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Männistö VT, Kaminska D, Haal S, Asteljoki J, Luukkonen PK, Käkelä P, Tavaglione F, van Weeghel M, Neuvonen M, Niemi M, Romeo S, Nieuwdorp M, Pihlajamäki J, Groen AK. Protein Phosphatase 1 Regulatory Subunit 3 Beta rs4240624 Genotype Is Associated With Gallstones and With Significant Changes in Bile Lipidome. GASTRO HEP ADVANCES 2024; 3:594-601. [PMID: 39165418 PMCID: PMC11330930 DOI: 10.1016/j.gastha.2024.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 03/07/2024] [Indexed: 08/22/2024]
Abstract
Background and Aims Gallstone disease (GSD) associates with significant morbidity and mortality. Decreased secretion of bile acids has been suggested as a driving factor for GSD. Recently, we linked the protein phosphatase 1 regulatory subunit 3 beta (PPP1R3B) rs4240624 genotype to decreased bile acid levels in bile. In this study, we investigated whether these individuals had an increased risk for GSD as well as the differences in the lipid composition of the gallbladder bile of these individuals compared to controls and patients with GSD. Methods Bile acids, cholesterol, and phospholipid levels in gallbladder bile samples were enzymatically measured in 46 patients (34 female, age 45.7 ± 9.8 years, BMI 41.3 ± 4.4 kg/m2) who underwent elective laparoscopic Roux-en-Y gastric bypass. The lipidome of gallbladder bile was analyzed using high-performance liquid chromatography-mass spectrometry. Gallstone status was evaluated using abdominal ultrasonography before the surgery. Results The G allele of PPP1R3B rs4240624 was significantly associated with GSD in patients with obesity. We validated this association in the UK Biobank. Bile lipidomics demonstrated that 13 of the 17 minor lipid classes measured were higher in individuals with the G allele. The concentrations of bile acids, cholesterol, and phospholipids, as well as the cholesterol saturation index, were lower in patients with GSD than in those without gallstones. GSD had an effect similar to that of PPP1R3B genotype on minor lipids. Conclusion The PPP1R3B rs4240624 genotype is associated with gallstones and with changes in gallbladder bile similar to those observed in patients with gallstones, suggesting that the PPP1R3B genotype contributes to the risk of gallstones by altering the bile lipidome.
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Affiliation(s)
- Ville T. Männistö
- Departments of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
- Department of Experimental Vascular Medicine, Amsterdam UMC, Location AMC at University of Amsterdam, Amsterdam, The Netherlands
| | - Dorota Kaminska
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Finland
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Sylke Haal
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
- Department of Internal Medicine, Spaarne Gasthuis, Hoofddorp, The Netherlands
| | - Juho Asteljoki
- Department of Internal Medicine, University of Helsinki, Helsinki, Finland
- Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Panu K. Luukkonen
- Department of Internal Medicine, University of Helsinki, Helsinki, Finland
- Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Pirjo Käkelä
- Department of Surgery, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| | - Federica Tavaglione
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
- Department of Medicine and Surgery, Research Unit of Clinical Medicine and Hepatology, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Michel van Weeghel
- Laboratory of Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands
- Core Facility Metabolomics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Mikko Neuvonen
- Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland
- Faculty of Medicine, Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland
| | - Mikko Niemi
- Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland
- Faculty of Medicine, Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland
- Department of Clinical Pharmacology, HUS Diagnostic Services, Helsinki University Hospital, Helsinki, Finland
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
- Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden
- Department of Medical and Surgical Sciences, Clinical Nutrition Unit, University Magna Graecia, Catanzaro, Italy
| | - Max Nieuwdorp
- Department of Experimental Vascular Medicine, Amsterdam UMC, Location AMC at University of Amsterdam, Amsterdam, The Netherlands
| | - Jussi Pihlajamäki
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Finland
- Department of Medicine, Endocrinology, and Clinical Nutrition, Kuopio University Hospital, Kuopio, Finland
| | - Albert K. Groen
- Department of Experimental Vascular Medicine, Amsterdam UMC, Location AMC at University of Amsterdam, Amsterdam, The Netherlands
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Eiamkulbutr S, Tubjareon C, Sanpavat A, Phewplung T, Srisan N, Sintusek P. Diseases of bile duct in children. World J Gastroenterol 2024; 30:1043-1072. [PMID: 38577180 PMCID: PMC10989494 DOI: 10.3748/wjg.v30.i9.1043] [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: 10/19/2023] [Revised: 12/26/2023] [Accepted: 02/04/2024] [Indexed: 03/06/2024] Open
Abstract
Several diseases originate from bile duct pathology. Despite studies on these diseases, certain etiologies of some of them still cannot be concluded. The most common disease of the bile duct in newborns is biliary atresia, whose prognosis varies according to the age of surgical correction. Other diseases such as Alagille syndrome, inspissated bile duct syndrome, and choledochal cysts are also time-sensitive because they can cause severe liver damage due to obstruction. The majority of these diseases present with cholestatic jaundice in the newborn or infant period, which is quite difficult to differentiate regarding clinical acumen and initial investigations. Intraoperative cholangiography is potentially necessary to make an accurate diagnosis, and further treatment will be performed synchronously or planned as findings suggest. This article provides a concise review of bile duct diseases, with interesting cases.
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Affiliation(s)
- Sutha Eiamkulbutr
- Department of Pediatrics, King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
| | - Chomchanat Tubjareon
- Department of Pediatrics, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
| | - Anapat Sanpavat
- Department of Pathology, Chulalongkorn University, Bangkok 10330, Thailand
| | - Teerasak Phewplung
- Department of Radiology, Chulalongkorn University, Bangkok 10330, Thailand
| | - Nimmita Srisan
- Department of Surgery, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
| | - Palittiya Sintusek
- Center of Excellence in Thai Pediatric Gastroenterology, Hepatology and Immunology, Division of Gastroenterology, Department of Pediatrics, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok 10330, Thailand
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Unalp-Arida A, Der JS, Ruhl CE. Longitudinal Study of Comorbidities and Clinical Outcomes in Persons with Gallstone Disease Using Electronic Health Records. J Gastrointest Surg 2023; 27:2843-2856. [PMID: 37914859 DOI: 10.1007/s11605-023-05861-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 10/07/2023] [Indexed: 11/03/2023]
Abstract
BACKGROUND Gallstone disease (GSD) is common and leads to significant morbidity, mortality, and health care utilization in the USA. We examined comorbidities and clinical outcomes among persons with GSD using electronic health records (EHR). METHODS In this retrospective study of 1,381,004 adults, GSD was defined by ICD-9 code 574 or ICD-10 code K80 using Optum® longitudinal EHR from January 2007 to March 2021. We obtained diagnosis, procedure, prescription, and vital sign records and evaluated associations between demographics, comorbidities, and medications with cholecystectomy, digestive cancers, and mortality. RESULTS Among persons with GSD, 30% had a cholecystectomy and were more likely to be women, White, and younger, and less likely to have comorbidities, except for obesity, gastroesophageal reflux disease (GERD), abdominal pain, hyperlipidemia, and pancreatitis. Among persons with GSD, 2.2% had a non-colorectal digestive cancer diagnosis during follow-up and risk was 40% lower among persons with a cholecystectomy. Non-colorectal digestive cancer predictors included older age, male sex, non-White race-ethnicity, lower BMI, other cancers, diabetes, chronic liver disease, pancreatitis, GERD, and abdominal pain. Among persons with GSD, mortality was 15.1% compared with 9.7% for the whole EHR sample. Persons with a cholecystectomy had 40% lower mortality risk and mortality predictors included older age, male sex, Black race, lower BMI, and most comorbidities. CONCLUSIONS In this EHR analysis of persons with GSD, 30% had a cholecystectomy. Mortality was higher compared with the whole EHR sample. Persons with cholecystectomy were less likely to have non-colorectal digestive cancer or to die.
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Affiliation(s)
- Aynur Unalp-Arida
- Department of Health and Human Services, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Two Democracy Plaza, Room 6009, 6707 Democracy Blvd., Bethesda, MD, 20892-5458, USA
| | - Jane S Der
- Social & Scientific Systems, Inc., a DLH Holdings Corp company, 8757 Georgia Avenue, 12th floor, Silver Spring, MD, 20910, USA
| | - Constance E Ruhl
- Social & Scientific Systems, Inc., a DLH Holdings Corp company, 8757 Georgia Avenue, 12th floor, Silver Spring, MD, 20910, USA.
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Roesch-Dietlen F, Pérez-Morales A, Grube-Pagola P, González-Santes M, Díaz-Roesch F, Triana-Romero A, Roesch-Ramos L, Remes-Troche J, Cruz-Aguilar M. Prevalencia de la esteatosis hepática metabólica (EHMet) en pacientes con litiasis vesicular. Estudio de una cohorte de casos en el sur-sureste de México. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2023; 88:225-231. [DOI: 10.1016/j.rgmx.2021.09.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Roesch-Dietlen F, Pérez-Morales AG, Grube-Pagola P, González-Santes M, Díaz-Roesch F, Triana-Romero A, Roesch-Ramos L, Remes-Troche JM, Cruz-Aguilar M. Prevalence of metabolic associated fatty liver disease (MAFLD) in patients with gallstone disease. Study on a cohort of cases in South-Southeastern Mexico. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2023; 88:225-231. [PMID: 37258385 DOI: 10.1016/j.rgmxen.2021.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 09/07/2021] [Indexed: 06/02/2023]
Abstract
INTRODUCTION Metabolic (dysfunction) associated fatty liver disease (MAFLD) and gallstone disease are entities that share similar risk factors. Numerous publications confirm their elevated frequency, but few studies have considered their prevalence and possible association. AIMS To determine the prevalence of MAFLD in patients with gallstone disease and the usefulness of liver biopsy for diagnosing the liver disease. MATERIALS AND METHODS A prospective study was conducted on patients that underwent laparoscopic cholecystectomy, in whom liver biopsy was performed. VARIABLES ANALYZED Anthropometric characteristics, biochemical profile, conventional ultrasound, risk factors, and histopathologic study of the liver biopsy. STATISTICAL ANALYSIS Descriptive statistics were carried out for the quantitative variables and the Student's t test and multivariate analysis through binary logistic regression were employed for the continuous variables, utilizing IBM-SPSS, 25.0 (Windows) software. RESULTS A total of 136 patients were classified into 2 groups: 40 (29.41%) with normal liver and 96 (70.59%) with MAFLD. Of the 136 patients, 71 patients (52.21%) corresponded to hepatic steatosis, 21 (15.44%) to steatohepatitis, and 4 (2.94%) to cirrhosis. Perisinusoidal inflammation was found in 39 cases (28.68%) and fibrosis was found in 10 (7.35%). The risk factors for both groups were age, diabetes, high blood pressure, and obesity. Glucose, triglyceride, and aminotransferase levels were significantly higher in the MAFLD group and conventional ultrasound demonstrated moderate concordance for its detection. DISCUSSION AND CONCLUSIONS The results confirmed the elevated frequency of MAFLD associated with gallstone disease, justifying liver biopsy during cholecystectomy for diagnosing MAFLD.
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Affiliation(s)
- F Roesch-Dietlen
- Departamento de Gastroenterología, Instituto de Investigaciones Médico-Biológicas, Universidad Veracruzana, Veracruz, Mexico.
| | - A G Pérez-Morales
- Profesor de la Facultad de Medicina y Vicerrector, Universidad Veracruzana, Región Veracruz-Boca del Río, Mexico
| | - P Grube-Pagola
- Anatomopatólogo, Instituto de Investigaciones Médico-Biológicas, Universidad Veracruzana, Veracruz, Mexico
| | - M González-Santes
- Profesor de la Facultad de Bioanálisis, Universidad Veracruzana, Veracruz, Mexico
| | | | - A Triana-Romero
- Médico en Servicio Social CONACyT, Instituto de Investigaciones Médico-Biológicas, Universidad Veracruzana, Veracruz, Mexico
| | - L Roesch-Ramos
- Profesora y Directora, Facultad de Odontología, Universidad Veracruzana, Mexico
| | - J M Remes-Troche
- Departamento de Neurogastroenterología, Instituto de Investigaciones Médico-Biológicas, Universidad Veracruzana, Veracruz, Mexico
| | - M Cruz-Aguilar
- Profesor de la Facultad de Bioanálisis, Universidad Veracruzana, Veracruz, Mexico
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Conti Bellocchi MC, Crinò SF, De Marchi G, De Pretis N, Ofosu A, Caldart F, Ciccocioppo R, Frulloni L. A Clinical and Pathophysiological Overview of Intestinal and Systemic Diseases Associated with Pancreatic Disorders: Causality or Casualty? Biomedicines 2023; 11:biomedicines11051393. [PMID: 37239064 DOI: 10.3390/biomedicines11051393] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 05/01/2023] [Accepted: 05/05/2023] [Indexed: 05/28/2023] Open
Abstract
The relationship between chronic intestinal disease, including inflammatory bowel disease (IBD) and celiac disease (CelD), and pancreatic disorders has been little investigated. Although an increased risk of acute pancreatitis (AP), exocrine pancreatic insufficiency with or without chronic pancreatitis, and chronic asymptomatic pancreatic hyperenzymemia have been described in these patients, the pathogenetic link remains unclear. It may potentially involve drugs, altered microcirculation, gut permeability/motility with disruption of enteric-mediated hormone secretion, bacterial translocation, and activation of the gut-associated lymphoid tissue related to chronic inflammation. In addition, the risk of pancreatic cancer seems to be increased in both IBD and CelD patients with unknown pathogenesis. Finally, other systemic conditions (e.g., IgG4-related disease, sarcoidosis, vasculitides) might affect pancreatic gland and the intestinal tract with various clinical manifestations. This review includes the current understandings of this enigmatic association, reporting a clinical and pathophysiological overview about this topic.
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Affiliation(s)
| | - Stefano Francesco Crinò
- Diagnostic and Interventional Endoscopy of Pancreas, Pancreas Institute, University of Verona, 37134 Verona, Italy
| | - Giulia De Marchi
- Gastroenterology Unit, Department of Medicine, Pancreas Institute, University of Verona, 37134 Verona, Italy
| | - Nicolò De Pretis
- Gastroenterology Unit, Department of Medicine, Pancreas Institute, University of Verona, 37134 Verona, Italy
| | - Andrew Ofosu
- Division of Gastroenterology and Hepatology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Federico Caldart
- Gastroenterology Unit, Department of Medicine, Pancreas Institute, University of Verona, 37134 Verona, Italy
| | - Rachele Ciccocioppo
- Gastroenterology Unit, Department of Medicine, Pancreas Institute, University of Verona, 37134 Verona, Italy
| | - Luca Frulloni
- Gastroenterology Unit, Department of Medicine, Pancreas Institute, University of Verona, 37134 Verona, Italy
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Kinoo SM, Naidoo P, Singh B, Chuturgoon A, Nagiah S. Human Hepatocyte Nuclear Factors (HNF1 and LXRb) Regulate CYP7A1 in HIV-Infected Black South African Women with Gallstone Disease: A Preliminary Study. Life (Basel) 2023; 13:life13020273. [PMID: 36836631 PMCID: PMC9968087 DOI: 10.3390/life13020273] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 01/13/2023] [Accepted: 01/14/2023] [Indexed: 01/20/2023] Open
Abstract
Female sex, high estrogen levels, aging, obesity, and dyslipidemia are some of the risk factors associated with gallstone formation. HIV-infected patients on combination antiretroviral therapy (cART) are more prone to hypercholesterolemia. Bile acid synthesis is initiated by cholesterol 7-alpha hydroxylase (CYP7A1) and regulated by hepatocyte nuclear factors (HNF1α, HNF4α, and LXRb). The aim of this study was to evaluate the expression of HNF1α, HNF4α, LXRb, and miRNAs (HNF4α specific: miR-194-5p and miR-122*_1) that regulate CYP7A1 transcription in HIV-infected Black South African women on cART and presenting with gallstones relative to HIV-negative patients with gallstone disease. Females (n = 96) presenting with gallstone disease were stratified based on HIV status. The gene expression of CYP7A1, HNF1α, HNF4α, LXRb, miR-194-5p, and miR-122*_1 was determined using RT-qPCR. Messenger RNA and miRNA levels were reported as fold change expressed as 2-ΔΔCt (RQ min; RQ max). Fold changes >2 and <0.5 were considered significant. HIV-infected females were older in age (p = 0.0267) and displayed higher low-density lipoprotein cholesterol (LDL-c) (p = 0.0419), CYP7A1 [2.078-fold (RQ min: 1.278; RQ max: 3.381)], LXRb [2.595-fold (RQ min: 2.001; RQ max: 3.000)], and HNF1α [3.428 (RQ min: 1.806; RQ max: 6.507] levels. HNF4α [0.642-fold (RQ min: 0.266; RQ max: 1.55)], miR-194-5p [0.527-fold (RQ min: 0.37; RQ max: 0.752)], and miR-122*_1 [0.595-fold (RQ min: 0.332; RQ max: 1.066)] levels were lower in HIV-infected females. In conclusion, HIV-infected women with gallstone disease displayed higher LDL-c levels and increased bile acid synthesis, which was evidenced by the elevated expression of CYP7A1, HNF1α, and LXRb. This could have been further influenced by cART and aging.
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Affiliation(s)
- Suman Mewa Kinoo
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, College of Health Science, University of KwaZulu Natal, Glenwood, Durban 4041, South Africa
- Discipline of General Surgery, School of Clinical Medicine, College of Health Science, University of KwaZulu Natal, Umbilo, Durban 4001, South Africa
| | - Pragalathan Naidoo
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, College of Health Science, University of KwaZulu Natal, Glenwood, Durban 4041, South Africa
| | - Bhugwan Singh
- Discipline of General Surgery, School of Clinical Medicine, College of Health Science, University of KwaZulu Natal, Umbilo, Durban 4001, South Africa
| | - Anil Chuturgoon
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, College of Health Science, University of KwaZulu Natal, Glenwood, Durban 4041, South Africa
- Correspondence: (A.C.); (S.N.)
| | - Savania Nagiah
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, College of Health Science, University of KwaZulu Natal, Glenwood, Durban 4041, South Africa
- Department of Human Biology, Medical School, Faculty of Health Sciences, Nelson Mandela University, Missionvale, Port Elizabeth 6065, South Africa
- Correspondence: (A.C.); (S.N.)
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Tsibranska-Gyoreva S, Petkov V, Katev V, Krastev D, Vinarov Z, Tcholakova S. Cholesterol solubilization: interplay between phytosterols, saponins and lipid digestion products. Colloids Surf A Physicochem Eng Asp 2023. [DOI: 10.1016/j.colsurfa.2023.131052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
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Lammert F. Gallstones: The thing in itself. Clin Liver Dis (Hoboken) 2022; 20:57-72. [PMID: 36518788 PMCID: PMC9742755 DOI: 10.1002/cld.1269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 08/30/2022] [Indexed: 12/14/2022] Open
Abstract
Content available: Audio Recording.
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Wang R, Nissen NN, Zhang Y, Shao C, Chu CY, Huynh C, Posadas EM, Tomlinson JS, Lewis MS, Pandol SJ. Circulating Fatty Objects and Their Preferential Presence in Pancreatic Cancer Patient Blood Samples. Front Physiol 2022; 13:827531. [PMID: 35237181 PMCID: PMC8883044 DOI: 10.3389/fphys.2022.827531] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 01/10/2022] [Indexed: 01/28/2023] Open
Abstract
Human cancers are often complicated with increased incidences of blood vessel occlusion, which are mostly insensitive to anticoagulation therapy. We searched for causal factors of cancer-associated embolism. A total of 2,017 blood samples was examined for visible abnormalities. Examined were peripheral blood samples from cancer patients who were about to undergo surgical treatment for genitourinary, breast, gastrointestinal or abdominal tumors. Samples from ambulatory patients being treated for recurrent or castration-resistant prostate cancers were included in the study. The lipid-rich nature was studied with lipophilic stains and lipid panel analysis, while surface membrane was assessed with specific staining and antibody detection. We identified a new entity, lipid droplet-like objects or circulating fatty objects (CFOs), visible in the blood samples of many cancer patients, with the potential of causing embolism. CFOs were defined as lipid-rich objects with a membrane, capable of gaining in volume through interaction with peripheral blood mononuclear cells in ex vivo culture. Blood samples from pancreatic cancer patients were found to have the highest CFO incidence and largest CFO numbers. Most noticeably, CFOs from many pancreatic cancer samples presented as large clusters entangled in insoluble fiber networks, suggestive of intravascular clotting. This study identifies CFO as an abnormal entity in cancer patient blood, and a contributory factor to intravascular embolism during cancer development and progression.
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Affiliation(s)
- Ruoxiang Wang
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Nicholas N. Nissen
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Yi Zhang
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Chen Shao
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Chia-Yi Chu
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Carissa Huynh
- Biobank and Translational Research Core, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Edwin M. Posadas
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - James S. Tomlinson
- Department of Surgery, VA Greater Los Angeles Healthcare System, Los Angeles, CA, United States
| | - Michael S. Lewis
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Department of Pathology, VA Greater Los Angeles Healthcare System, Los Angeles, CA, United States
| | - Stephen J. Pandol
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
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Large-scale integration of the plasma proteome with genetics and disease. Nat Genet 2021; 53:1712-1721. [PMID: 34857953 DOI: 10.1038/s41588-021-00978-w] [Citation(s) in RCA: 604] [Impact Index Per Article: 151.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 10/22/2021] [Indexed: 11/08/2022]
Abstract
The plasma proteome can help bridge the gap between the genome and diseases. Here we describe genome-wide association studies (GWASs) of plasma protein levels measured with 4,907 aptamers in 35,559 Icelanders. We found 18,084 associations between sequence variants and levels of proteins in plasma (protein quantitative trait loci; pQTL), of which 19% were with rare variants (minor allele frequency (MAF) < 1%). We tested plasma protein levels for association with 373 diseases and other traits and identified 257,490 associations. We integrated pQTL and genetic associations with diseases and other traits and found that 12% of 45,334 lead associations in the GWAS Catalog are with variants in high linkage disequilibrium with pQTL. We identified 938 genes encoding potential drug targets with variants that influence levels of possible biomarkers. Combining proteomics, genomics and transcriptomics, we provide a valuable resource that can be used to improve understanding of disease pathogenesis and to assist with drug discovery and development.
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12
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Gertzen CGW, Gohlke H, Häussinger D, Herebian D, Keitel V, Kubitz R, Mayatepek E, Schmitt L. The many facets of bile acids in the physiology and pathophysiology of the human liver. Biol Chem 2021; 402:1047-1062. [PMID: 34049433 DOI: 10.1515/hsz-2021-0156] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 05/14/2021] [Indexed: 12/12/2022]
Abstract
Bile acids perform vital functions in the human liver and are the essential component of bile. It is therefore not surprising that the biology of bile acids is extremely complex, regulated on different levels, and involves soluble and membrane receptors as well as transporters. Hereditary disorders of these proteins manifest in different pathophysiological processes that result in liver diseases of varying severity. In this review, we summarize our current knowledge of the physiology and pathophysiology of bile acids with an emphasis on recently established analytical approaches as well as the molecular mechanisms that underlie signaling and transport of bile acids. In this review, we will focus on ABC transporters of the canalicular membrane and their associated diseases. As the G protein-coupled receptor, TGR5, receives increasing attention, we have included aspects of this receptor and its interaction with bile acids.
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Affiliation(s)
- Christoph G W Gertzen
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Center for Structural Studies (CSS), Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Holger Gohlke
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- John von Neumann Institute for Computing (NIC), Jülich Supercomputing Centre (JSC), Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Institute of Bio- and Geosciences (IBG-4: Bioinformatics), Forschungszentrum Jülich GmbH, Jülich, Germany
| | - Dieter Häussinger
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Diran Herebian
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Verena Keitel
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Ralf Kubitz
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Ertan Mayatepek
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Lutz Schmitt
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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Kubica K, Balbus J. A computer study of the risk of cholesterol gallstone associated with obesity and normal weight. Sci Rep 2021; 11:8868. [PMID: 33893348 PMCID: PMC8065120 DOI: 10.1038/s41598-021-88249-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 04/07/2021] [Indexed: 11/29/2022] Open
Abstract
Obese people differ from the people of normal weight in gall bladder motility and have a higher risk of cholesterol stone formation. In this study, using a mathematical model of cholesterol homeostasis, which also considers the enterohepatic circulation of bile as well as cholesterol, we investigated the risk of cholesterol stone formation in obese and normal-weight groups who had normal blood cholesterol levels. We associated the risk of stone formation with the amount of cholesterol released into bile and the amount of de novo-synthesized cholic acid. For both groups, we determined the conditions of low and high risk. In addition, we analyzed the potential effects of changes in gall bladder motility with increased weight. The results showed that the obese group exhibited increased kinetics of enterohepatic circulation, leading to a significant increase in blood cholesterol levels, which can be reduced by increasing the amount of cholesterol in bile. Based on this finding, we suggest that for obese people, it is beneficial to reduce the amount and change the composition of circulating bile through the inhibition of cholic acid synthesis along with cholesterol synthesis. Furthermore, obese people should maintain a triglyceride-lowering diet and consume small meals containing fat, preferably in combination with agents that can reduce bile output from the gall bladder.
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Affiliation(s)
- Krystian Kubica
- Faculty of Fundamental Problems of Technology, Department of Biomedical Engineering, Wroclaw University of Science and Technology, 50-370, Wroclaw, Poland.
| | - Joanna Balbus
- Department of Pure and Applied Mathematics, Wroclaw University of Science and Technology, 50-372, Wroclaw, Poland
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14
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Mewa Kinoo S, Nagiah S, Chuturgoon A, Singh B. Symptomatic gallstones and HIV in black South African women: Changing trends of gallstone disease? South Afr J HIV Med 2021; 22:1208. [PMID: 33936792 PMCID: PMC8063772 DOI: 10.4102/sajhivmed.v22i1.1208] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 02/05/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The incidence of metabolic disorders in human immunodeficiency virus (HIV) endemic settings is a prevailing burden in developing countries. Cholesterol homeostasis and fat metabolism are altered by HIV and antiretroviral therapy (ART), thereby possibly contributing to complications such as gallstone formation. OBJECTIVES The aim of this study was to evaluate established risk factors for the formation of cholesterol gallstones in black South African women living with HIV (WLHIV). METHOD A case series study was conducted of all black South African women undergoing cholecystectomy for gallstone disease over a 1-year period at King Edward VIII Hospital, Durban, South Africa. Age, body mass index (BMI), family history of gallstones, oestrogen exposure and lipograms were compared between WLHIV and uninfected women. Categorical variables were tested using either the Fisher's exact test or Pearson's chi-square test. Means were compared using independent t-tests. For non-normally distributed data, the Mann-Whitney U test was used. Statistical tests were two-sided, and p-values of less than 0.05 were considered statistically significant. RESULTS A total of 52 patients were assessed, 34 HIV-uninfected and 18 WLHIV. The median age of WLHIV versus the uninfected women was 35 and 50 years, respectively, (p = 0.015). A statistically significant number of uninfected women were in the overweight/obese category (BMI > 25 kg/m2) compared to the normal weight category (BMI < 25 kg/m2) (p < 0.001). The number of obese WLHIV did not reach statistical significance. CONCLUSION The age of occurrence of gallstone disease amongst black South African WLHIV was significantly lower and fewer women were obese compared with the uninfected women with gallstone disease. These findings differ from known gallstone risk factors in other populations and in uninfected black South African women. This could be attributed to the metabolic alterations caused by HIV infection itself and/or to the long-term use of ART. Larger cohort studies are required to elucidate the role of HIV and ART in cholestatic disease.
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Affiliation(s)
- Suman Mewa Kinoo
- Department of General Surgery, Faculty of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Savania Nagiah
- Department of Human Biology, Faculty of Health Sciences, Nelson Mandela University Missionvale, Port Elizabeth, South Africa
| | - Anil Chuturgoon
- Department of Medical Biochemistry, Faculty of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Bhugwan Singh
- Department of General Surgery, Faculty of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
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15
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Kinoo SM, Chuturgoon AA, Singh B, Nagiah S. Hepatic expression of cholesterol regulating genes favour increased circulating low-density lipoprotein in HIV infected patients with gallstone disease: a preliminary study. BMC Infect Dis 2021; 21:294. [PMID: 33757439 PMCID: PMC7986270 DOI: 10.1186/s12879-021-05977-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 03/04/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND HIV endemic populations are displaying higher incidence of metabolic disorders. HIV and the standard treatment are both associated with altered lipid and cholesterol metabolism, however gallstone disease (a cholesterol related disorder) in Sub-Saharan African populations is rarely investigated. METHODS This study sought to evaluate hepatic expression of key genes in cholesterol metabolism (LDLr, HMGCR, ABCA1) and transcriptional regulators of these genes (microRNA-148a, SREBP2) in HIV positive patients on antiretroviral therapy presenting with gallstones. Liver biopsies from HIV positive patients (cases: n = 5) and HIV negative patients (controls: n = 5) were analysed for miR-148a and mRNA expression using quantitative PCR. RESULTS Circulating total cholesterol was elevated in the HIV positive group with significantly elevated LDL-c levels(3.16 ± 0.64 mmol/L) relative to uninfected controls (2.10 ± 0.74 mmol/L; p = 0.04). A scavenging receptor for LDL-c, LDLr was significantly decreased (0.18-fold) in this group, possibly contributing to higher LDL-c levels. Transcriptional regulator of LDLr, SREBP2 was also significantly lower (0.13-fold) in HIV positive patients. Regulatory microRNA, miR-148a-3p, was reduced in HIV positive patients (0.39-fold) with a concomitant increase in target ABCA1 (1.5-fold), which regulates cholesterol efflux. CONCLUSIONS Collectively these results show that HIV patients on antiretroviral therapy display altered hepatic regulation of cholesterol metabolizing genes, reducing cholesterol scavenging, and increasing cholesterol efflux.
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Affiliation(s)
- Suman Mewa Kinoo
- Department of Medical Biochemistry, School of Laboratory Medicine and Medical Science, College of Health Science, University of KwaZulu Natal, Durban, Glenwood 4041 South Africa
- Discipline of General Surgery, School of Clinical Medicine, College of Health Science, University of KwaZulu Natal, Umbilo, Durban, 4001 South Africa
| | - Anil A. Chuturgoon
- Department of Medical Biochemistry, School of Laboratory Medicine and Medical Science, College of Health Science, University of KwaZulu Natal, Durban, Glenwood 4041 South Africa
| | - Bugwan Singh
- Discipline of General Surgery, School of Clinical Medicine, College of Health Science, University of KwaZulu Natal, Umbilo, Durban, 4001 South Africa
| | - Savania Nagiah
- Department of Medical Biochemistry, School of Laboratory Medicine and Medical Science, College of Health Science, University of KwaZulu Natal, Durban, Glenwood 4041 South Africa
- Present address: Department of Human Biology, Medical Programme, Faculty of Health Sciences, Nelson Mandela University Missionvale Campus, Room 113, 2nd floor, Road, Salt Pan, Bethelsdorp, Port Elizabeth, 6059 South Africa
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16
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Caponio GR, Wang DQH, Di Ciaula A, De Angelis M, Portincasa P. Regulation of Cholesterol Metabolism by Bioactive Components of Soy Proteins: Novel Translational Evidence. Int J Mol Sci 2020; 22:227. [PMID: 33379362 PMCID: PMC7794713 DOI: 10.3390/ijms22010227] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 12/21/2020] [Accepted: 12/22/2020] [Indexed: 02/07/2023] Open
Abstract
Hypercholesterolemia represents one key pathophysiological factor predisposing to increasing risk of developing cardiovascular disease worldwide. Controlling plasma cholesterol levels and other metabolic risk factors is of paramount importance to prevent the overall burden of disease emerging from cardiovascular-disease-related morbidity and mortality. Dietary cholesterol undergoes micellization and absorption in the small intestine, transport via blood, and uptake in the liver. An important amount of cholesterol originates from hepatic synthesis, and is secreted by the liver into bile together with bile acids (BA) and phospholipids, with all forming micelles and vesicles. In clinical medicine, dietary recommendations play a key role together with pharmacological interventions to counteract the adverse effects of chronic hypercholesterolemia. Bioactive compounds may also be part of initial dietary plans. Specifically, soybean contains proteins and peptides with biological activity on plasma cholesterol levels and this property makes soy proteins a functional food. Here, we discuss how soy proteins modulate lipid metabolism and reduce plasma cholesterol concentrations in humans, with potential outcomes in improving metabolic- and dyslipidemia-related conditions.
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Affiliation(s)
- Giusy Rita Caponio
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, via Amendola 165/a, 70126 Bari, Italy;
- Division of Internal Medicine Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, 70124 Bari, Italy;
| | - 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;
| | - Agostino Di Ciaula
- Division of Internal Medicine Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, 70124 Bari, Italy;
| | - Maria De Angelis
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, via Amendola 165/a, 70126 Bari, Italy;
| | - Piero Portincasa
- Division of Internal Medicine Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, 70124 Bari, Italy;
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Park S, Sut TN, Ma GJ, Parikh AN, Cho NJ. Crystallization of Cholesterol in Phospholipid Membranes Follows Ostwald’s Rule of Stages. J Am Chem Soc 2020; 142:21872-21882. [DOI: 10.1021/jacs.0c10674] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Affiliation(s)
- Soohyun Park
- School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, 639798 Singapore, Singapore
| | - Tun Naw Sut
- School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, 639798 Singapore, Singapore
| | - Gamaliel Junren Ma
- School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, 639798 Singapore, Singapore
| | - Atul N. Parikh
- School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, 639798 Singapore, Singapore
- Department of Biomedical Engineering, University of California, Davis, Davis, California 95616, United States
| | - Nam-Joon Cho
- School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, 639798 Singapore, Singapore
- Department of Biomedical Engineering, University of California, Davis, Davis, California 95616, United States
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18
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Sun D, Niu Z, Zheng HX, Wu F, Jiang L, Han TQ, Wei Y, Wang J, Jin L. A Mitochondrial DNA Variant Elevates the Risk of Gallstone Disease by Altering Mitochondrial Function. Cell Mol Gastroenterol Hepatol 2020; 11:1211-1226.e15. [PMID: 33279689 PMCID: PMC8053626 DOI: 10.1016/j.jcmgh.2020.11.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 11/27/2020] [Accepted: 11/30/2020] [Indexed: 01/06/2023]
Abstract
BACKGROUND AND AIMS Gallstone disease (cholelithiasis) is a cholesterol-related metabolic disorders with strong familial predisposition. Mitochondrial DNA (mtDNA) variants accumulated during human evolution are associated with some metabolic disorders related to modified mitochondrial function. The mechanistic links between mtDNA variants and gallstone formation need further exploration. METHODS In this study, we explored the possible associations of mtDNA variants with gallstone disease by comparing 104 probands and 300 controls in a Chinese population. We constructed corresponding cybrids using trans-mitochondrial technology to investigate the underlying mechanisms of these associations. Mitochondrial respiratory chain complex activity and function and cholesterol metabolism were assessed in the trans-mitochondrial cell models. RESULTS Here, we found a significant association of mtDNA 827A>G with an increased risk of familial gallstone disease in a Chinese population (odds ratio [OR]: 4.5, 95% confidence interval [CI]: 2.1-9.4, P=1.2×10-4). Compared with 827A cybrids (haplogroups B4a and B4c), 827G cybrids (haplogroups B4b and B4d) had impaired mitochondrial respiratory chain complex activity and function and activated JNK and AMPK signaling pathways. Additionally, the 827G cybrids showed disturbances in cholesterol transport and accelerated development of gallstones. Specifically, cholesterol transport through the transporter ABCG5/8 was increased via activation of the AMPK signaling pathway in 827G cybrids. CONCLUSIONS Our findings reveal that mtDNA 827A>G induces aberrant mitochondrial function and abnormal cholesterol transport, resulting in increased occurrence of gallstones. The results provide an important biological basis for the clinical diagnosis and prevention of gallstone disease in the future.
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Affiliation(s)
- Dayan Sun
- State Key Laboratory of Genetic Engineering, School of Life Sciences, and Human Phenome Institute, Fudan University, Shanghai, China; Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, China
| | - Zhenmin Niu
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai and Shanghai Academy of Science and Technology, Shanghai, China
| | - Hong-Xiang Zheng
- Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, China; Ministry of Education Key Laboratory of Contemporary Anthropology, Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, China
| | - Fei Wu
- State Key Laboratory of Genetic Engineering, School of Life Sciences, and Human Phenome Institute, Fudan University, Shanghai, China
| | - Liuyiqi Jiang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, and Human Phenome Institute, Fudan University, Shanghai, China
| | - Tian-Quan Han
- Shanghai Institute of Digestive Surgery, Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yang Wei
- State Key Laboratory of Genetic Engineering, School of Life Sciences, and Human Phenome Institute, Fudan University, Shanghai, China
| | - Jiucun Wang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, and Human Phenome Institute, Fudan University, Shanghai, China; Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, China; Research Unit of Dissecting the Population Genetics and Developing New Technologies for Treatment and Prevention of Skin Phenotypes and Dermatological Diseases (2019RU058), Chinese Academy of Medical Sciences, Shanghai, China; Taizhou Institute of Health Sciences, Fudan University, Taizhou, China.
| | - Li Jin
- State Key Laboratory of Genetic Engineering, School of Life Sciences, and Human Phenome Institute, Fudan University, Shanghai, China; Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, China; Research Unit of Dissecting the Population Genetics and Developing New Technologies for Treatment and Prevention of Skin Phenotypes and Dermatological Diseases (2019RU058), Chinese Academy of Medical Sciences, Shanghai, China; Taizhou Institute of Health Sciences, Fudan University, Taizhou, China.
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19
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In vitro analysis of gallstone formation in the presence of bacteria. Indian J Gastroenterol 2020; 39:473-480. [PMID: 33201443 DOI: 10.1007/s12664-020-01055-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 05/12/2020] [Indexed: 02/04/2023]
Abstract
AIM In our previous study, we have isolated different genera of bacteria from gallstones and this intrigued us to study their role in gallstone formation. The isolates exhibited certain biliary activities like urease activity, slime production, and β-glucuronidase production. We aimed to investigate the role of these factors in the formation of gallstone in in vitro conditions at a supersaturated concentration of cholesterol. METHODOLOGY To mimic bile in in vitro state, Brilliant Green Bile Broth (BGBB) media having a composition similar to human bile was used. Four different experimental sets were prepared, each having nine flasks with varying concentrations of cholesterol and CaCO3 (calcium carbonate). Test sets I, II, III, and IV were inoculated with Salmonella, Enterococcus, Helicobacter, and Neisseria respectively, which were isolated from gallstone itself. Out of these four bacteria, only Helicobacter did not possess slime activity. A control set was also established which was devoid of bacteria. The control also had nine flasks with different concentrations of cholesterol and CaCO3. All the sets were incubated in the incubator shaker at 37 °C and 80 revolution per minutes (RPM) for 20 days. RESULT It was observed that the sets having bacteria had a less nucleation time as compared to the control (F = 5.274; p < 0.001). Solidification of gallstone was observed only in the set with bacteria having slime activity (sets I, II, and IV). CONCLUSION The slime activity of bacteria leads to solidification of gallstones, whereas the other activities accelerate the nucleation of gallstone formation enhancing the severity of the disease.
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20
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Neutrophils as Main Players of Immune Response Towards Nondegradable Nanoparticles. NANOMATERIALS 2020; 10:nano10071273. [PMID: 32610567 PMCID: PMC7408411 DOI: 10.3390/nano10071273] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 06/25/2020] [Accepted: 06/25/2020] [Indexed: 12/12/2022]
Abstract
Many nano/microparticles (n/µP), to which our body is exposed, have no physiological way of removal. Our immune system sense these “small particulate objects”, and tries to decrease their harmfulness. Since oxidation, phagocytosis and other methods of degradation do not work with small, chemically resistant, and hydrophobic nanoparticles (nP). This applies to soot from air pollution, nano-diamonds from cosmic impact, polishing and related machines, synthetic polymers, and dietary n/µP. Our body tries to separate these from the surrounding tissue using aggregates from neutrophil extracellular traps (NETs). This effectively works in soft tissues where n/µP are entrapped into granuloma-like structures and isolated. The interactions of hydrophobic nanocrystals with circulating or ductal patrolling neutrophils and the consequent formation of occlusive aggregated NETs (aggNETs) are prone to obstruct capillaries, bile ducts in gallbladder and liver, and many more tubular structures. This may cause serious health problems and often fatality. Here we describe how specific size and surface properties of n/µP can activate neutrophils and lead to aggregation-related pathologies. We discuss “natural” sources of n/µP and those tightly connected to unhealthy diets.
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21
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Wang HH, Liu M, Portincasa P, Wang DQH. Recent Advances in the Critical Role of the Sterol Efflux Transporters ABCG5/G8 in Health and Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1276:105-136. [PMID: 32705597 PMCID: PMC8118135 DOI: 10.1007/978-981-15-6082-8_8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cardiovascular disease is characterized by lipid accumulation, inflammatory response, cell death, and fibrosis in the arterial wall and is the leading cause of morbidity and mortality worldwide. Cholesterol gallstone disease is caused by complex genetic and environmental factors and is one of the most prevalent and costly digestive diseases in the USA and Europe. Although sitosterolemia is a rare inherited lipid storage disease, its genetic studies led to identification of the sterol efflux transporters ABCG5/G8 that are located on chromosome 2p21 in humans and chromosome 17 in mice. Human and animal studies have clearly demonstrated that ABCG5/G8 play a critical role in regulating hepatic secretion and intestinal absorption of cholesterol and plant sterols. Sitosterolemia is caused by a mutation in either the ABCG5 or the ABCG8 gene alone, but not in both simultaneously. Polymorphisms in the ABCG5/G8 genes are associated with abnormal plasma cholesterol metabolism and may play a key role in the genetic determination of plasma cholesterol concentrations. Moreover, ABCG5/G8 is a new gallstone gene, LITH9. Gallstone-associated variants in ABCG5/G8 are involved in the pathogenesis of cholesterol gallstones in European, Asian, and South American populations. In this chapter, we summarize the latest advances in the critical role of the sterol efflux transporters ABCG5/G8 in regulating hepatic secretion of biliary cholesterol, intestinal absorption of cholesterol and plant sterols, the classical reverse cholesterol transport, and the newly established transintestinal cholesterol excretion, as well as in the pathogenesis and pathophysiology of ABCG5/G8-related metabolic diseases such as sitosterolemia, cardiovascular disease, and cholesterol gallstone disease.
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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, USA
| | - Min Liu
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Piero Portincasa
- Department of Biomedical Sciences and Human Oncology, Clinica Medica "A. Murri", University of Bari Medical School, Bari, Italy
| | - 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, USA.
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22
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Azum N, Rub MA, Asiri AM. Association behavior of bile salts binary mixtures in an aqueous system: A tensiometric and fluorometric study. J PHYS ORG CHEM 2019. [DOI: 10.1002/poc.4015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Naved Azum
- Chemistry Department, Faculty of ScienceKing Abdulaziz University Jeddah Saudi Arabia
- Center of Excellence for Advanced Materials ResearchKing Abdulaziz University Jeddah Saudi Arabia
| | - Malik Abdul Rub
- Chemistry Department, Faculty of ScienceKing Abdulaziz University Jeddah Saudi Arabia
- Center of Excellence for Advanced Materials ResearchKing Abdulaziz University Jeddah Saudi Arabia
| | - Abdullah M. Asiri
- Chemistry Department, Faculty of ScienceKing Abdulaziz University Jeddah Saudi Arabia
- Center of Excellence for Advanced Materials ResearchKing Abdulaziz University Jeddah Saudi Arabia
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Neutrophil Extracellular Traps Initiate Gallstone Formation. Immunity 2019; 51:443-450.e4. [PMID: 31422870 DOI: 10.1016/j.immuni.2019.07.002] [Citation(s) in RCA: 112] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 05/31/2019] [Accepted: 07/12/2019] [Indexed: 02/05/2023]
Abstract
The presence of gallstones (cholelithiasis) is a highly prevalent and severe disease and one of the leading causes of hospital admissions worldwide. Due to its substantial health impact, we investigated the biological mechanisms that lead to the formation and growth of gallstones. We show that gallstone assembly essentially requires neutrophil extracellular traps (NETs). We found consistent evidence for the presence of NETs in human and murine gallstones and describe an immune-mediated process requiring activation of the innate immune system for the formation and growth of gallstones. Targeting NET formation via inhibition of peptidyl arginine deiminase type 4 or abrogation of reactive oxygen species (ROS) production, as well as damping of neutrophils by metoprolol, effectively inhibit gallstone formation in vivo. Our results show that after the physicochemical process of crystal formation, NETs foster their assembly into larger aggregates and finally gallstones. These insights provide a feasible therapeutic concept to prevent cholelithiasis in patients at risk.
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Vauthier V, Ben Saad A, Elie J, Oumata N, Durand-Schneider AM, Bruneau A, Delaunay JL, Housset C, Aït-Slimane T, Meijer L, Falguières T. Structural analogues of roscovitine rescue the intracellular traffic and the function of ER-retained ABCB4 variants in cell models. Sci Rep 2019; 9:6653. [PMID: 31040306 PMCID: PMC6491434 DOI: 10.1038/s41598-019-43111-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 04/16/2019] [Indexed: 12/12/2022] Open
Abstract
Adenosine triphosphate binding cassette transporter, subfamily B member 4 (ABCB4) is the transporter of phosphatidylcholine at the canalicular membrane of hepatocytes. ABCB4 deficiency, due to genetic variations, is responsible for progressive familial intrahepatic cholestasis type 3 (PFIC3) and other rare biliary diseases. Roscovitine is a molecule in clinical trial that was shown to correct the F508del variant of cystic fibrosis transmembrane conductance regulator (CFTR), another ABC transporter. In the present study, we hypothesized that roscovitine could act as a corrector of ABCB4 traffic-defective variants. Using HEK and HepG2 cells, we showed that roscovitine corrected the traffic and localisation at the plasma membrane of ABCB4-I541F, a prototypical intracellularly retained variant. However, roscovitine caused cytotoxicity, which urged us to synthesize non-toxic structural analogues. Roscovitine analogues were able to correct the intracellular traffic of ABCB4-I541F in HepG2 cells. Importantly, the phospholipid secretion activity of this variant was substantially rescued by three analogues (MRT2-235, MRT2-237 and MRT2-243) in HEK cells. We showed that these analogues also triggered the rescue of intracellular traffic and function of two other intracellularly retained ABCB4 variants, i.e. I490T and L556R. Our results indicate that structural analogues of roscovitine can rescue genetic variations altering the intracellular traffic of ABCB4 and should be considered as therapeutic means for severe biliary diseases caused by this class of variations.
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Affiliation(s)
- Virginie Vauthier
- Inserm, Sorbonne Université, Centre de Recherche Saint-Antoine (CRSA), UMR_S 938, Institute of Cardiometabolism and Nutrition (ICAN), F-75012, Paris, France
| | - Amel Ben Saad
- Inserm, Sorbonne Université, Centre de Recherche Saint-Antoine (CRSA), UMR_S 938, Institute of Cardiometabolism and Nutrition (ICAN), F-75012, Paris, France
| | - Jonathan Elie
- ManRos Therapeutics, Hôtel de Recherche, Centre de Perharidy, F-29680, Roscoff, France
| | - Nassima Oumata
- ManRos Therapeutics, Hôtel de Recherche, Centre de Perharidy, F-29680, Roscoff, France
| | - Anne-Marie Durand-Schneider
- Inserm, Sorbonne Université, Centre de Recherche Saint-Antoine (CRSA), UMR_S 938, Institute of Cardiometabolism and Nutrition (ICAN), F-75012, Paris, France
| | - Alix Bruneau
- Inserm, Sorbonne Université, Centre de Recherche Saint-Antoine (CRSA), UMR_S 938, Institute of Cardiometabolism and Nutrition (ICAN), F-75012, Paris, France
| | - Jean-Louis Delaunay
- Inserm, Sorbonne Université, Centre de Recherche Saint-Antoine (CRSA), UMR_S 938, Institute of Cardiometabolism and Nutrition (ICAN), F-75012, Paris, France
| | - Chantal Housset
- Inserm, Sorbonne Université, Centre de Recherche Saint-Antoine (CRSA), UMR_S 938, Institute of Cardiometabolism and Nutrition (ICAN), F-75012, Paris, France.,Assistance Publique - Hôpitaux de Paris, Hôpital Saint-Antoine, Centre de Référence des Maladies Rares - Maladies Inflammatoires des Voies Biliaires & Service d'Hépatologie, F-75012, Paris, France
| | - Tounsia Aït-Slimane
- Inserm, Sorbonne Université, Centre de Recherche Saint-Antoine (CRSA), UMR_S 938, Institute of Cardiometabolism and Nutrition (ICAN), F-75012, Paris, France
| | - Laurent Meijer
- ManRos Therapeutics, Hôtel de Recherche, Centre de Perharidy, F-29680, Roscoff, France
| | - Thomas Falguières
- Inserm, Sorbonne Université, Centre de Recherche Saint-Antoine (CRSA), UMR_S 938, Institute of Cardiometabolism and Nutrition (ICAN), F-75012, Paris, France.
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Oikonomou P, Giatromanolaki A, Tsaroucha AK, Balaska K, Tsalikidis CH, Nikolaou CH, Pitiakoudis M, Simopoulos C. Expression of autophagy-related proteins Beclin-1 and LC3A and proliferation marker Ki-67 in calculous and acalculous human gallbladder epithelium. Hippokratia 2019; 23:64-69. [PMID: 32265586 PMCID: PMC7127918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
BACKGROUND Autophagy is an inducible intracellular process that has been studied mostly in cancer and less in inflammatory diseases. To establish the relation between cholecystitis (calculous and acalculous) and autophagy, we studied the expressions of immunohistochemical markers Beclin-1, LC3A, and Ki-67 in gallbladder epithelium and their significance in the induction of autophagy. METHODS Adult human gallbladder tissues were obtained from 100 patients (45 male, 55 female) who underwent cholecystectomy. According to the findings, the patients were divided into two groups: group A (calculous gallbladder: 24 male, 46 female; mean age 52.6 ± 16.0 years) and group B (acalculous gallbladder: 21 male, nine female; mean age 65.3 ± 12.4 years). The expressions of immunohistochemical markers Beclin-1, LC3A, and Ki-67 in gallbladder epithelium were studied using immunohistochemistry techniques. RESULTS Beclin-1 expression was correlated with LC3A expression in group A with increased Beclin-1 expression promoting LC3A expression (p =0.0001). In group B, the LC3A expression did not follow Beclin-1 expression (p =0.09). The mean percentage of Beclin-1 expression in group A patients was 23.8 % compared to group B patients, where the corresponding percentage was only 17.3 %. Corresponding mean percent expressions of LC3A in groups A and B were 38.9 % and 50.7 %, respectively. The expression of Ki-67 was higher in group A patients compared to group B patients. The mean percentage of Ki-67 expression in group A patients was 3.75 %, whereas, in group B patients, it was only 0.5 % (statistically significantly different; p =0.0003). CONCLUSION In the epithelium of calculous cholecystitis, overexpression of LC3A is related to Beclin-1 overexpression, which reinforces the view that Beclin-1 promotes autophagy in stone cholecystitis. HIPPOKRATIA 2019, 23(2): 64-69.
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Affiliation(s)
- P Oikonomou
- 2 Department of Surgery and Laboratory of Experimental Surgery & Surgical Research, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - A Giatromanolaki
- Department of Pathology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - A K Tsaroucha
- 2 Department of Surgery and Laboratory of Experimental Surgery & Surgical Research, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - K Balaska
- Department of Pathology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - C H Tsalikidis
- 2 Department of Surgery and Laboratory of Experimental Surgery & Surgical Research, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - C H Nikolaou
- 2 Department of Surgery and Laboratory of Experimental Surgery & Surgical Research, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - M Pitiakoudis
- 2 Department of Surgery and Laboratory of Experimental Surgery & Surgical Research, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - C Simopoulos
- 2 Department of Surgery and Laboratory of Experimental Surgery & Surgical Research, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
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Rudling M, Laskar A, Straniero S. Gallbladder bile supersaturated with cholesterol in gallstone patients preferentially develops from shortage of bile acids. J Lipid Res 2019; 60:498-505. [PMID: 30610083 PMCID: PMC6399503 DOI: 10.1194/jlr.s091199] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 12/28/2018] [Indexed: 12/15/2022] Open
Abstract
Gallstone (GS) formation requires that bile is supersaturated with cholesterol, which is estimated by a cholesterol saturation index (CSI) calculated from gallbladder (GB) total lipids and the mol% (mole percent) of bile acids (BAs), cholesterol, and phospholipids (PLs). Whereas CSI indicates GS risk, we hypothesized that additional comparisons of GB lipid mol% data are inappropriate to identify why CSI is increased in GS disease. We anticipated that GB lipid mmol/l (millimole per liter) levels should instead identify that, and therefore retrieved GB mmol/l data for BAs, cholesterol, and PLs from a study on 145 GS and 87 GS-free patients and compared them with the corresponding mol% data. BA and PL mmol/l levels were 33% and 31% lower in GS patients, while cholesterol was unaltered. CSI was higher in GS patients and correlated inversely with GB levels of BAs and PLs, but not with cholesterol. A literature search confirmed, in 13 studies from 11 countries, that GB BA levels and, to a certain extent, PLs are strongly reduced in GS patients, while cholesterol levels are not elevated. Our findings show that a shortage of BAs is a major reason why GB bile is supersaturated with cholesterol in GS patients. These results are sustainable because they are also valid from a global perspective.
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Affiliation(s)
- Mats Rudling
- Metabolism Unit, Endocrinology, Metabolism and Diabetes, and Integrated CardioMetabolic Center (ICMC), Department of Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, S-141 86 Stockholm, Sweden
| | - Amit Laskar
- Metabolism Unit, Endocrinology, Metabolism and Diabetes, and Integrated CardioMetabolic Center (ICMC), Department of Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, S-141 86 Stockholm, Sweden
| | - Sara Straniero
- Metabolism Unit, Endocrinology, Metabolism and Diabetes, and Integrated CardioMetabolic Center (ICMC), Department of Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, S-141 86 Stockholm, Sweden
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Ferkingstad E, Oddsson A, Gretarsdottir S, Benonisdottir S, Thorleifsson G, Deaton AM, Jonsson S, Stefansson OA, Norddahl GL, Zink F, Arnadottir GA, Gunnarsson B, Halldorsson GH, Helgadottir A, Jensson BO, Kristjansson RP, Sveinbjornsson G, Sverrisson DA, Masson G, Olafsson I, Eyjolfsson GI, Sigurdardottir O, Holm H, Jonsdottir I, Olafsson S, Steingrimsdottir T, Rafnar T, Bjornsson ES, Thorsteinsdottir U, Gudbjartsson DF, Sulem P, Stefansson K. Genome-wide association meta-analysis yields 20 loci associated with gallstone disease. Nat Commun 2018; 9:5101. [PMID: 30504769 PMCID: PMC6269469 DOI: 10.1038/s41467-018-07460-y] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 11/01/2018] [Indexed: 01/07/2023] Open
Abstract
Gallstones are responsible for one of the most common diseases in the Western world and are commonly treated with cholecystectomy. We perform a meta-analysis of two genome-wide association studies of gallstone disease in Iceland and the UK, totaling 27,174 cases and 736,838 controls, uncovering 21 novel gallstone-associated variants at 20 loci. Two distinct low frequency missense variants in SLC10A2, encoding the apical sodium-dependent bile acid transporter (ASBT), associate with an increased risk of gallstone disease (Pro290Ser: OR = 1.36 [1.25-1.49], P = 2.1 × 10-12, MAF = 1%; Val98Ile: OR = 1.15 [1.10-1.20], P = 1.8 × 10-10, MAF = 4%). We demonstrate that lower bile acid transport by ASBT is accompanied by greater risk of gallstone disease and highlight the role of the intestinal compartment of the enterohepatic circulation of bile acids in gallstone disease susceptibility. Additionally, two low frequency missense variants in SERPINA1 and HNF4A and 17 common variants represent novel associations with gallstone disease.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Florian Zink
- deCODE Genetics/Amgen, Inc., Reykjavik, 101, Iceland
| | | | | | | | | | | | | | | | | | - Gisli Masson
- deCODE Genetics/Amgen, Inc., Reykjavik, 101, Iceland
| | - Isleifur Olafsson
- Department of Clinical Biochemistry, Landspítali University Hospital, Reykjavik, 101, Iceland
| | | | - Olof Sigurdardottir
- Department of Clinical Biochemistry, Akureyri Hospital, Akureyri, 600, Iceland
| | - Hilma Holm
- deCODE Genetics/Amgen, Inc., Reykjavik, 101, Iceland
| | - Ingileif Jonsdottir
- deCODE Genetics/Amgen, Inc., Reykjavik, 101, Iceland
- Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland
- Department of Immunology, Landspitali University Hospital, Reykjavik, 101, Iceland
| | - Sigurdur Olafsson
- Department of Internal Medicine, Landspitali University Hospital, Reykjavik, 101, Iceland
| | - Thora Steingrimsdottir
- Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland
- Department of Obstetrics and Gynecology, Landspitali University Hospital, Reykjavik, 101, Iceland
| | | | - Einar S Bjornsson
- Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland
- Department of Internal Medicine, Landspitali University Hospital, Reykjavik, 101, Iceland
| | - Unnur Thorsteinsdottir
- deCODE Genetics/Amgen, Inc., Reykjavik, 101, Iceland
- Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland
| | - Daniel F Gudbjartsson
- deCODE Genetics/Amgen, Inc., Reykjavik, 101, Iceland
- School of Engineering and Natural Sciences, University of Iceland, Reykjavik, 101, Iceland
| | - Patrick Sulem
- deCODE Genetics/Amgen, Inc., Reykjavik, 101, Iceland.
| | - Kari Stefansson
- deCODE Genetics/Amgen, Inc., Reykjavik, 101, Iceland.
- Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland.
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Gutiérrez-Díaz I, Molinero N, Cabrera A, Rodríguez JI, Margolles A, Delgado S, González S. Diet: Cause or Consequence of the Microbial Profile of Cholelithiasis Disease? Nutrients 2018; 10:nu10091307. [PMID: 30223526 PMCID: PMC6163750 DOI: 10.3390/nu10091307] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 09/05/2018] [Accepted: 09/13/2018] [Indexed: 01/06/2023] Open
Abstract
Recent dietary habits and lifestyle could explain the shaping of the gut microbiota composition and, in consequence, the increasing prevalence of certain pathologies. However, little attention has been paid to the influence of diet on microbiotas, other than the gut microbiota. This is important in cholelithiasis, given that changes in the production of bile acids may affect gallbladder microbial communities. Our aim was to assess the association between regular dietary intake and gallbladder microbial composition. Fourteen adults with cholelithiasis and 14 controls, sex‒age-matched and without gastrointestinal pathology, were included. Diet was assessed through a food frequency questionnaire and quantification of gallbladder microbiota sequences by Illumina 16S rRNA gene-based analysis. The cholelithiasic patients showed greater intake of potatoes and lower consumption of vegetables, non-alcoholic drinks, and sauces, which resulted in a lower intake of energy, lipids, digestible polysaccharides, folate, calcium, magnesium, vitamin C, and some phenolic compounds. Regarding the altered bile microorganisms in cholelithiasic patients, dairy product intake was negatively associated with the proportions of Bacteroidaceae and Bacteroides, and several types of fiber, phenolics, and fatty acids were linked to the abundance of Bacteroidaceae, Chitinophagaceae, Propionibacteraceae, Bacteroides, and Escherichia‒Shigella. These results support a link between diet, biliary microbiota, and cholelithiasis.
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Affiliation(s)
- Isabel Gutiérrez-Díaz
- Department of Functional Biology, University of Oviedo, C/Julián Clavería s/n, 33006 Oviedo, Asturias, Spain.
- Group Diet, Microbiota and Health, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Avda. Roma s/n, 33011 Oviedo, Asturias, Spain.
| | - Natalia Molinero
- Department of Microbiology and Biochemistry of Dairy Products, Dairy Research Institute of Asturias⁻Spanish National Research Council (IPLA-CSIC), Paseo Río Linares s/n, 33300 Villaviciosa, Asturias, Spain.
| | - Ana Cabrera
- General Surgery Service, Colorectal Surgery Unit, Cabueñes University Hospital, Calle Los Prados 395, 33394 Gijón, Asturias, Spain.
| | - José Ignacio Rodríguez
- General Surgery Service, Colorectal Surgery Unit, Cabueñes University Hospital, Calle Los Prados 395, 33394 Gijón, Asturias, Spain.
| | - Abelardo Margolles
- Department of Microbiology and Biochemistry of Dairy Products, Dairy Research Institute of Asturias⁻Spanish National Research Council (IPLA-CSIC), Paseo Río Linares s/n, 33300 Villaviciosa, Asturias, Spain.
| | - Susana Delgado
- Department of Microbiology and Biochemistry of Dairy Products, Dairy Research Institute of Asturias⁻Spanish National Research Council (IPLA-CSIC), Paseo Río Linares s/n, 33300 Villaviciosa, Asturias, Spain.
| | - Sonia González
- Department of Functional Biology, University of Oviedo, C/Julián Clavería s/n, 33006 Oviedo, Asturias, Spain.
- Group Diet, Microbiota and Health, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Avda. Roma s/n, 33011 Oviedo, Asturias, Spain.
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Mixed Micelles Loaded with Bile Salt: An Approach to Enhance Intestinal Transport of the BCS Class III Drug Cefotaxime in Rats. Eur J Drug Metab Pharmacokinet 2018; 42:635-645. [PMID: 27686853 DOI: 10.1007/s13318-016-0375-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
BACKGROUND AND OBJECTIVES Cefotaxime is a class III drug according to the Biopharmaceutical Classification System due to low intestinal permeability based on poor oral bioavailability. Bile salt compounds have been shown to be effective additive for drug permeation through several biological membranes. The main purpose of this study was to investigate the ability of a mixed micelles made of phosphatidylcholine, sodium deoxycholate, and loaded with a cefotaxime-3α,7α-dihydroxy-12-keto-5β-cholanate complex to enhance the oral bioavailability of cefotaxime in rats. METHODS Thin-film hydration method was used to prepare cefotaxime-loaded mixed micelles using different bile salt concentrations (0.87-25 mM of sodium deoxycholate). Overall, micelle sizes ranging from 86.9 to 155.6 nm were produced with negative zeta potential values from -15.9 to -19.5 mV and drug loading from 10.5 to 18.9 %. The oral bioavailability of cefotaxime in mixed micellar formulation was assessed and the pharmacokinetic parameters were compared with cefotaxime-3α,7α-dihydroxy-12-keto-5β-cholanate complex and cefotaxime aqueous solution. 24 Male Wistar rats were randomly allocated into four groups (n = 6, per group) to receive the following: (1) a single intravenous dose of cefotaxime (25 mg/kg) in sterilized normal saline solution for injection; (2) a single oral dose of mixed micelles (100 mg/kg of cefotaxime) in phosphate buffered saline administered by oral gavage; (3) a single oral dose of cefotaxime-3α,7α-dihydroxy-12-keto-5β-cholanate complex (100 mg/kg of cefotaxime) in phosphate buffered saline administered by oral gavage; (4) a single oral dose of free cefotaxime (100 mg/kg) in aqueous solution administered by oral gavage. Blood samples were collected for up to 24 h and cefotaxime analyzed using a validated HPLC assay. RESULTS Pharmacokinetic data showed that the oral bioavailability of cefotaxime in mixed micelles was found to be 4.91 % higher compared to the cefotaxime in aqueous solution (1.30 %). Maximum concentration (C max) of cefotaxime in mixed micellar formulation was higher (1.08 ± 0.1 µg/ml) compared to the cefotaxime-3α,7α-dihydroxy-12-keto-5β-cholanate complex (0.69 ± 0.1 µg/ml) and cefotaxime in aqueous solution (0.52 ± 0.1 µg/ml). Similarly, the mean values for area under the plasma concentration-time curve extrapolated to infinity (AUC0-∞) of cefotaxime in the mixed micellar formulation was higher (3.89 ± 0.9 μg·h/mL) compared to the cefotaxime-3α,7α-dihydroxy-12-keto-5β-cholanate complex (1.52 ± 0.2 μg·h/mL) and cefotaxime in aqueous solution (1.03 ± 0.4 μg·h/mL), respectively. CONCLUSION The mixed micellar formulation was able to increase the oral bioavailability of the BCS Class III drug cefotaxime up to fourfold by enhancing drug permeation through the mucosal membrane of the small intestine.
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Abstract
PURPOSE OF REVIEW To discuss recent insights into the measurement and cellular basis of transintestinal cholesterol excretion (TICE) in humans and to explore TICE as a therapeutic target for increasing reverse cholesterol transport. RECENT FINDINGS TICE is the net effect of cholesterol excretion by the enterocyte into the intestinal lumen and is the balance between input and output fluxes through the enterocytes. These fluxes are: cholesterol excretion into the intestinal lumen mainly via ATP-binding cassette (ABC) G5/8, cholesterol absorption from the intestine by Niemann-Pick C1 like protein 1, the uptake of plasma lipoproteins by enterocytes at the basolateral membrane, and the excretion of cholesterol in chylomicrons into the lymph. Multiple studies have shown that TICE contributes to fecal neutral sterol (FNS) excretion in humans. TICE can be targeted with plant sterols, liver X receptor agonists, bile acids, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors. SUMMARY TICE contributes significantly to FNS excretion in humans, independently of the biliary pathway. Knowledge about its underlying cellular mechanisms surges through in-vivo and in-vitro studies in mice and humans. TICE might be an interesting therapeutic target for increasing cholesterol disposal with the feces. Albeit multiple therapeutic options are available, studies showing clinical benefit are still needed.
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Affiliation(s)
| | | | - Albert K Groen
- Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam
- Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands
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Wang HH, Garruti G, Liu M, Portincasa P, Wang DQH. Cholesterol and Lipoprotein Metabolism and Atherosclerosis: Recent Advances In reverse Cholesterol Transport. Ann Hepatol 2017; 16:s27-s42. [PMID: 29080338 DOI: 10.5604/01.3001.0010.5495] [Citation(s) in RCA: 170] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 09/18/2017] [Indexed: 02/04/2023]
Abstract
Atherosclerosis is characterized by lipid accumulation, inflammatory response, cell death and fibrosis in the arterial wall, and is major pathological basis for ischemic coronary heart disease (CHD), which is the leading cause of morbidity and mortality in the USA and Europe. Intervention studies with statins have shown to reduce LDL cholesterol levels and subsequently the risk of developing CHD. However, not all the aggressive statin therapy could decrease the risk of developing CHD. Many clinical and epidemiological studies have clearly demonstrated that the HDL cholesterol is inversely associated with risk of CHD and is a critical and independent component of predicting its risk. Elucidations of HDL metabolism give rise to therapeutic targets with potential to raising plasma HDL cholesterol levels, thereby reducing the risk of developing CHD. The concept of reverse cholesterol transport is based on the hypothesis that HDL displays an cardioprotective function, which is a process involved in the removal of excess cholesterol that is accumulated in the peripheral tissues (e.g., macrophages in the aortae) by HDL, transporting it to the liver for excretion into the feces via the bile. In this review, we summarize the latest advances in the role of the lymphatic route in reverse cholesterol transport, as well as the biliary and the non-biliary pathways for removal of cholesterol from the body. These studies will greatly increase the likelihood of discovering new lipid-lowering drugs, which are more effective in the prevention and therapeutic intervention of CHD that is the major cause of human death and disability worldwide.
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Affiliation(s)
- Helen H Wang
- Department of Medicine, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Gabriella Garruti
- Department of Emergency and Organ Transplants, Unit of Endocrinology, University of Bari Medical School, Bari, Italy
| | - Min Liu
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA
| | - Piero Portincasa
- Department of Biomedical Sciences and Human Oncology, Clinica Medica "A. Murri", University of Bari "Aldo Moro" Medical School, Bari, Italy
| | - David Q-H Wang
- Department of Medicine, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA
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Risk factors for gallstones and kidney stones in a cohort of patients with inflammatory bowel diseases. PLoS One 2017; 12:e0185193. [PMID: 29023532 PMCID: PMC5638235 DOI: 10.1371/journal.pone.0185193] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 09/07/2017] [Indexed: 12/23/2022] Open
Abstract
Background Gallstones and kidney stones are known complications of inflammatory bowel diseases (IBD). Risk factors have been insufficiently studied and explanatory studies date back up to 30 years. It remains unclear, whether improved treatment options also influenced risk factors for these complications. Objectives Identifying risk factors for gallstones and kidney stones in IBD patients. Methods Using data from the Swiss Inflammatory Bowel Disease Cohort Study we assessed associations of diseases characteristics with gallstones and kidney stones in univariate and multivariate logistic regression analyses. Results Out of 2323 IBD patients, 104 (7.8%) Crohn’s disease (CD) and 38 (3.8%) ulcerative colitis (UC) patients were diagnosed with gallstones. Significant risk factors for gallstones were diagnosis of CD, age at diagnosis, disease activity and duration, NSAID intake, extra-intestinal manifestations and intestinal surgery. Kidney stones were described in 61 (4.6%) CD and 30 (3.0%) UC patients. Male gender, disease activity, intestinal surgery, NSAID usage and reduced physical activity were significant risk factors. Hospitalization was associated with gallstones and kidney stones. The presence of gallstones increased the risk for kidney stones (OR 4.87, p<0.001). Conclusion The diagnosis of CD, intestinal surgery, prolonged NSAID use, disease activity and duration and bowel stenosis were significantly associated with cholecystonephrolithiasis in IBD.
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Suys EJA, Warren DB, Porter CJH, Benameur H, Pouton CW, Chalmers DK. Computational Models of the Intestinal Environment. 3. The Impact of Cholesterol Content and pH on Mixed Micelle Colloids. Mol Pharm 2017; 14:3684-3697. [DOI: 10.1021/acs.molpharmaceut.7b00446] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Affiliation(s)
| | | | | | - Hassan Benameur
- Capsugel Research & Development, Parc d’Innovation, Strasbourg, France
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Shabanzadeh DM, Novovic S. Alcohol, smoking and benign hepato-biliary disease. Best Pract Res Clin Gastroenterol 2017; 31:519-527. [PMID: 29195671 DOI: 10.1016/j.bpg.2017.09.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 08/29/2017] [Accepted: 09/03/2017] [Indexed: 01/31/2023]
Abstract
Gallstone disease and pancreatitis are the most frequent benign hepato-biliary causes of hospital admissions. Gallstone disease is prevalent, but symptomatic disease develops only in about one out of five carriers. Alcohol intake seems to protect gallstone formation in cohort studies possibly through effects on bile cholesterol metabolism, the enterohepatic circulation, and gallbladder function. The impact of smoking on gallstone formation seems minor. Both alcohol intake and smoking do not alter the clinical course of gallstone disease carriers. Cholecystectomy is the preferred treatment for symptomatic gallstone disease. Studies about the impact of alcohol and smoking on the post-cholecystectomy state are few and future studies should be performed. Pancreatitis is associated with both excessive alcohol intake and smoking in observational studies. Interpretation of associations with pancreatitis is hampered by an incomplete understanding of underlying mechanisms and by the co-existence of excessive alcohol intake and smoking. Smoking cessation and alcohol abstinence is recommended in the treatment of pancreatitis, but higher-level evidence is needed.
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Affiliation(s)
- Daniel Mønsted Shabanzadeh
- Digestive Disease Center, Bispebjerg University Hospital, Copenhagen, Denmark; Research Centre for Prevention and Health, Denmark.
| | - Srdan Novovic
- Department of Gastroenterology and Gastrointestinal Surgery, Copenhagen University Hospital Hvidovre, Denmark.
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Abstract
Cholesterol gallstone disease is highly prevalent in Western countries, particularly in women and some specific ethnic groups. The mechanisms behind the formation of gallstones are not clearly understood, but gallbladder dysmotility seems to be a key factor that triggers the precipitation of cholesterol microcrystals from supersaturated lithogenic bile.Given that newly described interstitial cells, telocytes, are present in the gallbladder and they are located in close vicinity of smooth muscle cell and neural fibers possibly interfering with gallbladder motility or contractility, authors are trying to summarize the current knowledge on the role of telocytes with respect to disturbed gallbladder function in gallstone disease.
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Wang Y, Yu X, Zhao QZ, Zheng S, Qing WJ, Miao CD, Sanjay J. Thyroid dysfunction, either hyper or hypothyroidism, promotes gallstone formation by different mechanisms. J Zhejiang Univ Sci B 2017; 17:515-25. [PMID: 27381728 DOI: 10.1631/jzus.b1500210] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
We have investigated comprehensively the effects of thyroid function on gallstone formation in a mouse model. Gonadectomized gallstone-susceptible male C57BL/6 mice were randomly distributed into three groups each of which received an intervention to induce hyperthyroidism, hypothyroidism, or euthyroidism. After 5 weeks of feeding a lithogenic diet of 15% (w/w) butter fat, 1% (w/w) cholesterol, and 0.5% (w/w) cholic acid, mice were killed for further experiments. The incidence of cholesterol monohydrate crystal formation was 100% in mice with hyperthyroidism, 83% in hypothyroidism, and 33% in euthyroidism, the differences being statistically significant. Among the hepatic lithogenic genes, Trβ was found to be up-regulated and Rxr down-regulated in the mice with hypothyroidism. In contrast, Lxrα, Rxr, and Cyp7α1 were up-regulated and Fxr down-regulated in the mice with hyperthyroidism. In conclusion, thyroid dysfunction, either hyperthyroidism or hypothyroidism, promotes the formation of cholesterol gallstones in C57BL/6 mice. Gene expression differences suggest that thyroid hormone disturbance leads to gallstone formation in different ways. Hyperthyroidism induces cholesterol gallstone formation by regulating expression of the hepatic nuclear receptor genes such as Lxrα and Rxr, which are significant in cholesterol metabolism pathways. However, hypothyroidism induces cholesterol gallstone formation by promoting cholesterol biosynthesis.
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Affiliation(s)
- Yong Wang
- Department of Thyroid Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Xing Yu
- Cancer Institute, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Qun-Zi Zhao
- Department of Thyroid Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Shu Zheng
- Cancer Institute, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Wen-Jie Qing
- Department of Clinical Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China
| | - Chun-di Miao
- Department of Clinical Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China
| | - Jaiswal Sanjay
- Department of Clinical Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China
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Ramana Ramya J, Thanigai Arul K, Epple M, Giebel U, Guendel-Graber J, Jayanthi V, Sharma M, Rela M, Narayana Kalkura S. Chemical and structural analysis of gallstones from the Indian subcontinent. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2017; 78:878-885. [PMID: 28576062 DOI: 10.1016/j.msec.2017.04.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2016] [Revised: 03/29/2017] [Accepted: 04/01/2017] [Indexed: 02/03/2023]
Abstract
Representative gallstones from north and southern parts of India were analyzed by a combination of physicochemical methods: X-ray diffraction (XRD), infrared spectroscopy (IR), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), CHNS analysis, thermal analysis and Nuclear Magnetic Resonance (NMR) spectroscopy (1H and 13C). The stones from north Indian were predominantly consisting of cholesterol monohydrate and anhydrous cholesterol which was confirmed by XRD analysis. FTIR spectroscopy confirmed the presence of cholesterol and calcium bilirubinate in the south Indian gallstones. EDX spectroscopy revealed the presence of carbon, nitrogen, oxygen, calcium, sulfur, sodium and magnesium and chloride in both south Indian and north Indian gallstones. FTIR and NMR spectroscopy confirmed the occurrence of cholesterol in north Indian gallstones. The respective colour of the north Indian and south Indian gallstones was yellowish and black. The morphology of the constituent crystals of the north Indian and south Indian gallstones were platy and globular respectively. The appreciable variation in colour, morphology and composition of south and north Indian gallstones may be due to different food habit and habitat.
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Affiliation(s)
- J Ramana Ramya
- Crystal Growth Centre, Anna University, Chennai 600 025, Tamil Nadu, India
| | - K Thanigai Arul
- Department of Physics, AMET University, Kanathur, Chennai 603 112, Tamil Nadu, India
| | - M Epple
- Inorganic Chemistry and Center for Nanointegration Duisburg-Essen (CeNIDE), University of Duisburg-Essen, 45117 Essen, Germany
| | - U Giebel
- Inorganic Chemistry and Center for Nanointegration Duisburg-Essen (CeNIDE), University of Duisburg-Essen, 45117 Essen, Germany
| | - J Guendel-Graber
- Inorganic Chemistry and Center for Nanointegration Duisburg-Essen (CeNIDE), University of Duisburg-Essen, 45117 Essen, Germany
| | - V Jayanthi
- Department of Hepatology and Liver Transplantation, Global Hospitals and Health City, Chennai 600 100, Tamil Nadu, India
| | - M Sharma
- Jaswant Rai Speciality Hospital, Meerut 250 003, Uttar Pradesh, India
| | - M Rela
- Department of Hepatology and Liver Transplantation, Global Hospitals and Health City, Chennai 600 100, Tamil Nadu, India
| | - S Narayana Kalkura
- Crystal Growth Centre, Anna University, Chennai 600 025, Tamil Nadu, India.
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Abstract
Despite the overwhelming prevalence of cholelithiasis, many health care professionals are not familiar with the basic pathophysiology of gallstone formation. This article provides an overview of the biochemical pathways related to bile, with a focus on the physical chemistry of bile. We describe the important factors in bile synthesis and secretion that affect the composition of bile and consequently its liquid state. Within this biochemical background lies the foundation for understanding the clinical and sonographic manifestation of cholelithiasis, including the pathophysiology of cholesterol crystallization, gallbladder sludge, and gallstones. There is a brief discussion of the clinical manifestations of inflammatory and obstructive cholestasis and the impact on bile metabolism and subsequently on liver function tests. Despite being the key modality in diagnosing cholelithiasis, ultrasound has a limited role in the characterization of stone composition.
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Bile acids and their receptors during liver regeneration: "Dangerous protectors". Mol Aspects Med 2017; 56:25-33. [PMID: 28302491 DOI: 10.1016/j.mam.2017.03.002] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 02/07/2017] [Accepted: 03/10/2017] [Indexed: 02/07/2023]
Abstract
Tissue repair is orchestrated by a finely tuned interplay between processes of regeneration, inflammation and cell protection, allowing organisms to restore their integrity after partial loss of cells or organs. An important, although largely unexplored feature is that after injury and during liver repair, liver functions have to be maintained to fulfill the peripheral demand. This is particularly critical for bile secretion, which has to be finely modulated in order to preserve liver parenchyma from bile-induced injury. However, mechanisms allowing the liver to maintain biliary homeostasis during repair after injury are not completely understood. Besides cytokines and growth factors, bile acids (BA) and their receptors constitute an insufficiently explored signaling network during liver regeneration and repair. BA signal through both nuclear (mainly Farnesoid X Receptor, FXR) and membrane (mainly G Protein-coupled BA Receptor 1, GPBAR-1 or TGR5) receptors which distributions are large in the organism, and which activation elicits a wide array of biological responses. While a number of studies have been dedicated to FXR signaling in liver repair processes, TGR5 remains poorly explored in this context. Because of the massive and potentially harmful BA overload that faces the remnant liver after partial ablation or destruction, both BA-induced adaptive and proliferative responses may stand in a central position to contribute to the regenerative response. Based on the available literature, both BA receptors may act in synergy during the regeneration process, in order to protect the remnant liver and maintain biliary homeostasis, otherwise potentially toxic BA overload would result in parenchymal insult and compromise optimal restoration of a functional liver mass.
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Dugardin C, Briand O, Touche V, Schonewille M, Moreau F, Le May C, Groen AK, Staels B, Lestavel S. Retrograde cholesterol transport in the human Caco-2/TC7 cell line: a model to study trans-intestinal cholesterol excretion in atherogenic and diabetic dyslipidemia. Acta Diabetol 2017; 54:191-199. [PMID: 27796655 DOI: 10.1007/s00592-016-0936-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Accepted: 10/18/2016] [Indexed: 12/19/2022]
Abstract
AIMS The dyslipidemia associated with type 2 diabetes is a major risk factor for the development of atherosclerosis. Trans-intestinal cholesterol excretion (TICE) has recently been shown to contribute, together with the classical hepatobiliary route, to fecal cholesterol excretion and cholesterol homeostasis. The aim of this study was to develop an in vitro cell model to investigate enterocyte-related processes of TICE. METHODS Differentiated Caco-2/TC7 cells were grown on transwells and incubated basolaterally (blood side) with human plasma and apically (luminal side) with lipid micelles. Radioactive and fluorescent cholesterol tracers were used to investigate cholesterol uptake at the basolateral membrane, intracellular distribution and apical excretion. RESULTS Our results show that cholesterol is taken up at the basolateral membrane, accumulates intracellularly as lipid droplets and undergoes a cholesterol acceptor-facilitated and progressive excretion through the apical membrane of enterocytes. The overall process is abolished at 4 °C, suggesting a biologically active phenomenon. Moreover, this trans-enterocytic retrograde cholesterol transport displays some TICE features like modulation by PCSK9 and an ABCB1 inhibitor. Finally, we highlight the involvement of microtubules in the transport of plasma cholesterol from basolateral to apical pole of enterocytes. CONCLUSIONS The human Caco-2/TC7 cell line appears a good in vitro model to investigate the enterocytic molecular mechanisms of TICE, which may help to identify intestinal molecular targets to enhance reverse cholesterol transport and fight against dyslipidemia.
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Affiliation(s)
- Camille Dugardin
- Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, Univ. Lille, 59000, Lille, France
| | - Olivier Briand
- Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, Univ. Lille, 59000, Lille, France
| | - Véronique Touche
- Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, Univ. Lille, 59000, Lille, France
| | - Marleen Schonewille
- University Medical Center Groningen, Department of Pediatrics, University of Groningen, Groningen, The Netherlands
| | | | - Cédric Le May
- INSERM, UMR 1087, CNRS UMR 6291, 44000, Nantes, France
| | - Albert K Groen
- University Medical Center Groningen, Department of Pediatrics, University of Groningen, Groningen, The Netherlands
- Academic Medical Center, Amsterdam, The Netherlands
| | - Bart Staels
- Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, Univ. Lille, 59000, Lille, France.
| | - Sophie Lestavel
- Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, Univ. Lille, 59000, Lille, France
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Floreani A, Sun Y, Zou ZS, Li B, Cazzagon N, Bowlus CL, Gershwin ME. Proposed therapies in primary biliary cholangitis. Expert Rev Gastroenterol Hepatol 2016; 10:371-382. [PMID: 26577047 PMCID: PMC4935759 DOI: 10.1586/17474124.2016.1121810] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a model autoimmune disease with chronic cholestasis characterized by the hallmark of anti-mitochondrial antibodies and treated with ursodeoxycholic acid (UDCA). However, approximately 20-40% of patients incompletely respond to UDCA and have an increased risk of disease progression. Although there have been significant advances in the immunobiology of PBC, these have yet to be translated into newer therapeutic modalities. Current approaches to controlling the immune response include broad immunosuppression with corticosteroids as well as targeted therapies directed against T and B cells. In contrast, ameliorating cholestasis is the focus of other therapies in development, including obeticholic acid. In this article the authors will discuss ongoing clinical trials and, in particular, the rationale for choosing agents that may effectively target the aberrant immune response.
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Affiliation(s)
- Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Italy
| | - Ying Sun
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis School of Medicine, Davis, CA, USA.,Diagnostic and Treatment Center for Non-Infectious Liver Diseases, 302 Military Hospital, Beijing, China
| | - Zheng Sheng Zou
- Diagnostic and Treatment Center for Non-Infectious Liver Diseases, 302 Military Hospital, Beijing, China
| | - Baosen Li
- Diagnostic and Treatment Center for Non-Infectious Liver Diseases, 302 Military Hospital, Beijing, China
| | - Nora Cazzagon
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Italy
| | - Christopher L Bowlus
- Division of Gastroenterology and Hepatology, University of California Davis, Davis, CA, USA
| | - M Eric Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis School of Medicine, Davis, CA, USA
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43
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Jayanthi V, Sarika S, Varghese J, Vaithiswaran V, Sharma M, Reddy MS, Srinivasan V, Reddy GMM, Rela M, Kalkura S. Composition of gallbladder bile in healthy individuals and patients with gallstone disease from north and South India. Indian J Gastroenterol 2016; 35:347-353. [PMID: 27633032 DOI: 10.1007/s12664-016-0685-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Accepted: 08/08/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND Gallstones (GS) in south India (SI) are predominantly pure pigment or mixed, while in North India (NI), these are either pure cholesterol or mixed. While cholesterol rich gallbladder (GB) bile predicts cholesterol GS, constituent of bile in primary pigment GS is not known. We compared the composition of GB bile from healthy liver donors and patients with GS from north and south India. METHODS Gallbladder bile from healthy liver donors from north (10) and south India (8) served as controls. Cases were patients from north (21) and south India (17) who underwent cholecystectomy for GS disease. Gallbladder bile from both cases and controls was analyzed for cholesterol, lecithin (phospholipid), and bile salts. Gallstones were classified as cholesterol, mixed, and pigment based on morphology and biochemical analysis. RESULTS The median cholesterol concentration in control bile from north was significantly high compared to south (p<0.001) with no difference in lecithin and bile salts (p NS). Except for one sample each from north and south, the cholesterol solubility of controls was within the critical micellar zone. Mixed GS were most frequent in north India (61.9 %) while pigment GS dominated in south (61.9 %). The median cholesterol concentration in bile samples of cholecystectomy patients from north India was significantly high GS (p < 0.00001) with significant lowering of bile salts and lecithin (p < 0.00001). In south India, patients with mixed GS had high cholesterol content in bile compared to controls and patients with pigment GS; bile in latter had significantly higher concentration of bile salt compared to controls and mixed GS. The ternary plot confirmed the composition of GB bile from north and south India. CONCLUSIONS Gallbladder bile in controls and patients with GS from north India had significantly high cholesterol concentration. In south India, patients with mixed GS had cholesterol rich bile while pigment GS had higher concentrations of bile salts.
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Affiliation(s)
- V Jayanthi
- Gastroenterology and Hepatology, Institute of Gastrosciences, Global Health City, 439, Cheran Nagar, Chennai, 600 100, India.
| | - S Sarika
- Crystal Growth Center, AC Technology, University of Madras, Chepauk, Chennai, 600 005, India
| | - Joy Varghese
- Institute of Liver Disease and Liver Transplant, Global Health City, 439, Cheran Nagar, Chennai, 600 100, India
| | - V Vaithiswaran
- Gastroenterology and Hepatology, Institute of Gastrosciences, Global Health City, 439, Cheran Nagar, Chennai, 600 100, India
| | - Malay Sharma
- Jaswant Rai Specialty Hospital, Mawana Road, Meerut, 250 001, India
| | - Mettu Srinivas Reddy
- Institute of Liver Disease and Liver Transplant, Global Health City, 439, Cheran Nagar, Chennai, 600 100, India
| | - Vijaya Srinivasan
- Gastroenterology and Hepatology, Institute of Gastrosciences, Global Health City, 439, Cheran Nagar, Chennai, 600 100, India
| | - G M M Reddy
- Chettinad Hospital and Research Institute, Rajiv Gandhi Salai, OMR Chennai, Kelambakkam, Chennai, 603 103, India
| | - Mohamed Rela
- Institute of Liver Disease and Liver Transplant, Global Health City, 439, Cheran Nagar, Chennai, 600 100, India
| | - S Kalkura
- Crystal Growth Center, AC Technology, University of Madras, Chepauk, Chennai, 600 005, India
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45
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Joshi AD, Andersson C, Buch S, Stender S, Noordam R, Weng LC, Weeke PE, Auer PL, Boehm B, Chen C, Choi H, Curhan G, Denny JC, De Vivo I, Eicher JD, Ellinghaus D, Folsom AR, Fuchs C, Gala M, Haessler J, Hofman A, Hu F, Hunter DJ, Janssen HL, Kang JH, Kooperberg C, Kraft P, Kratzer W, Lieb W, Lutsey PL, Murad SD, Nordestgaard BG, Pasquale LR, Reiner AP, Ridker PM, Rimm E, Rose LM, Shaffer CM, Schafmayer C, Tamimi RM, Uitterlinden AG, Völker U, Völzke H, Wakabayashi Y, Wiggs JL, Zhu J, Roden DM, Stricker BH, Tang W, Teumer A, Hampe J, Tybjærg-Hansen A, Chasman DI, Chan AT, Johnson AD. Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies. Gastroenterology 2016; 151:351-363.e28. [PMID: 27094239 PMCID: PMC4959966 DOI: 10.1053/j.gastro.2016.04.007] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Revised: 04/06/2016] [Accepted: 04/07/2016] [Indexed: 01/01/2023]
Abstract
BACKGROUND & AIMS A genome-wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale, meta-analysis of GWASs of individuals of European ancestry with available prior genotype data, to identify additional genetic risk factors for gallstone disease. METHODS We obtained per-allele odds ratio (OR) and standard error estimates using age- and sex-adjusted logistic regression models within each of the 10 discovery studies (8720 cases and 55,152 controls). We performed an inverse variance weighted, fixed-effects meta-analysis of study-specific estimates to identify single-nucleotide polymorphisms that were associated independently with gallstone disease. Associations were replicated in 6489 cases and 62,797 controls. RESULTS We observed independent associations for 2 single-nucleotide polymorphisms at the ABCG8 locus: rs11887534 (OR, 1.69; 95% confidence interval [CI], 1.54-1.86; P = 2.44 × 10(-60)) and rs4245791 (OR, 1.27; P = 1.90 × 10(-34)). We also identified and/or replicated associations for rs9843304 in TM4SF4 (OR, 1.12; 95% CI, 1.08-1.16; P = 6.09 × 10(-11)), rs2547231 in SULT2A1 (encodes a sulfoconjugation enzyme that acts on hydroxysteroids and cholesterol-derived sterol bile acids) (OR, 1.17; 95% CI, 1.12-1.21; P = 2.24 × 10(-10)), rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07-1.17; P = 2.55 × 10(-10)), and rs6471717 near CYP7A1 (encodes an enzyme that catalyzes conversion of cholesterol to primary bile acids) (OR, 1.11; 95% CI, 1.08-1.15; P = 8.84 × 10(-9)). Among individuals of African American and Hispanic American ancestry, rs11887534 and rs4245791 were associated positively with gallstone disease risk, whereas the association for the rs1260326 variant was inverse. CONCLUSIONS In this large-scale GWAS of gallstone disease, we identified 4 loci in genes that have putative functions in cholesterol metabolism and transport, and sulfonylation of bile acids or hydroxysteroids.
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Affiliation(s)
- Amit D. Joshi
- Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, MA,Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA,Clinical and Translational Epidemiology Unit, Massachusetts General Hospital Boston, MA,To whom correspondence should be addressed: Amit D. Joshi, MBBS, PhD, Clinical and Translational Epidemiology Unit, Division of Gastroenterology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA. Tel: +1 617 724 7558; Charlotte Andersson, MD, PhD, The Framingham Heart Study, 73 Mt Wayte Avenue, Framingham, Massachusetts 01702, USA. , Andrew T. Chan, MD, MPH, Massachusetts General Hospital and Harvard Medical School, Clinical and Translational Epidemiology Unit, Division of Gastroenterology, GRJ-825C, Boston, Massachusetts 02114, USA. Tel:+1 617 724 0283; Fax: +1 617 726 3673; , Andrew D. Johnson, PhD, Division of Intramural Research, National Heart, Lung and Blood Institute, Cardiovascular Epidemiology and Human Genomics Branch, The Framingham Heart Study, 73 Mt. Wayte Ave., Suite #2, Framingham, MA, 01702, USA. Tel: +1 508 663 4082; Fax: +1 508 626 1262;
| | - Charlotte Andersson
- The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts.
| | - Stephan Buch
- Medical Department 1, University Hospital Dresden, TU Dresden, Dresden Germany
| | - Stefan Stender
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
| | - Raymond Noordam
- Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands,Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Lu-Chen Weng
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, MN
| | - Peter E. Weeke
- Department of Medicine, Vanderbilt University, Nashville, TN,Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Denmark
| | - Paul L. Auer
- Joseph J. Zilber School of Public Health, University of Wisconsin, Milwaukee,Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Bernhard Boehm
- Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
| | - Constance Chen
- Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, MA
| | - Hyon Choi
- Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, MA
| | - Gary Curhan
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA,Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - Joshua C. Denny
- Department of Medicine, Vanderbilt University, Nashville, TN,Department of Biomedical Informatics, Vanderbilt University, Nashville, TN
| | - Immaculata De Vivo
- Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, MA,Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA,Department of Epidemiology, Harvard School of Public Health, Boston, MA
| | - John D. Eicher
- The National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, MA,Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Framingham, MA
| | - David Ellinghaus
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Aaron R. Folsom
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, MN
| | - Charles Fuchs
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA,Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Manish Gala
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Jeffrey Haessler
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Albert Hofman
- Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Frank Hu
- Department of Epidemiology, Harvard School of Public Health, Boston, MA,Department of Nutrition, Harvard School of Public Health, Boston, MA
| | - David J. Hunter
- Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, MA,Department of Epidemiology, Harvard School of Public Health, Boston, MA
| | - Harry L.A. Janssen
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, the Netherlands,Toronto Centre for Liver Disease, Toronto Western and General Hospital, University Health Network, Toronto, Canada
| | - Jae H. Kang
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
| | - Charles Kooperberg
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Peter Kraft
- Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, MA,Department of Epidemiology, Harvard School of Public Health, Boston, MA
| | - Wolfgang Kratzer
- Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
| | - Wolfgang Lieb
- Institute of Epidemiology, Christian Albrechts Universität Kiel, Niemannsweg 11, Kiel, Germany
| | - Pamela L. Lutsey
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, MN
| | - Sarwa Darwish Murad
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, the Netherlands
| | - Børge G. Nordestgaard
- The Copenhagen General Population Study and,Department of Clinical Biochemistry, Herlev Hospital, Herlev Denmark,Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Louis R. Pasquale
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA,Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA
| | - Alex P. Reiner
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Paul M Ridker
- Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
| | - Eric Rimm
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA,Department of Epidemiology, Harvard School of Public Health, Boston, MA,Department of Nutrition, Harvard School of Public Health, Boston, MA
| | - Lynda M. Rose
- Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
| | | | - Clemens Schafmayer
- Department of General, Abdominal, Thoracic and Transplantation Surgery, University of Kiel, Kiel, Germany
| | - Rulla M. Tamimi
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA,Department of Epidemiology, Harvard School of Public Health, Boston, MA
| | - André G Uitterlinden
- Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands,Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Uwe Völker
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Germany
| | - Henry Völzke
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany,German Center for Cardiovascular Research, Partner Site Greifswald,German Center for Diabetes Research, Site Greifswald
| | - Yoshiyuki Wakabayashi
- The National Heart, Lung, and Blood Institute, DNA Sequencing Core Laboratory, Bethesda, MD
| | - Janey L. Wiggs
- Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA
| | - Jun Zhu
- The National Heart, Lung, and Blood Institute, DNA Sequencing Core Laboratory, Bethesda, MD
| | - Dan M. Roden
- Department of Medicine, Vanderbilt University, Nashville, TN
| | - Bruno H. Stricker
- Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands,Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Weihong Tang
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, MN
| | - Alexander Teumer
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Jochen Hampe
- Medical Department 1, University Hospital Dresden, TU Dresden, Dresden Germany
| | - Anne Tybjærg-Hansen
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark,Department of Clinical Biochemistry, Herlev Hospital, Herlev Denmark
| | - Daniel I. Chasman
- Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
| | - Andrew T. Chan
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA,Clinical and Translational Epidemiology Unit, Massachusetts General Hospital Boston, MA,Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA,To whom correspondence should be addressed: Amit D. Joshi, MBBS, PhD, Clinical and Translational Epidemiology Unit, Division of Gastroenterology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA. Tel: +1 617 724 7558; Charlotte Andersson, MD, PhD, The Framingham Heart Study, 73 Mt Wayte Avenue, Framingham, Massachusetts 01702, USA. , Andrew T. Chan, MD, MPH, Massachusetts General Hospital and Harvard Medical School, Clinical and Translational Epidemiology Unit, Division of Gastroenterology, GRJ-825C, Boston, Massachusetts 02114, USA. Tel:+1 617 724 0283; Fax: +1 617 726 3673; , Andrew D. Johnson, PhD, Division of Intramural Research, National Heart, Lung and Blood Institute, Cardiovascular Epidemiology and Human Genomics Branch, The Framingham Heart Study, 73 Mt. Wayte Ave., Suite #2, Framingham, MA, 01702, USA. Tel: +1 508 663 4082; Fax: +1 508 626 1262;
| | - Andrew D. Johnson
- The National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, MA,Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Framingham, MA,To whom correspondence should be addressed: Amit D. Joshi, MBBS, PhD, Clinical and Translational Epidemiology Unit, Division of Gastroenterology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA. Tel: +1 617 724 7558; Charlotte Andersson, MD, PhD, The Framingham Heart Study, 73 Mt Wayte Avenue, Framingham, Massachusetts 01702, USA. , Andrew T. Chan, MD, MPH, Massachusetts General Hospital and Harvard Medical School, Clinical and Translational Epidemiology Unit, Division of Gastroenterology, GRJ-825C, Boston, Massachusetts 02114, USA. Tel:+1 617 724 0283; Fax: +1 617 726 3673; , Andrew D. Johnson, PhD, Division of Intramural Research, National Heart, Lung and Blood Institute, Cardiovascular Epidemiology and Human Genomics Branch, The Framingham Heart Study, 73 Mt. Wayte Ave., Suite #2, Framingham, MA, 01702, USA. Tel: +1 508 663 4082; Fax: +1 508 626 1262;
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Dwivedi S, Agrawal S, Singh S, Madeshiya AK, Singh D, Mahdi AA, Chandra A. Association of Cytochrome-17 (MspA1) Gene Polymorphism with Risk of Gall Bladder Stones and Cancer in North India. Asian Pac J Cancer Prev 2015. [PMID: 26225710 DOI: 10.7314/apjcp.2015.16.13.5557] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Cholelithiasis is associated in 54%-98% of patients with carcinoma of the gallbladder, and a high incidence among females suggests a role of female hormones in the etiology of the disease. Cytochrome P450C17α (CYP-17) is a key enzyme involved in estrogen metabolism and polymorphisms in CYP-17 are associated with altered serum levels of estrogens. Thus, we investigated whether the CYP-17 MspA1 gene polymorphism might impact on risk of gall bladder cancers or gallstones, as well as to determine if this gene polymorphism might be linked with estrogen serum levels and lipid profile among the North Indian gall bladder cancer or gallstone patients. MATERIALS AND METHODS CYP-17 gene polymorphisms (MspA1) were genotyped with PCR-RFLP in cancer patients (n=96), stone patients (n=102), cancer+stone patients (n=52) and age/sex matched control subjects (n=256). Lipid profile was estimated using a commercial kit and serum estrogen was measured using ELISA. RESULTS The majority of the patients in all groups were females. The lipid profile and estrogen level were significantly higher among the study as compared to control groups. The frequency of mutant allele A2 of CYP17 MspA1 gene polymorphism was higher among cancer (OR=5.13, 95% CI+3.10-8.51, p=0.0001), stone (OR=5.69, 95%CI=3.46-9.37, p=0.0001) and cancer+stone (OR=3.54, 95%CI=1.90-6.60, p=0.0001) when compared with the control group. However there was no significant association between genotypes of CYP17 MspA1 gene polymorphism and circulating serum level of estrogen and lipid profile. CONCLUSIONS A higher frequency of mutant genotype A1A2 as well as mutant allele A2 of CYP-17 gene polymorphism is significantly associated with risk of gallbladder cancer and stones. Elevated levels of estrogen and an altered lipid profile can be used as predictors ofgall bladder stones and cancer in post menopausal females in India.
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Affiliation(s)
- Shipra Dwivedi
- Department of physiology, King George's Medical University, Lucknow, India E-mail :
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Srinivasan K. Anti-cholelithogenic potential of dietary spices and their bioactives. Crit Rev Food Sci Nutr 2015; 57:1749-1758. [DOI: 10.1080/10408398.2014.1003783] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Khoshakhlagh P, Johnson R, Langguth P, Nawroth T, Schmueser L, Hellmann N, Decker H, Szekely NK. Fasted-State Simulated Intestinal Fluid "FaSSIF-C", a Cholesterol Containing Intestinal Model Medium for In Vitro Drug Delivery Development. J Pharm Sci 2015; 104:2213-24. [DOI: 10.1002/jps.24470] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Revised: 04/02/2015] [Accepted: 04/02/2015] [Indexed: 11/05/2022]
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Falguières T, Aït-Slimane T, Housset C, Maurice M. ABCB4: Insights from pathobiology into therapy. Clin Res Hepatol Gastroenterol 2014; 38:557-63. [PMID: 24953525 DOI: 10.1016/j.clinre.2014.03.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Revised: 02/25/2014] [Accepted: 03/05/2014] [Indexed: 02/04/2023]
Abstract
Adenosine triphosphate (ATP)-binding cassette, sub-family B, member 4 (ABCB4), also called multidrug resistance 3 (MDR3), is a member of the ATP-binding cassette transporter superfamily, which is localized at the canalicular membrane of hepatocytes, and mediates the translocation of phosphatidylcholine into bile. Phosphatidylcholine secretion is crucial to ensure solubilization of cholesterol into mixed micelles and to prevent bile acid toxicity towards hepatobiliary epithelia. Genetic defects of ABCB4 may cause progressive familial intrahepatic cholestasis type 3 (PFIC3), a rare autosomic recessive disease occurring early in childhood that may be lethal in the absence of liver transplantation, and other cholestatic or cholelithiasic diseases in heterozygous adults. Development of therapies for these conditions requires understanding of the biology of this transporter and how gene variations may cause disease. This review focuses on our current knowledge on the regulation of ABCB4 expression, trafficking and function, and presents recent advances in fundamental research with promising therapeutic perspectives.
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Affiliation(s)
- Thomas Falguières
- INSERM, UMR_S 938, CDR Saint-Antoine, 75012 Paris, France; UMR_S 938, CDR Saint-Antoine, Sorbonne Universités, UPMC - Université Paris-06, 75012 Paris, France
| | - Tounsia Aït-Slimane
- INSERM, UMR_S 938, CDR Saint-Antoine, 75012 Paris, France; UMR_S 938, CDR Saint-Antoine, Sorbonne Universités, UPMC - Université Paris-06, 75012 Paris, France
| | - Chantal Housset
- INSERM, UMR_S 938, CDR Saint-Antoine, 75012 Paris, France; UMR_S 938, CDR Saint-Antoine, Sorbonne Universités, UPMC - Université Paris-06, 75012 Paris, France; Service d'hépatologie, Centre Maladies Rares (CMR) Maladies Inflammatoires des Voies Biliaires, Hôpital Saint-Antoine, Assistance publique-Hôpitaux de Paris, 75012 Paris, France
| | - Michèle Maurice
- INSERM, UMR_S 938, CDR Saint-Antoine, 75012 Paris, France; UMR_S 938, CDR Saint-Antoine, Sorbonne Universités, UPMC - Université Paris-06, 75012 Paris, France.
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Cheng CY, Oh H, Wang TY, Raghavan SR, Tung SH. Mixtures of lecithin and bile salt can form highly viscous wormlike micellar solutions in water. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2014; 30:10221-10230. [PMID: 25121460 DOI: 10.1021/la502380q] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
The self-assembly of biological surfactants in water is an important topic for study because of its relevance to physiological processes. Two common types of biosurfactants are lecithin (phosphatidylcholine) and bile salts, which are both present in bile and involved in digestion. Previous studies on lecithin-bile salt mixtures have reported the formation of short, rodlike micelles. Here, we show that lecithin-bile salt micelles can be further induced to grow into long, flexible wormlike structures. The formation of long worms and their resultant entanglement into transient networks is reflected in the rheology: the fluids become viscoelastic and exhibit Maxwellian behavior, and their zero-shear viscosity can be up to a 1000-fold higher than that of water. The presence of worms is further confirmed by data from small-angle neutron and X-ray scattering and from cryo-transmission electron microscopy (cryo-TEM). We find that micellar growth peaks at a specific molar ratio (near equimolar) of bile salt:lecithin, which suggests a strong binding interaction between the two species. In addition, micellar growth also requires a sufficient concentration of background electrolyte such as NaCl or sodium citrate that serves to screen the electrostatic repulsion of the amphiphiles and to "salt out" the amphiphiles. We postulate a mechanism based on changes in the molecular geometry caused by bile salts and electrolytes to explain the micellar growth.
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Affiliation(s)
- Chih-Yang Cheng
- Institute of Polymer Science and Engineering and ‡Instrumentation Center, National Taiwan University , Taipei 10617, Taiwan
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