | - Yvonne Lange
- Department of Pathology, Rush University Medical Center, Chicago, Illinois
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22
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Patel SB, Graf GA, Temel RE. ABCG5 and ABCG8: more than a defense against xenosterols. J Lipid Res 2018; 59:1103-1113. [PMID: 29728459 DOI: 10.1194/jlr.r084244] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 04/17/2018] [Indexed: 12/14/2022] Open
Abstract
The elucidation of the molecular basis of the rare disease, sitosterolemia, has revolutionized our mechanistic understanding of how dietary sterols are excreted and how cholesterol is eliminated from the body. Two proteins, ABCG5 and ABCG8, encoded by the sitosterolemia locus, work as obligate dimers to pump sterols out of hepatocytes and enterocytes. ABCG5/ABCG8 are key in regulating whole-body sterol trafficking, by eliminating sterols via the biliary tree as well as the intestinal tract. Importantly, these transporters keep xenosterols from accumulating in the body. The sitosterolemia locus has been genetically associated with lipid levels and downstream atherosclerotic disease, as well as formation of gallstones and the risk of gallbladder cancer. While polymorphic variants raise or lower the risks of these phenotypes, loss of function of this locus leads to more dramatic phenotypes, such as premature atherosclerosis, platelet dysfunction, and thrombocytopenia, and, perhaps, increased endocrine disruption and liver dysfunction. Whether small amounts of xenosterol exposure over a lifetime cause pathology in normal humans with polymorphic variants at the sitosterolemia locus remains largely unexplored. The purpose of this review will be to summarize the current state of knowledge, but also highlight key conceptual and mechanistic issues that remain to be explored.
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Affiliation(s)
- Shailendra B Patel
- Division of Endocrinology, Diabetes, and Metabolism, University of Cincinnati, Cincinnati, OH 45219
| | - Gregory A Graf
- Department of Pharmaceutical Sciences and Saha Cardiovascular Research Center and University of Kentucky, Lexington, KY 40536
| | - Ryan E Temel
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536
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23
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Eckstein J, Holzhütter HG, Berndt N. The importance of membrane microdomains for bile salt-dependent biliary lipid secretion. J Cell Sci 2018; 131:jcs211524. [PMID: 29420298 PMCID: PMC5897720 DOI: 10.1242/jcs.211524] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Accepted: 01/23/2018] [Indexed: 12/13/2022] Open
Abstract
Alternative models explaining the biliary lipid secretion at the canalicular membrane of hepatocytes exist: successive lipid extraction by preformed bile salt micelles, or budding of membrane fragments with formation of mixed micelles. To test the feasibility of the latter mechanism, we developed a mathematical model that describes the formation of lipid microdomains in the canalicular membrane. Bile salt monomers intercalate into the external hemileaflet of the canalicular membrane, to form a rim to liquid disordered domain patches that then pinch off to form nanometer-scale mixed micelles. Model simulations perfectly recapitulate the measured dependence of bile salt-dependent biliary lipid extraction rates upon modulation of the membrane cholesterol (lack or overexpression of the cholesterol transporter Abcg5-Abcg8) and phosphatidylcholine (lack of Mdr2, also known as Abcb4) content. The model reveals a strong dependence of the biliary secretion rate on the protein density of the membrane. Taken together, the proposed model is consistent with crucial experimental findings in the field and provides a consistent explanation of the central molecular processes involved in bile formation.
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Affiliation(s)
- Johannes Eckstein
- Charité - Universitätsmedizin Berlin, Institute of Biochemistry, Charitéplatz 1, 10117 Berlin, Germany
| | - Hermann-Georg Holzhütter
- Charité - Universitätsmedizin Berlin, Institute of Biochemistry, Charitéplatz 1, 10117 Berlin, Germany
| | - Nikolaus Berndt
- Charité - Universitätsmedizin Berlin, Institute of Biochemistry, Charitéplatz 1, 10117 Berlin, Germany
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Eckstein J, Berndt N, Holzhütter HG. Computer simulations suggest a key role of membranous nanodomains in biliary lipid secretion. PLoS Comput Biol 2015; 11:e1004033. [PMID: 25692493 PMCID: PMC4333117 DOI: 10.1371/journal.pcbi.1004033] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Accepted: 11/12/2014] [Indexed: 01/06/2023] Open
Abstract
The bile fluid contains various lipids that are secreted at the canalicular membrane of hepatocytes. As the secretion mechanism is still a matter of debate and a direct experimental observation of the secretion process is not possible so far, we used a mathematical model to simulate the extraction of the major bile lipids cholesterol, phosphatidylcholine and sphingomyelin from the outer leaflet of the canalicular membrane. Lipid diffusion was modeled as random movement on a triangular lattice governed by next-neighbor interaction energies. Phase separation in liquid-ordered and liquid-disordered domains was modeled by assigning two alternative ordering states to each lipid species and minimization of next-neighbor ordering energies. Parameterization of the model was performed such that experimentally determined diffusion rates and phases in ternary lipid mixtures of model membranes were correctly recapitulated. The model describes the spontaneous formation of nanodomains in the external leaflet of the canalicular membrane in a time window between 0.1 ms to 10 ms at varying lipid proportions. The extraction of lipid patches from the bile salt soluble nanodomain into the bile reproduced observed biliary phospholipid compositions for a physiologi-cal membrane composition. Comparing the outcome of model simulations with available experi-mental observations clearly favors the extraction of tiny membrane patches composed of about 100–400 lipids as the likely mechanism of biliary lipid secretion. Formation of the bile is one of the central functions of the liver. The bile fluid aids in the digestion of edible fats and removal of drugs and toxins from the body. The bile fluid is mainly composed of bile salts (BS), phosphatidylcholine (PC) and cholesterol (CH) in a fairly fixed proportion that prevents liver impairment by gallstone formation or cholestasis. During bile formation, BS are actively pumped out of the hepatocyte into the extracellular space where they extract PC and CH from the canalicular membrane. This extraction process bears the risk for the canalicular membrane to be destructed. Hence, only a certain fraction of the membrane should be accessible to the solubilizing activity of BS. We have developed a mathematical model that describes the temporal formation of CH-enriched ordered and PC-enriched disordered nanodomains in the canalicular membrane. Model simulations reveal that the disordered nanodomains exhibit a composition of PC and CH similar to that also found in the bile. From this finding and the good concordance of model simulations with experimental data we conclude that PC and CH are mainly secreted into the bile from the disordered nanodomain. Our work adds a new layer of physiological importance to the spontaneous formation of lipid domains in biological membranes.
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Affiliation(s)
- Johannes Eckstein
- Charité—University Medicine Berlin, Institute of Biochemistry, Berlin, Germany
| | - Nikolaus Berndt
- Charité—University Medicine Berlin, Institute of Biochemistry, Berlin, Germany
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Hismiogullari AA, Hismiogullari SE, Rahman K. Isolation and biochemical analysis of vesicles from taurohyodeoxycholic acid-infused isolated perfused rat livers. World J Gastroenterol 2013; 19:6228-6236. [PMID: 24115821 PMCID: PMC3787354 DOI: 10.3748/wjg.v19.i37.6228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2013] [Revised: 06/12/2013] [Accepted: 07/05/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To isolate biliary lipid-carrying vesicles from isolated perfused rat livers after taurohyodeoxycholic acid (THDC) infusion. Biliary lipid vesicles have been implicated in hepatic disease and THDC was used since it increases biliary phospholipid secretion.
METHODS: Rat livers were isolated and perfused via the hepatic portal vein with THDC dissolved in Krebs Ringer Bicarbonate solution, pH 7.4, containing 1 mmol/L CaCl2, 5 mmol/L glucose, a physiological amino acid mixture, 1% bovine serum albumin and 20% (v/v) washed human erythrocytes at a rate of 2000 nmol/min for 2 h. The livers were then removed, homogenized and subjected to centrifugation, and the microsomal fraction was obtained and further centrifuged at 350000 g for 90 min to obtain subcellular fractions. These were analyzed for total phospholipid, cholesterol, protein and alkaline phosphodiesterase I (PDE).
RESULTS: No significant changes were observed in the total phospholipid, cholesterol and protein contents of the gradient fractions obtained from the microsomal preparation. However, the majority of the gradient fractions (ρ= 1.05-1.07 g/mL and ρ = 1.95-1.23 g/mL) obtained from THDC-infused livers had significantly higher PDE activity compared to the control livers. The low density gradient fraction (ρ = 1.05-1.07 g/mL) which was envisaged to contain the putative vesicle population isolated from THDC-perfused livers had relatively small amounts of phospholipids and protein when compared to the relevant control fractions; however, they displayed an increase in cholesterol and PDE activity. The phospholipids were also isolated by thin layer chromatography and subjected to fractionation by high performance liquid chromatography; however, no differences were observed in the pattern of the fatty acid composition of the phospholipids isolated from THDC and control perfused livers. The density gradient fractions (ρ = 1.10-1.23 g/mL) displayed an increase in all the parameters measured from both control and THDC-infused livers.
CONCLUSION: No significant changes in biliary lipids were observed in the fractions from THDC-infused livers; however, PDE activity was significantly increased compared to the control livers.
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Kunne C, Acco A, Hohenester S, Duijst S, de Waart DR, Zamanbin A, Oude Elferink RPJ. Defective bile salt biosynthesis and hydroxylation in mice with reduced cytochrome P450 activity. Hepatology 2013. [PMID: 23184615 DOI: 10.1002/hep.26133] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
UNLABELLED The difference in bile salt (BS) composition between rodents and humans is mainly caused by formation of muricholate in rodents as well as by efficient rehydroxylation of deoxycholic acid. The aim of this study was to characterize bile formation in a mouse model (Hrn mice) with hepatic disruption of the cytochrome p450 (CYP) oxidoreductase gene, encoding the single electron donor for all CYPs. Bile formation was studied after acute BS infusion or after feeding a BS-supplemented diet for 3 weeks. Fecal BS excretion in Hrn mice was severely reduced to 7.6% ± 1.8% of wild-type (WT), confirming strong reduction of (CYP-mediated) BS synthesis. Hrn bile contained 48% ± 18% dihydroxy BS, whereas WT bile contained only 5% ± 1% dihydroxy BS. Upon tauroursodeoxycholate infusion, biliary BS output was equal in WT versus Hrn, indicating that canalicular secretion capacity was normal. In contrast, taurodeoxycholic acid (TDC) infusion led to markedly impaired bile flow and BS output, suggesting onset of cholestasis. Feeding a cholate-supplemented diet (0.1%) resulted in a completely restored bile salt pool in Hrn mice, with 50% ± 9% TDC and 42% ± 10% taurocholic acid in bile, as opposed to 2% ± 1% and 80% ± 3% in WT mice, respectively. Under these conditions, biliary cholesterol secretion was strongly increased in Hrn mice, whereas serum alanine aminotransferase levels were decreased. CONCLUSION Hrn mice have strongly impaired bile salt synthesis and (re)hydroxylation capacity and are more susceptible to acute TDC-induced cholestasis. In this mouse model, a more-human BS pool can be instilled by BS feeding, without hepatic damage, which makes Hrn mice an attractive model to study the effects of human BS.
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Affiliation(s)
- Cindy Kunne
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
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Yoon JH, Choi HS, Jun DW, Yoo KS, Lee J, Yang SY, Kuver R. ATP-binding cassette sterol transporters are differentially expressed in normal and diseased human gallbladder. Dig Dis Sci 2013. [PMID: 23179156 DOI: 10.1007/s10620-012-2481-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND AND AIMS Gallbladder epithelial cells (GBEC) are exposed to high cholesterol concentrations in bile, and export cholesterol via an ATP-binding cassette (ABC) transporter-mediated pathway in vitro. These findings suggest that aberrant expression and/or function of ABC sterol transporters may be associated with cholesterol-related gallbladder diseases (CAGD). In this study, we investigated the relative levels of the sterol transporters ABCA1, ABCG5, and ABCG8 in human gallbladders in CAGD, and the relationship between ABCA1 and inflammation. METHODS Expression of ABCA1, ABCG5, and ABCG8 was evaluated in 31 gallbladders with CAGD and 6 normal gallbladders by western blotting and immunohistochemistry. RT-PCR was used to measure ABCA1 mRNA expression. To investigate the relationship between ABCA1 and inflammation, wWestern blots were performed on cultured dog GBEC treated with lipopolysaccharide (LPS) using an anti-ABCA1 antibody. RESULTS Immunohistochemistry showed ABCA1 to be localized predominantly to the basolateral membrane, while ABCG8 formed a diffuse intracellular pattern at the apical pole of human GBEC. ABCA1 and ABCG8 expression was more prominent in GBEC that were surrounded by cholesterol-laden macrophages. ABCA1 and ABCG8 expression was increased in gallbladders with CAGD. Western blots showed increased ABCA1, ABCG5, and ABCG8 expression in CAGD. ABCA1 mRNA levels were increased in all gallbladders with CAGD. LPS treatment of cultured dog GBEC enhanced ABCA1 expression. CONCLUSIONS The sterol transporters ABCA1, ABCG5, and ABCG8 may play a role in the pathogenesis of human CAGD. Inflammation appears to be a key factor that increases ABCA1 expression and activity in the human gallbladder.
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Affiliation(s)
- Jai Hoon Yoon
- Department of Internal Medicine, Hallym University College of Medicine, Chucheon, Korea
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Wang J, Jiang Z, Ji J, Li Y, Chen M, Wang Y, Zhang Y, Tai T, Wang T, Zhang L. Evaluation of hepatotoxicity and cholestasis in rats treated with EtOH extract of Fructus Psoraleae. JOURNAL OF ETHNOPHARMACOLOGY 2012; 144:73-81. [PMID: 22954498 DOI: 10.1016/j.jep.2012.08.028] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2012] [Revised: 07/21/2012] [Accepted: 08/16/2012] [Indexed: 06/01/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Fructus Psoraleae (FP) has been widely used to heal skin diseases as well as osteoporosis, osteomalacia, and bone fracture. There also exist many clinical reports about FP-induced hepatotoxicity associated with acute cholestatic hepatic injury. However, the FP-induced hepatotoxicity and the underlying mechanisms remain unclear. AIMS OF THE STUDY The present study aims to determine the hepatotoxicity of FP in Sprague-Dawley (SD) rats and to investigate the underlying mechanisms. MATERIALS AND METHODS Sprague-Dawley rats of both sexes were intragastrically administered with the EtOH extract of FP (EEFP) at doses of 1.875, 1.25 and 0.625 g/kg for 28 day. Body weight, relative liver weight, biochemical analysis, histopathology, the mRNA and protein expression of Cholesterol 7α-hydroxylase (CYP7A1), farnesoid X receptor (FXR), bile-salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), multidrug resistance-associated protein 3 (MRP3) were evaluated to study the EEFP-induced hepatotoxicity and its underlying mechanisms. RESULTS Many abnormalities were observed in the EEFP-treated groups including suppression of weight gain and food intake, change of some parameters in serum biochemistry, increased weight of liver, and decreased concentration of bile acid in bile. The mRNA and protein expression of CYP7A1, MRP3, MRP2, BSEP increased and the expression of FXR decreased in EEFP-treated female groups; the mRNA and protein of FXR and CYP7A1 decreased and that of the others remained the same in EEFP-treated male groups. CONCLUSION In conclusion, we provide evidence for the first time that EEFP can induce sex-related cholestatic hepatotoxicity, and that female rats are more sensitive to EEFP-induced hepatotoxicity, which involves the destruction of the biosynthesis and transportation of bile acid. Further investigation is still needed to uncover the mechanism of the sex-dimorphic EEFP-induced hepatotoxicity.
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Affiliation(s)
- Jiaying Wang
- Jiangsu Provincial Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
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Abstract
Mammalian physiological processes, and likely any organism with a biliary tree, can distinguish between dietary cholesterol and non-cholesterols, retaining very little of the non-cholesterol in their bodies. Historically, the distinction between plant sterols and cholesterol has been known about for a century or more. That plants sterols were not 'absorbed' has been investigated for almost half a century. Indeed, the oral of plant sterols in gram quantities was shown to interfere with cholesterol absorption and is one of the oldest pharmacological therapies for hypercholesterolemia. Although the basis for the latter was shown to be caused by exclusion of cholesterol from intestinal micelles by plant sterols, it was not until the identification of the a rare genetic disease, sitosterolemia, first described in 1974, that led to the hypothesis that specific molecular mechanism(s) governed both the entry and excretion of sterols by the body. This talk will cover the physiology of dietary sterol metabolism, genetics and pathophysiology of sitosterolemia. Additionally, the role of plant sterols in normal and abnormal metabolism in humans as well as selected animal models will be discussed.
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Affiliation(s)
- Shailendra B Patel
- Division of Endocrinology, Metabolism and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, WI
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30
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Abstract
Bile salts, cholesterol and phosphatidylcholine are secreted across the canalicular membrane of hepatocytes into bile by ATP-binding cassette (ABC) transporters. Secretion of bile salts by ABCB11 is essential for bile flow and for absorption of lipids and fat-soluble vitamins. ABCG5 and ABCG8 eliminate excess cholesterol and sterols from the body by secreting them into bile. There are two mechanisms to protect the canalicular membrane from solubilization by bile salts; ABCB4 secretes phosphatidylcholine into bile to form mixed micelles with bile salts, and ATP8B1 maintains the canalicular membrane in a liquid-ordered state. Three different forms of progressive familial intrahepatic cholestasis (PFIC) disorders, PFIC1, PFIC2 and PFIC3, are caused by mutations in ATP8B1, ABCB11 and ABCB4, respectively. Sitosterolemia is caused by mutations in ABCG5 and ABCG8. This article reviews the physiological roles of these canalicular transporters, and the pathophysiological processes and clinical features associated with their mutations.
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Affiliation(s)
- Jeannie Chan
- Southwest National Primate Research Center & Department of Genetics, Texas Biomedical Research Institute, PO Box 760549, San Antonio, TX, USA
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The chylomicron: relationship to atherosclerosis. Int J Vasc Med 2011; 2012:784536. [PMID: 22007304 PMCID: PMC3189596 DOI: 10.1155/2012/784536] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2011] [Accepted: 08/08/2011] [Indexed: 12/20/2022] Open
Abstract
The B-containing lipoproteins are the transporters of cholesterol, and the evidence suggests that the apo B48-containing postprandial chylomicron particles and the triglyceride-rich very low density lipoprotein (VLDL) particles play an important part in the development of the plaque both directly and indirectly by their impact on LDL composition. The ratio of dietary to synthesised cholesterol is variable but tightly regulated: hence intervention with diet at best reduces serum cholesterol by <20% andusually <10%. Statins are the mainstay of cholesterol reduction therapy, but they increase cholesterol absorption, an example of the relationship between synthesis and absorption. Inhibition of cholesterol absorption with Ezetimibe, an inhibitor of Niemann Pick C1-like 1 (NPC1-L1), the major regulator of cholesterol absorption, increases cholesterol synthesis and hence the value of adding an inhibitor of cholesterol absorption to an inhibitor of cholesterol synthesis. Apo B48, the structural protein of the chylomicron particle, is synthesised in abundance so that the release of these particles is dependent on the amount of cholesterol and triglyceride available in the intestine. This paper will discuss cholesterol absorption and synthesis, chylomicron formation, and the effect of postprandial lipoproteins on factors involved in atherosclerosis.
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Kolouchova G, Brcakova E, Hirsova P, Sispera L, Tomsik P, Cermanova J, Hyspler R, Slanarova M, Fuksa L, Lotkova H, Micuda S. Pravastatin modulates liver bile acid and cholesterol homeostasis in rats with chronic cholestasis. J Gastroenterol Hepatol 2011; 26:1544-51. [PMID: 21501227 DOI: 10.1111/j.1440-1746.2011.06748.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM The administration of pravastatin to patients with cholestatic liver disease has suggested the potential of the drug with regard to reducing raised plasma cholesterol and bile acid levels. Information about the mechanisms associated with this effect is lacking. Thus, the aim of the present study is to evaluate pravastatin effects on the liver bile acid and cholesterol homeostasis in healthy and cholestatic rats. METHODS Control sham-operated and reversibly bile duct-obstructed (BDO) rats were treated with pravastatin (1 or 5 mg/kg) or the vehicle alone for 7 days after surgery. RESULTS Lower doses of pravastatin reduced bile acid plasma concentrations in cholestatic animals. The effect was associated with reduced liver mRNA expression of Cyp7a1, Cyp8b1, Mrp2, Ugt1a1 and the increased expression of Bsep. In addition, BDO-induced increase in the liver content of cholesterol was normalized by pravastatin. The change was accompanied by the reduced liver expression of Hmg-CoA reductase, LDL receptor, and Acat2, and induced the expression of Abca1 and Mdr2. These changes corresponded with the upregulation of nuclear receptors LXRα and PPARα, and the downregulation of FXR, CAR, SREBP-2 and HNF1α. High doses of pravastatin lacked any positive effects on bile acids and cholesterol homeostasis, and blocked bile formation through the reduction of the biliary excretion of bile acids. CONCLUSIONS Pravastatin rendered a positive reduction in BDO-induced increases in plasma bile acid concentrations and cholesterol liver content, mainly through the transcriptionally-mediated downregulation of genes involved in the synthesis of these compounds in the liver.
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Tomkin GH. Dyslipidaemia--hepatic and intestinal cross-talk. ATHEROSCLEROSIS SUPP 2011; 11:5-9. [PMID: 20434963 DOI: 10.1016/j.atherosclerosissup.2010.03.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2010] [Accepted: 03/25/2010] [Indexed: 01/22/2023]
Abstract
Cholesterol metabolism is tightly regulated with the majority of de novo cholesterol synthesis occurring in the liver and intestine. 3 Hydroxy-3-methylglutaryl coenzyme A reductase, a major enzyme involved in cholesterol synthesis, is raised in both liver and intestine in diabetic animals. Niemann PickC1-like1 protein regulates cholesterol absorption in the intestine and facilitates cholesterol transport through the liver. There is evidence to suggest that the effect of inhibition of Niemann PickC1-like1 lowers cholesterol through its effect not only in the intestine but also in the liver. ATP binding cassette proteins G5/G8 regulate cholesterol re-excretion in the intestine and in the liver, cholesterol excretion into the bile. Diabetes is associated with reduced ATP binding cassette protein G5/G8 expression in both the liver and intestine in animal models. Microsomal triglyceride transfer protein is central to the formation of the chylomicron in the intestine and VLDL in the liver. Microsomal triglyceride transfer protein mRNA is increased in diabetes in both the intestine and liver. Cross-talk between the intestine and liver is poorly documented in humans due to the difficulty in obtaining liver biopsies but animal studies are fairly consistent in showing relationships that explain in part mechanisms involved in cholesterol homeostasis.
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Affiliation(s)
- Gerald H Tomkin
- Trinity College Dublin and Diabetes Institute of Ireland, Beacon Hospital, Sandyford, Clontra, Quinns Road, Shankill Co, Dublin, Ireland. ,
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Steck TL, Lange Y. Cell cholesterol homeostasis: mediation by active cholesterol. Trends Cell Biol 2010; 20:680-7. [PMID: 20843692 DOI: 10.1016/j.tcb.2010.08.007] [Citation(s) in RCA: 98] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2010] [Revised: 08/03/2010] [Accepted: 08/12/2010] [Indexed: 12/15/2022]
Abstract
Recent evidence suggests that the major pathways mediating cell cholesterol homeostasis respond to a common signal: active membrane cholesterol. Active cholesterol is the fraction that exceeds the complexing capacity of the polar bilayer lipids. Increments in plasma membrane cholesterol exceeding this threshold have an elevated chemical activity (escape tendency) and redistribute via diverse transport proteins to both circulating plasma lipoproteins and intracellular organelles. Active cholesterol thereby prompts several feedback responses. It is the substrate for its own esterification and for the synthesis of regulatory side-chain oxysterols. It also stimulates manifold pathways that down-regulate the biosynthesis, curtail the ingestion and increase the export of cholesterol. Thus, the abundance of cell cholesterol is tightly coupled to that of its polar lipid partners through active cholesterol.
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Affiliation(s)
- Theodore L Steck
- Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA.
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Paulusma CC, de Waart DR, Kunne C, Mok KS, Elferink RPJO. Activity of the bile salt export pump (ABCB11) is critically dependent on canalicular membrane cholesterol content. J Biol Chem 2009; 284:9947-54. [PMID: 19228692 DOI: 10.1074/jbc.m808667200] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Mutations in ATP8B1 cause severe inherited liver disease. The disease is characterized by impaired biliary bile salt excretion (cholestasis), but the mechanism whereby impaired ATP8B1 function results in cholestasis is poorly understood. ATP8B1 is a type 4 P-type ATPase and is a flippase for phosphatidylserine. Atp8b1-deficient mice display a dramatic increase in the biliary extraction of cholesterol from the canalicular (apical) membrane of the hepatocyte. Here we studied the hypothesis that disproportionate cholesterol extraction from the canalicular membrane impairs the activity of the bile salt transporter, ABCB11, and as a consequence causes cholestasis. Using single pass liver perfusions, we show that not only ABCB11-mediated transport but also Abcc2-mediated transport were reduced at least 4-fold in Atp8b1 deficiency. We show that canalicular membranes of cholestatic Atp8b1-deficient mice have a dramatically reduced cholesterol to phospholipid ratio, i.e. 0.75 +/- 0.24 versus 2.03 +/- 0.71 for wild type. In vitro depletion of cholesterol from mouse liver plasma membranes using methyl-beta-cyclodextrin demonstrated a near linear relation between cholesterol content of the membranes and ATP-dependent taurocholate transport. Abcc2-mediated transport activity was not affected up to 30% of membrane cholesterol depletion but declined to negligible levels at 70% of membrane cholesterol depletion. These effects were reversible as cholesterol repletion of the liver membranes completely restored Abcb11- and Abcc2-mediated transport. Our data demonstrate that membrane cholesterol content is a critical determinant of ABCB11/ABCC2 transport activity, provide an explanation for the etiology of ATP8B1 disease, and suggest a novel mechanism protecting the canalicular membrane against luminal bile salt overload.
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Affiliation(s)
- Coen C Paulusma
- AMC Liver Center, Academic Medical Center, Meibergdreef 69-71, 1105 BK, Amsterdam, The Netherlands.
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Abstract
PURPOSE OF REVIEW Hyperglycaemia and dyslipidaemia are closely linked, yet, there has been difficulty in demonstrating that lowering blood sugar reduces cardiovascular events. The pathways linking abnormalities in fatty acid metabolism, insulin resistance and diabetes with abnormalities in cholesterol metabolism are being rapidly unravelled with new understandings of the effect of antidiabetic drugs on lipoprotein metabolism. The purpose of this review is to explore the recent literature. RECENT FINDINGS Postprandial lipoproteins are now firmly established as a postprandial risk factor. Both insulin resistance and diabetes are associated with abnormalities in chylomicron production, and clearance and regulatory genes have been identified. Metformin, the most commonly used drug in type 2 diabetes, has multiple actions affecting numerous genes. The peroxisome proliferator-activated receptor-gamma regulation of insulin sensitivity and the important effects on lipoproteins are described. The entero-insulin axis and glucagon-like peptide-1 agonists, together with inhibitors of dipeptidyl peptidase 4 may have lipoprotein implications, but the evidence at present is sparse even though glucagon-like peptide-1 is found in high concentrations in the lymph. SUMMARY Although antidiabetic drugs affect lipid metabolism, there is little evidence to suggest that these drugs can prevent atherosclerosis in diabetes and some may promote atherosclerosis through their adverse effect on lipoproteins.
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Affiliation(s)
- Gerald H Tomkin
- Diabetes Institute of Ireland, Beacon Hospital, Dublin, Ireland.
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Kidambi S, Patel SB. Cholesterol and non-cholesterol sterol transporters: ABCG5, ABCG8 and NPC1L1: a review. Xenobiotica 2008; 38:1119-39. [PMID: 18668442 DOI: 10.1080/00498250802007930] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
1. Whole-body sterol (cholesterol and xenosterol) balance is delicately regulated by the gastrointestinal tract and liver, which control sterol absorption and excretion, respectively, in addition to the contribution to the cholesterol pool by whole-body cholesterol synthesis. In the past ten years enormous strides have been made not only in establishing that specific transporters mediate the entry and exit of sterols and how these may regulate selective sterol access to the body pools, but also in how these pathways operate to integrate these physiological pathways. 2. The entry of sterols from the gastrointestinal and biliary canalicular lumen into the body is mediated by NPC1L1, which was discovered by a novel method, via a genomics-bioinformatics approach. 3. Identification of the genetic basis responsible for causing sitosterolaemia, characterized by plant sterol accumulation, led to the identification of two half-transporters (ABCG5 and ABCG8) that normally efflux plant sterols (and cholesterol) into the intestinal and biliary lumen for faecal excretion. 4. The objective of this review is to provide up-to-date knowledge on genomics, proteomics and function of these two transporter systems.
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Affiliation(s)
- S Kidambi
- Division of Endocrinology, Metabolism and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
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Kuo KK, Shin SJ, Chen ZC, Yang YHC, Yang JF, Hsiao PJ. Significant association of ABCG5 604Q and ABCG8 D19H polymorphisms with gallstone disease. Br J Surg 2008; 95:1005-11. [PMID: 18457353 DOI: 10.1002/bjs.6178] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND Adenosine triphosphate-binding cassette (ABC) transporters ABCG5 and ABCG8 are sterol export pumps regulating biliary cholesterol excretion. The formation of gallstones, supersaturated with cholesterol in bile, is determined by genetic and environmental factors. The interaction of susceptible gene polymorphisms with age, sex and body mass index in gallstone disease is unclear. METHODS In a cross-sectional study, 979 subjects (880 men and 99 women, mean(s.d.) age 47.7(10.4) years) were recruited from a hospital-based population. Of these, 74 were diagnosed with gallstone disease by abdominal ultrasonography. Five non-synonymous polymorphisms, E604Q (ABCG5), D19H, C54Y, T400K and A632V (ABCG8), were analysed using the TaqMan genotyping assay. RESULTS The serum total cholesterol and both low- and high-density lipoprotein cholesterol levels were significantly lower in subjects with gallstones than in those without. 604Q (CC) and D19H (GC) genotypes were significantly associated with gallstone disease, even when adjusted for age, sex and body mass index. The genetic risk of developing gallstone disease was further stratified by age. The risk was greatly increased in subjects younger than 50 years with the D19H genotype and those of 50 years or more with the 604Q genotype. CONCLUSION Carriers of ABCG5 604Q or ABCG8 D19H polymorphisms have an increased risk of gallstone disease independent of age, sex and body mass index.
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Affiliation(s)
- K-K Kuo
- Division of Hepatobiliopancreatic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Taiwan
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The intestine as a regulator of cholesterol homeostasis in diabetes. ATHEROSCLEROSIS SUPP 2008; 9:27-32. [PMID: 18693145 DOI: 10.1016/j.atherosclerosissup.2008.05.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2008] [Revised: 02/27/2008] [Accepted: 05/13/2008] [Indexed: 11/24/2022]
Abstract
The chylomicron influences very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) composition but itself is atherogenic. Thus abnormalities of chylomicron production are of interest particularly in conditions such as diabetes which confer major cardiovascular risk. Intestinal function is abnormal in diabetes and is a major cause of the dyslipidaemia found in this condition. Studies have suggested that cholesterol absorption is decreased in diabetes and cholesterol synthesis increased. Molecular mechanisms involved in insulin resistance in the intestine and its effect on cholesterol homeostasis in diabetes are described. Abnormalities in triglyceride synthesis and alterations genes regulating cholesterol absorption and intestinal synthesis are discussed. In particular, increase in apolipoprotein B48 synthesis has been demonstrated in animal models of diabetes and insulin resistance. Intestinal mRNA expression of Niemann Pick C1-like 1, protein is increased in both experimental and human diabetes suggesting that an increase in cholesterol transportation does occur. mRNA expression of the ATP binding cassette proteins (ABC) G5 and G8, two proteins working in tandem to excrete cholesterol have been shown to be decreased suggesting increased delivery of cholesterol for absorption. Expression of microsomal triglyceride transfer protein, which assembles the chylomicron particle, is increased in diabetes leading to increase in both number and cholesterol content. In conclusion, diabetes is associated with considerable dysfunction of the intestine leading to abnormal chylomicron composition which may play a major part in the premature development of atherosclerosis.
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Groen A, Kunne C, Jongsma G, van den Oever K, Mok KS, Petruzzelli M, Vrins CLJ, Bull L, Paulusma CC, Oude Elferink RPJ. Abcg5/8 independent biliary cholesterol excretion in Atp8b1-deficient mice. Gastroenterology 2008; 134:2091-100. [PMID: 18466903 DOI: 10.1053/j.gastro.2008.02.097] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2007] [Revised: 02/22/2008] [Accepted: 02/29/2008] [Indexed: 12/24/2022]
Abstract
BACKGROUNDS & AIMS ATP8B1 is a phosphatidylserine flippase in the canalicular membrane; patients with mutations in ATP8B1 develop severe chronic (PFIC1) or periodic (BRIC1) cholestatic liver disease. We have observed that Atp8b1 deficiency leads to enhanced biliary cholesterol excretion. It has been established that biliary cholesterol excretion depends on transport by the heterodimer Abcg5/Abcg8. We hypothesized that the increased cholesterol output was due to enhanced extraction from the altered canalicular membrane rather than to higher Abcg5/Abcg8 activity. We therefore studied the relation between Abcg5/Abcg8 expression and biliary cholesterol excretion in mice lacking Atp8b1, Abcg8, or both (GF mice). METHODS Bile formation was studied in LXR agonist-fed wild-type mice as well as mice lacking Atp8b1 or Abcg8, or in GF mice upon infusion of taurocholate. Bile samples were analyzed for cholesterol, bile salt, phospholipids, and ectoenzyme content. RESULTS LXR agonist increased Abcg5/8 expression, and this was accompanied by increased biliary cholesterol output in both wild-type and Atp8b1(G308V/G308V) mice. However, Atp8b1(G308V/G308V) mice maintained higher cholesterol output. Although in Abcg8(-/-) mice biliary cholesterol output was severely reduced, GF mice displayed high biliary cholesterol output, which was comparable with wild-type mice. Bile of both Atp8b1(G308V/G308V) and GF mice displayed elevated levels of phosphatidylserine and sphingomyelin, indicating membrane stress. CONCLUSIONS Our data demonstrate that the increased biliary cholesterol excretion in Atp8b1-deficient mice is independent of Abcg5/8 activity. This implicates that Atp8b1 deficiency leads to a decrease in the detergent resistance and subsequent nonspecific extraction of cholesterol from the canalicular membrane by bile salts.
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Affiliation(s)
- Annemiek Groen
- AMC Liver Center, Academic Medical Center, Amsterdam, The Netherlands
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Lee J, Scheri RC, Curtis LR. Chlordecone altered hepatic disposition of [14C]cholesterol and plasma cholesterol distribution but not SR-BI or ABCG8 proteins in livers of C57BL/6 mice. Toxicol Appl Pharmacol 2008; 229:265-72. [PMID: 18387646 DOI: 10.1016/j.taap.2008.01.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2007] [Revised: 12/21/2007] [Accepted: 01/18/2008] [Indexed: 10/22/2022]
Abstract
Organochlorine (OC) insecticides continue to occur in tissues of humans and wildlife throughout the world although they were banned in the United States a few decades ago. Low doses of the OC insecticide chlordecone (CD) alter hepatic disposition of lipophilic xenobiotics and perturb lipid homeostasis in rainbow trout, mice and rats. CD pretreatment altered tissue and hepatic subcellular distribution of exogenous [(14)C]cholesterol (CH) equivalents 4 and 16 h after a bolus intraperitoneal (ip) injection of 5 ml corn oil/kg that contained 10 mg CH/kg. CD pretreatment altered tissue distribution of exogenously administered [(14)C]CH by decreased hepatic and renal accumulation, and increased biliary excretion up to 300%. Biliary excretion of polar [(14)C]CH metabolites was not altered by CD. CD pretreatment decreased subcellular distribution of [(14)C]CH equivalents in hepatic cytosol and microsomes and lipoprotein-rich fraction-to-homogenate ratio. CD pretreatment increased the ratio of [(14)C]CH equivalents in high density lipoprotein (HDL) to that in plasma and reduced [(14)C]CH equivalents in the non-HDL fraction 4 h after a bolus lipid dose. CD pretreatment increased plasma non-HDL total CH by 80% 4 h after a bolus lipid dose. Scavenger receptor class B type I (SR-BI) and ATP-binding cassette transporter G8 (ABCG8) proteins were quantified by western blotting in hepatic membranes from control and CD treated mice. Liver membrane contents of SR-BI and ABCG8 proteins were unchanged by CD pretreatment. The data demonstrated that a single dose of CD altered CH homeostasis and lipoprotein metabolism.
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Affiliation(s)
- Junga Lee
- Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA
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Vrins C, Vink E, Vandenberghe KE, Frijters R, Seppen J, Groen AK. The sterol transporting heterodimer ABCG5/ABCG8 requires bile salts to mediate cholesterol efflux. FEBS Lett 2007; 581:4616-20. [PMID: 17825296 DOI: 10.1016/j.febslet.2007.08.052] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2007] [Revised: 08/24/2007] [Accepted: 08/24/2007] [Indexed: 11/16/2022]
Abstract
The ATP binding cassette transporters ABCG5 and ABCG8 are indispensable for hepatobiliary cholesterol transport. In this study, we investigated the specificity of the heterodimer for cholesterol acceptors. Dog gallbladder epithelial cells were mono- or double-transfected with lentiviral mouse Abcg5 and Abcg8 vectors. Double-transfected cells showed increased efflux to different bile salt (BS) species, while mono-transfected cells did not show enhanced efflux. The efflux was initiated at micellar concentrations and addition of phosphatidylcholine increased efflux. Cholesterol secretion was highly BS dependent, whereas other cholesterol acceptors such as ApoAI, HDL or methyl-beta-cyclodextrin did not elicit Abcg5/g8 dependent cholesterol secretion.
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Affiliation(s)
- Carlos Vrins
- Academic Medical Center, Department of Medical Biochemistry, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
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Orlowski S, Coméra C, Tercé F, Collet X. Lipid rafts: dream or reality for cholesterol transporters? EUROPEAN BIOPHYSICS JOURNAL: EBJ 2007; 36:869-85. [PMID: 17576551 DOI: 10.1007/s00249-007-0193-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2007] [Revised: 05/11/2007] [Accepted: 05/15/2007] [Indexed: 01/12/2023]
Abstract
As a key constituent of the cell membranes, cholesterol is an endogenous component of mammalian cells of primary importance, and is thus subjected to highly regulated homeostasis at the cellular level as well as at the level of the whole body. This regulation requires adapted mechanisms favoring the handling of cholesterol in aqueous compartments, as well as its transfer into or out of membranes, involving membrane proteins. A membrane exhibits functional properties largely depending on its lipid composition and on its structural organization, which very often involves cholesterol-rich microdomains. Then there is the appealing possibility that cholesterol may regulate its own transmembrane transport at a purely functional level, independently of any transcriptional regulation based on cholesterol-sensitive nuclear factors controling the expression level of lipid transport proteins. Indeed, the main cholesterol "transporters" presently believed to mediate for instance the intestinal absorption of cholesterol, that are SR-BI, NPC1L1, ABCA1, ABCG1, ABCG5/G8 and even P-glycoprotein, all present privileged functional relationships with membrane cholesterol-containing microdomains. In particular, they all more or less clearly induce membrane disorganization, supposed to facilitate cholesterol exchanges with the close aqueous medium. The actual lipid substrates handled by these transporters are not yet unambiguously determined, but they likely concern the components of membrane microdomains. Conversely, raft alterations may provide specific modulations of the transporter activities, as well as they can induce indirect effects via local perturbations of the membrane. Finally, these cholesterol transporters undergo regulated intracellular trafficking, with presumably some relationships to rafts which remain to be clarified.
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Affiliation(s)
- Stéphane Orlowski
- SB2SM/IBTS and URA 2096 CNRS, CEA, Centre de Saclay, 91191, Gif-sur-Yvette cedex, France.
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Abstract
A hallmark of atherosclerotic cardiovascular disease (CVD) is the accumulation of cholesterol in arterial macrophages. Factors that modulate circulating and tissue cholesterol levels have major impacts on initiation, progression, and regression of CVD. Four members of the ATP-binding cassette (ABC) transporter family play important roles in this modulation. ABCA1 and ABCG1 export excess cellular cholesterol into the HDL pathway and reduce cholesterol accumulation in macrophages. ABCG5 and ABCG8 form heterodimers that limit absorption of dietary sterols in the intestine and promote cholesterol elimination from the body through hepatobiliary secretion. All 4 transporters are induced by the same sterol-sensing nuclear receptor system. ABCA1 expression and activity are also highly regulated posttranscriptionally by diverse processes. ABCA1 mutations can cause a severe HDL-deficiency syndrome characterized by cholesterol deposition in tissue macrophages and prevalent atherosclerosis. ABCG5 or ABCG8 mutations can cause sitosterolemia, in which patients accumulate cholesterol and plant sterols in the circulation and develop premature CVD. Disrupting Abca1 or Abcg1 in mice promotes accumulation of excess cholesterol in macrophages, and manipulating mouse macrophage ABCA1 expression affects atherogenesis. Overexpressing ABCG5 and ABCG8 in mice attenuates diet-induced atherosclerosis in association with reduced circulating and liver cholesterol. Metabolites elevated in individuals with the metabolic syndrome and diabetes destabilize ABCA1 protein and inhibit transcription of all 4 transporters. Thus, impaired ABC cholesterol transporters might contribute to the enhanced atherogenesis associated with common inflammatory and metabolic disorders. Their beneficial effects on cholesterol homeostasis have made these transporters important new therapeutic targets for preventing and reversing CVD.
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Affiliation(s)
- John F Oram
- Department of Medicine, Box 356426, University of Washington, Seattle, WA 98195-6426, USA.
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Burnett JR, Huff MW. Cholesterol absorption inhibitors as a therapeutic option for hypercholesterolaemia. Expert Opin Investig Drugs 2006; 15:1337-51. [PMID: 17040195 DOI: 10.1517/13543784.15.11.1337] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The development of cholesterol-lowering drugs (including a variety of statins, bile acid-binding resins and recently discovered inhibitors of cholesterol absorption) has expanded the options for cardiovascular prevention. Recent treatment guidelines emphasise that individuals at substantial risk for atherosclerotic coronary heart disease should meet defined targets for LDL cholesterol concentrations. Combination therapy with drugs that have different or complementary mechanisms of action is often needed to achieve lipid goals. Existing approaches to the treatment of hypercholesterolaemia are still ineffective in halting the progression of coronary artery disease in some patients despite combination therapies. Other patients are resistant to conventional drug treatment and remain at high risk for the development and progression of atherosclerotic cardiovascular disease and alternative approaches are needed. The discovery and development of ezetimibe (a novel, selective and potent cholesterol absorption inhibitor) has advanced the treatment of hypercholesterolaemia. New agents including the phytostanol preparation FM-VP4 and inhibitors of acyl coenzyme A:cholesterol acyltransferase, the apical Na(+)-dependent bile acid transporter and microsomal triglyceride transfer protein may also play a future role in combination therapy. This review focuses on the recent progress in the molecular mechanisms of intestinal cholesterol absorption and transport, and novel therapeutic approaches to inhibit the cholesterol absorption process.
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Affiliation(s)
- John R Burnett
- Royal Perth Hospital, Department of Core Clinical Pathology & Biochemistry, PathWest Laboratory Medicine WA, Wellington Street Campus, GPO Box X2213, Perth, WA 6847, Australia.
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Abstract
Drug-induced liver injury is an important clinical problem with significant morbidity and mortality. Whereas for most hepatocellular forms of drug-induced hepatic injury the underlying pathophysiological mechanism is poorly understood, there is increasing evidence that cholestatic forms of drug-induced liver damage result from a drug- or metabolite-mediated inhibition of hepatobiliary transporter systems. In addition to their key role in determining hepatic drug exposure and clearance, the coordinated action of these transport systems is essential for bile formation and the biliary secretion of cholephilic compounds and xenobiotics. Any drug-mediated functional disturbance of these processes can lead to an intracellular accumulation of potentially harmful bile constituents and result in the development of cholestatic liver cell damage. In addition to direct drug-mediated inhibition of hepatocellular transport, function of these transporters can be altered by pre-existing hepatic disease and genetic factors, which contribute to the development of drug-induced cholestasis in susceptible individuals. This review summarizes current knowledge about the function of hepatobiliary uptake and efflux systems and discusses factors that might predispose to drug-induced cholestasis.
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Affiliation(s)
- Christiane Pauli-Magnus
- Division of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland.
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