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Role of Baicalin and Liver X Receptor Alpha in the Formation of Cholesterol Gallstones in Mice. Gastroenterol Res Pract 2020; 2020:1343969. [PMID: 32382260 PMCID: PMC7191361 DOI: 10.1155/2020/1343969] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 02/17/2020] [Accepted: 03/28/2020] [Indexed: 12/23/2022] Open
Abstract
This study was aimed at investigating the effect of baicalin on experimental cholesterol gallstones in mice. The mouse gallstone model was induced by feeding with a lithogenic diet, and cholesterol stones were found in the gallbladder. The lithogenic diet caused elevation of triglycerides, cholesterol, and low-density lipoprotein concentrations and descent of high-density lipoprotein concentration in serum. Hyperplasia and inflammatory infiltration were observed in the gallbladder wall of lithogenic diet-fed mice. We also found the increase of cholesterol content and the decrease of bile acid in bile. Real-time PCR and western blot results demonstrated that the expression levels of two enzymes (cholesterol 7α-hydroxylase (CYP7a1) and sterol 12α-hydroxylase (CYP8b1)) to catalyze the synthesis of bile acid from cholesterol were decreased and that two cholesterol transporters (ATP-binding cassette transporter G5/G8 (ABCG5/8)) were increased in the liver of lithogenic diet-fed mice. The lithogenic diet also led to enhanced activity of alanine aminotransferase and aspartate aminotransferase in serum; increased concentrations of tumor necrosis factor-α, interleukin- (IL-) 1β, IL-6, and malondialdehyde; and decreased superoxide dismutase activity in the liver, suggesting inflammatory and oxidative stress. In addition, liver X receptor alpha (LXRα) was increased in the liver. After gavage of baicalin, the lithogenic diet-induced gallstones, hyperlipidemia, gallbladder hyperplasia, inflammation, and oxidative stress in liver and cholesterol metabolism disorders were all alleviated to some degree. The expression of LXRα in the liver was inhibited by baicalin. In addition, the LXRα agonist T0901317 aggravated lithogenic diet-induced harmful symptoms in mice, including the increase of gallstone formation, hyperlipidemia, hepatic injury, inflammation, and oxidative stress. In conclusion, we demonstrated that baicalin played a protective role in a lithogenic diet-induced gallstone mouse model, which may be mediated by inhibition of LXRα activity. These findings may provide novel insights for prevention and therapy of gallstones in the clinic.
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Han T, Lv Y, Wang S, Hu T, Hong H, Fu Z. Pioglitazone prevents cholesterol gallstone formation through the regulation of cholesterol homeostasis in guinea pigs with a lithogenic diet. Lipids Health Dis 2019; 18:218. [PMID: 31829191 PMCID: PMC6907187 DOI: 10.1186/s12944-019-1159-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 11/29/2019] [Indexed: 02/07/2023] Open
Abstract
Background The cholesterol gallstones diseases (CGD) is highly correlated with metabolic syndrome and type 2 diabetes. The present study aimed to investigate preventive effects of pioglitazone (PIO), an antidiabetic drug, on the CGD in guinea pigs fed with a lithogenic diet (LD). Methods The guinea pigs were fed with the LD for 8 weeks. All guinea pigs were grouped as follows: low fat diet; LD; LD plus PIO (4 mg/kg); LD plus PIO (8 mg/kg); LD plus ezetimibe (EZE) (2 mg/kg). Gallbladder stones were observed using microscopy. The profile of biliary composition, and blood glucose, insulin and lipid were analyzed. The liver or ileum was harvested for determinations of hydroxyl-methyl-glutaryl-CoA reductase (HMGCR), sterol regulatory element-binding proteins 2 (SREBP2), 7α-hydroxylase (CYP7A1), adenosine triphosphate-binding cassette (ABC) sterol transporters G5 and G8 (ABCG5, ABCG8), bile salt export pump (BSEP), Niemann-Pick C1-Like 1 (NPC1L1) and acetyl-coenzyme A cholesterol acyltransferase (ACAT2) by Western blot. The gallbladders were used for histological examination. Results The LD successfully induced gallstone. Both pioglitazone and ezetimibe prevented gallstone formation, as well as hepatic and cholecystic damages. Pioglitazone significantly decreased HMGCR and SREBP2, but increased CYP7A1, ABCG5, ABCG8, and BSEP in the liver. Pioglitazone also remarkably decreased NPC1L1 and ACAT2, while increased ABCG5/8 in the intestine. The beneficial alterations of cholesterol and bile acids in the bile, as well as profile of glucose, insulin and lipid in the blood were found in the guinea pigs treated with pioglitazone. Conclusion Pioglitazone has a noticeable benefit towards the CGD, which is involved in changes of synthesis, transformation, absorption, and transportation of cholesterol.
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Affiliation(s)
- Tao Han
- Department of Intensive Care Unit, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, Jiangsu, China
| | - Yangge Lv
- Department of Pharmacology, China Pharmaceutical University, Nanjing, 210009, China
| | - Shijia Wang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, Jiangsu, China
| | - Tao Hu
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, Jiangsu, China
| | - Hao Hong
- Department of Pharmacology, China Pharmaceutical University, Nanjing, 210009, China
| | - Zan Fu
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, Jiangsu, China.
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Ren S, Yan X, Ma J, Pan Y, Zhang W, Wang D, Fei Z, Liu X. Defatted walnut powder extract reduces cholesterol gallstones formation in C57BL/6 mice by downregulating the levels of ABCG5/8 in the liver and NPC1L1 in the intestine. J Funct Foods 2018. [DOI: 10.1016/j.jff.2018.06.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
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Kuang H, Yang F, Zhang Y, Wang T, Chen G. The Impact of Egg Nutrient Composition and Its Consumption on Cholesterol Homeostasis. CHOLESTEROL 2018; 2018:6303810. [PMID: 30210871 PMCID: PMC6126094 DOI: 10.1155/2018/6303810] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 08/08/2018] [Indexed: 02/07/2023]
Abstract
Nutrient deficiencies and excess are involved in many aspects of human health. As a source of essential nutrients, eggs have been used worldwide to support the nutritional needs of human societies. On the other hand, eggs also contain a significant amount of cholesterol, a lipid molecule that has been associated with the development of cardiovascular diseases. Whether the increase of egg consumption will lead to elevated cholesterol absorption and disruption of cholesterol homeostasis has been a concern of debate for a while. Cholesterol homeostasis is regulated through its dietary intake, endogenous biosynthesis, utilization, and excretion. Recently, some research interests have been paid to the effects of egg consumption on cholesterol homeostasis through the intestinal cholesterol absorption. Nutrient components in eggs such as phospholipids may contribute to this process. The goals of this review are to summarize the recent progress in this area and to discuss some potential benefits of egg consumption.
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Affiliation(s)
- Heqian Kuang
- Department of Nutrition, University of Tennessee at Knoxville, Knoxville, Tennessee, USA
| | - Fang Yang
- School of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, Hubei, China
| | - Yan Zhang
- Department of Nutrition, University of Tennessee at Knoxville, Knoxville, Tennessee, USA
| | - Tiannan Wang
- Department of Nutrition, University of Tennessee at Knoxville, Knoxville, Tennessee, USA
| | - Guoxun Chen
- Department of Nutrition, University of Tennessee at Knoxville, Knoxville, Tennessee, USA
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Abstract
PURPOSE OF REVIEW The establishment of mouse models of gallstones, and the contribution of mouse models to genetic studies of gallstone disease, as well as the latest advances in the pathophysiology of gallstones from mouse experiments are summarized. RECENT FINDINGS The combined uses of genomic strategies and phenotypic studies in mice have successfully led to the identification of many Lith genes, which pave the way for the discovery of human LITH genes. The physical-chemical, genetic, and molecular biological studies of gallstone disease in mice with knockout or transgene of specific target genes have provided many novel insights into the complex pathophysiological mechanisms of this very common hepatobiliary disease worldwide, showing that interactions of five primary defects play a critical role in the pathogenesis of cholesterol gallstones. Based on mouse studies, a new concept has been proposed that hepatic hypersecretion of biliary cholesterol is induced by multiple Lith genes, with insulin resistance as part of the metabolic syndrome interacting with cholelithogenic environmental factors to cause the phenotype. SUMMARY The mouse model of gallstones is crucial for elucidating the physical-chemical and genetic mechanisms of cholesterol crystallization and gallstone formation, which greatly increase our understanding of the pathogenesis of this disease in humans.
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Affiliation(s)
- Tony Y. Wang
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Piero Portincasa
- Department of Biomedical Sciences and Human Oncology, Clinica Medica ‘A. Murri’, University of Bari ‘Aldo Moro’ Medical School, Bari, Italy
| | - Min Liu
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Patrick Tso
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - David Q.-H. Wang
- Department of Medicine, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York, USA
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Lin J, Shao WQ, Chen QZ, Zhu WW, Lu L, Jia HL, Chen JH. Osteopontin deficiency protects mice from cholesterol gallstone formation by reducing expression of intestinal NPC1L1. Mol Med Rep 2017. [PMID: 28627641 PMCID: PMC5561929 DOI: 10.3892/mmr.2017.6774] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Homeostasis of cholesterol is regulated by absorption in the intestine and synthesis in the liver. The authors previously demonstrated that OPN (osteopontin) exhibits the ability to alter hepatic cholesterol metabolism, thus affecting cholesterol gallstone formation in mice. The present study investigated the role of OPN in cholesterol gallstone formation, focusing on its effect on intestinal absorption of cholesterol. OPN gene knockout (OPN−/−) mice and wild-type mice were respectively fed with a chow or lithogenic diet (LD) for 8 weeks. Following an 8-week LD period, the incidence of gallstone, bile composition, level of serum and fecal lipids and the expression of intestinal associated genes were analyzed. OPN−/− mice were protected from gallstone formation induced by 8 weeks' LD-feeding. This protective effect from OPN deficiency was associated with alterations in bile composition, including a reduced concentration of biliary cholesterol. Additionally, plasma cholesterol level was decreased in LD-fed OPN−/− mice. The alterations primarily resulted from the decreased expression of intestinal Niemann-Pick C1-like (NPC1 L) 1, which is important in the intestinal absorption of cholesterol. The present study demonstrated that OPN deficiency reduced intestinal absorption of cholesterol by suppressing the expression of NPC1L1, thus protecting mice from cholesterol gallstone formation.
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Affiliation(s)
- Jing Lin
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Wei-Qing Shao
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Qing-Zhi Chen
- Shanghai Huayu Private Middle School, Shanghai 200231, P.R. China
| | - Wen-Wei Zhu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Lu Lu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Hu-Liang Jia
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Jin-Hong Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
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Tharp KM, Khalifeh-Soltani A, Park HM, Yurek DA, Falcon A, Wong L, Feng R, Atabai K, Stahl A. Prevention of gallbladder hypomotility via FATP2 inhibition protects from lithogenic diet-induced cholelithiasis. Am J Physiol Gastrointest Liver Physiol 2016; 310:G855-64. [PMID: 27033116 PMCID: PMC4888547 DOI: 10.1152/ajpgi.00316.2015] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 03/28/2016] [Indexed: 01/31/2023]
Abstract
Gallstone disease is a widespread disorder costing billions for annual treatment in the United States. The primary mechanisms underlying gallstone formation are biliary cholesterol supersaturation and gallbladder hypomotility. The relative contribution of these two processes has been difficult to dissect, as experimental lithogenic diets cause both bile supersaturation and alterations in gallbladder motility. Importantly, there is no mechanistic explanation for obesity as a major risk factor for cholelithiasis. We discovered that lithogenic diets induce ectopic triacylglycerol (TAG) accumulation, a major feature of obesity and a known muscle contraction impairing condition. We hypothesized that prevention of TAG accumulation in gallbladder walls may prevent gallbladder contractile dysfunction without impacting biliary cholesterol saturation. We utilized adeno-associated virus-mediated knock down of the long-chain fatty acid transporter 2 (FATP2; Slc27A2), which is highly expressed by gallbladder epithelial cells, to downregulate lithogenic diet-associated TAG accumulation. FATP2-knockdown significantly reduced gallbladder TAG, but did not affect key bile composition parameters. Importantly, measurements with force displacement transducers showed that contractile strength in FATP2-knockdown gallbladders was significantly greater than in control gallbladders following lithogenic diet administration, and the magnitude of this effect was sufficient to prevent the formation of gallstones. FATP2-driven fatty acid uptake and the subsequent TAG accumulation in gallbladder tissue plays a pivotal role in cholelithiasis, and prevention of this process can protect from gallstone formation, even in the context of supersaturated bile cholesterol levels, thus pointing to new treatment approaches and targets.
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Affiliation(s)
- Kevin M. Tharp
- 1Program for Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California;
| | - Amin Khalifeh-Soltani
- 2Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California; and
| | - Hyo Min Park
- 1Program for Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California;
| | | | - Alaric Falcon
- 1Program for Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California;
| | - Louis Wong
- 1Program for Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California;
| | - Rouying Feng
- 1Program for Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California;
| | - Kamran Atabai
- 2Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California; and
| | - Andreas Stahl
- Program for Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California;
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Gong Y, Zhang L, Bie P, Wang H. Roles of ApoB-100 gene polymorphisms and the risks of gallstones and gallbladder cancer: a meta-analysis. PLoS One 2013; 8:e61456. [PMID: 23637837 PMCID: PMC3630192 DOI: 10.1371/journal.pone.0061456] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2013] [Accepted: 03/09/2013] [Indexed: 12/29/2022] Open
Abstract
Background Gallstones (GS) is the major manifestation of gallbladder disease, and is the most common risk factor for gallbladder cancer (GBC). Previous studies investigating the association between ApoB-100 gene polymorphisms and the risks of GS and GBC have yielded conflicting results. Therefore, we performed a meta-analysis to clarify the effects of ApoB-100 gene polymorphisms on the risks of GS and GBC. Methods A computerized literature search was conducted to identify the relevant studies from PubMed and Embase. Fixed or random effects model was selected based on heterogeneity test. Publication bias was estimated using Begg’s funnel plots and Egger’s regression test. Results A total of 10, 3, and 3 studies were included in the analyses of the association between ApoB-100 XbaI, EcoRI, or insertion/deletion (ID) polymorphisms and the GS risks, respectively, while 3 studies were included in the analysis for the association between XbaI polymorphism and GBC risk. The combined results showed a significant association in Chinese (X+ vs. X−, OR = 2.37, 95%CI 1.52–3.70; X+X+/X+X- vs. X+X+, OR = 2.47, 95%CI 1.55–3.92), but not in Indians or Caucasians. Null association was observed between EcoRI or ID polymorphisms and GS risks. With regard to the association between XbaI polymorphism and GBC risk, a significant association was detected when GBC patients were compared with healthy persons and when GBC patients were compared with GS patients. A significant association was still detected when GBC patients (with GS) were compared with the GS patients (X+X+ vs. X-X−, OR = 0.33, 95%CI 0.12–0.90). Conclusion The results of this meta-analysis suggest that the ApoB-100 X+ allele might be associated with increased risk of GS in Chinese but not in other populations, while the ApoB-100 X+X+ genotype might be associated with reduced risk of GBC. Further studies with larger sample sizes are needed to confirm these results.
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Affiliation(s)
- Yi Gong
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing City, P. R. China
| | - Leida Zhang
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing City, P. R. China
| | - Ping Bie
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing City, P. R. China
- * E-mail: (PB); (HW)
| | - Huaizhi Wang
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing City, P. R. China
- * E-mail: (PB); (HW)
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Di Ciaula A, Wang DQH, Bonfrate L, Portincasa P. Current views on genetics and epigenetics of cholesterol gallstone disease. CHOLESTEROL 2013; 2013:298421. [PMID: 23691293 PMCID: PMC3649201 DOI: 10.1155/2013/298421] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/28/2013] [Revised: 03/06/2013] [Accepted: 03/20/2013] [Indexed: 02/07/2023]
Abstract
Cholesterol gallstone disease, one of the commonest digestive diseases in western countries, is induced by an imbalance in cholesterol metabolism, which involves intestinal absorption, hepatic biosynthesis, and biliary output of cholesterol, and its conversion to bile acids. Several components of the metabolic syndrome (e.g., obesity, type 2 diabetes, dyslipidemia, and hyperinsulinemia) are also well-known risk factors for gallstones, suggesting the existence of interplay between common pathophysiological pathways influenced by insulin resistance, genetic, epigenetic, and environmental factors. Cholesterol gallstones may be enhanced, at least in part, by the abnormal expression of a set of the genes that affect cholesterol homeostasis and lead to insulin resistance. Additionally, epigenetic mechanisms (mainly DNA methylation, histone acetylation/deacetylation, and noncoding microRNAs) may modify gene expression in the absence of an altered DNA sequence, in response to different lithogenic environmental stimuli, such as diet, lifestyle, pollutants, also occurring in utero before birth. In this review, we will comment on various steps of the pathogenesis of cholesterol gallstones and interaction between environmental and genetic factors. The epigenomic approach may offer new options for therapy of gallstones and better possibilities for primary prevention in subjects at risk.
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Affiliation(s)
- Agostino Di Ciaula
- Division of Internal Medicine Hospital of Bisceglie, 76011 Bisceglie, Italy
| | - David Q.-H. Wang
- Saint Louis University School of Medicine, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Edward Doisy Research Center, St. Louis, MO 63104, USA
| | - Leonilde Bonfrate
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University “Aldo Moro“ of Bari Medical School, 70124 Bari, Italy
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University “Aldo Moro“ of Bari Medical School, 70124 Bari, Italy
- European Society for Clinical Investigation (ESCI), 3584 CJ Utrecht, The Netherlands
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Wang HH, Portincasa P, de Bari O, Liu KJ, Garruti G, Neuschwander-Tetri BA, Wang DQH. Prevention of cholesterol gallstones by inhibiting hepatic biosynthesis and intestinal absorption of cholesterol. Eur J Clin Invest 2013; 43:413-426. [PMID: 23419155 PMCID: PMC3996849 DOI: 10.1111/eci.12058] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2012] [Accepted: 01/22/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND Cholesterol cholelithiasis is a multifactorial disease influenced by a complex interaction of genetic and environmental factors and represents a failure of biliary cholesterol homoeostasis in which the physical-chemical balance of cholesterol solubility in bile is disturbed. DESIGN The primary pathophysiologic event is persistent hepatic hypersecretion of biliary cholesterol, which has both hepatic and small intestinal components. The majority of the environmental factors are probably related to Western-type dietary habits, including excess cholesterol consumption. RESULTS Laparoscopic cholecystectomy, one of the most commonly performed surgical procedures in the United States, is nowadays a major treatment for gallstones. However, it is invasive and can cause surgical complications, and not all patients with symptomatic gallstones are candidates for surgery. The hydrophilic bile acid, ursodeoxycholic acid (UDCA), has been employed as first-line pharmacological therapy in a subgroup of symptomatic patients with small, radiolucent cholesterol gallstones. Long-term administration of UDCA can promote the dissolution of cholesterol gallstones. However, the optimal use of UDCA is not always achieved in clinical practice because of failure to titrate the dose adequately. CONCLUSIONS Therefore, the development of novel, effective and noninvasive therapies is crucial for reducing the costs of health care associated with gallstones. In this review, we summarize recent progress in investigating the inhibitory effects of ezetimibe and statins on intestinal absorption and hepatic biosynthesis of cholesterol, respectively, for the treatment of gallstones, as well as in elucidating their molecular mechanisms by which combination therapy could prevent this very common liver disease worldwide.
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Affiliation(s)
- Helen H Wang
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO
| | - Piero Portincasa
- Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Ornella de Bari
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO
| | | | - Gabriella Garruti
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO
| | - Brent A Neuschwander-Tetri
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO
| | - David Q.-H Wang
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO
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Portincasa P, Ciaula AD, Bonfrate L, Wang DQ. Therapy of gallstone disease: What it was, what it is, what it will be. World J Gastrointest Pharmacol Ther 2012; 3:7-20. [PMID: 22577615 PMCID: PMC3348960 DOI: 10.4292/wjgpt.v3.i2.7] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2011] [Revised: 09/21/2011] [Accepted: 09/28/2011] [Indexed: 02/06/2023] Open
Abstract
Cholesterol gallstone disease is a common clinical condition influenced by genetic factors, increasing age, female gender, and metabolic factors. Although laparoscopic cholecystectomy is currently considered the gold standard in treating patients with symptomatic gallstones, new perspectives regarding medical therapy of cholelithiasis are currently under discussion, also taking into account the pathogenesis of gallstones, the natural history of the disease and the analysis of the overall costs of therapy. A careful selection of patients may lead to successful non-surgical therapy in symptomatic subjects with a functioning gallbladder harboring small radiolucent stones. The classical oral litholysis by ursodeoxycholic acid has been recently paralleled by new experimental observations, suggesting that cholesterol-lowering agents which inhibit cholesterol synthesis (statins) or intestinal cholesterol absorption (ezetimibe), or drugs acting on specific nuclear receptors involved in cholesterol and bile acid homeostasis, might be proposed as additional approaches for treating cholesterol gallstones. In this review we discuss old, recent and future perspectives on medical treatment of cholesterol cholelithiasis.
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Affiliation(s)
- Piero Portincasa
- Piero Portincasa, Leonilde Bonfrate, Department of Biomedical Sciences and Human Oncology, Clinica Medica "A. Murri", University of Bari Medical School, Piazza Giulio Cesare 11, Policlinico, 70124 Bari, Italy
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de Bari O, Neuschwander-Tetri BA, Liu M, Portincasa P, Wang DQH. Ezetimibe: its novel effects on the prevention and the treatment of cholesterol gallstones and nonalcoholic Fatty liver disease. J Lipids 2011; 2012:302847. [PMID: 22132342 PMCID: PMC3216277 DOI: 10.1155/2012/302847] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2011] [Accepted: 08/26/2011] [Indexed: 12/18/2022] Open
Abstract
The cholesterol absorption inhibitor ezetimibe can significantly reduce plasma cholesterol concentrations by inhibiting the Niemann-Pick C1-like 1 protein (NPC1L1), an intestinal sterol influx transporter that can actively facilitate the uptake of cholesterol for intestinal absorption. Unexpectedly, ezetimibe treatment also induces a complete resistance to cholesterol gallstone formation and nonalcoholic fatty liver disease (NAFLD) in addition to preventing hypercholesterolemia in mice on a Western diet. Because chylomicrons are the vehicles with which the enterocytes transport cholesterol and fatty acids into the body, ezetimibe could prevent these two most prevalent hepatobiliary diseases possibly through the regulation of chylomicron-derived cholesterol and fatty acid metabolism in the liver. It is highly likely that there is an intestinal and hepatic cross-talk through the chylomicron pathway. Therefore, understanding the molecular mechanisms whereby cholesterol and fatty acids are absorbed from the intestine could offer an efficacious novel approach to the prevention and the treatment of cholesterol gallstones and NAFLD.
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Affiliation(s)
- Ornella de Bari
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Edward Doisy Research Center, Saint Louis University School of Medicine, 1100 S. Grand Boulevard, Room 205, St. Louis, MO 63104, USA
| | - Brent A. Neuschwander-Tetri
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Edward Doisy Research Center, Saint Louis University School of Medicine, 1100 S. Grand Boulevard, Room 205, St. Louis, MO 63104, USA
| | - Min Liu
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA
| | - Piero Portincasa
- Department of Internal Medicine and Public Medicine, Clinica Medica “A. Murri”, University of Bari Medical School, 70124 Bari, Italy
| | - David Q.-H. Wang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Edward Doisy Research Center, Saint Louis University School of Medicine, 1100 S. Grand Boulevard, Room 205, St. Louis, MO 63104, USA
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Yamazaki Y, Hashizume T, Morioka H, Sadamitsu S, Ikari A, Miwa M, Sugatani J. Diet-induced lipid accumulation in liver enhances ATP-binding cassette transporter g5/g8 expression in bile canaliculi. Drug Metab Pharmacokinet 2011; 26:442-50. [PMID: 21628838 DOI: 10.2133/dmpk.dmpk-11-rg-025] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The ATP-binding cassette half-transporters Abcg5 and Abcg8 promote the secretion of neutral sterols into bile. Studies have demonstrated the diet-induced expression of these transporters in liver, but precisely where this occurs remains to be elucidated. This study investigated the changes in the expression of these transporters in bile canaliculi in cholesterol-loaded livers. Mice were fed either a standard (SD) diet or a high-fat and high-sucrose (HF/HS) diet for 3 weeks. Bile canaliculi proteins and cryosections were prepared from the liver, and the protein levels and distribution of Abcg5/Abcg8 were determined. The high-calorie diet induced a marked accumulation of lipids in mouse liver. Protein levels of Abcg5 and Abcg8 in bile canaliculi were significantly increased by the HF/HS diet compared to the SD diet. No significant differences in Abca1, Abcb4 (Mdr2), Abcb11 (Bsep), or Abcc2 (Mrp2) levels were observed. Immunohistochemical analyses confirmed that these increases occurred in bile canaliculi. These results suggest that diet-induced lipid loading of the liver causes a significant increase in the expression of Abcg5 and Abcg8 in bile canaliculi.
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Affiliation(s)
- Yasuhiro Yamazaki
- Department of Pharmaco-Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Japan
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14
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Amigo L, Quiñones V, Leiva A, Busso D, Zanlungo S, Nervi F, Rigotti A. Apolipoprotein A-I deficiency does not affect biliary lipid secretion and gallstone formation in mice. Liver Int 2011; 31:263-71. [PMID: 21134113 DOI: 10.1111/j.1478-3231.2010.02421.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND/AIMS Apolipoprotein A-I (apo A-I) is the main protein component of plasma high-density lipoproteins (HDL) and a key determinant of HDL cholesterol levels and metabolism. The relevance of HDL in controlling the traffic of cholesterol from plasma into bile has been partially addressed. The aim of this study was to evaluate the role of apo A-I expression in controlling the secretion of biliary lipids as well as the risk of gallstone disease in vivo. METHODS We evaluated biliary lipid secretion and bile acid homeostasis in mice deficient for apo A-I compared with wild-type animals when fed with low- or high-cholesterol diets. In addition, we assessed the importance of murine apoA-I expression for gallstone formation after feeding a lithogenic diet. RESULTS Bile acid pool size and faecal excretion were within the normal range in chow- and cholesterol-fed apo A-I knockout (KO) mice. Basal biliary cholesterol secretion was comparable and increased similarly in both murine strains after cholesterol feeding. Lithogenic diet-fed apo A-I KO mice exhibited an impaired hypercholesterolaemic response owing to a lower increase in cholesterol levels transported in large lipoproteins. However, the lack of apo A-I expression did not affect biliary cholesterol precipitation or gallstone formation in lithogenic diet-fed mice. CONCLUSIONS These findings indicate that biliary lipid secretion, bile acid metabolism and gallstone formation are independent of apo A-I expression and plasma HDL cholesterol levels in mice.
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Affiliation(s)
- Ludwig Amigo
- Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica, Santiago, Chile
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15
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Wang HH, Portincasa P, Afdhal NH, Wang DQH. Lith genes and genetic analysis of cholesterol gallstone formation. Gastroenterol Clin North Am 2010; 39:185-viii. [PMID: 20478482 DOI: 10.1016/j.gtc.2010.02.007] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/18/2023]
Abstract
Epidemiologic investigations, clinical observations, and family and twin studies in humans, as well as gallstone prevalence investigations in inbred mouse models, support the concept that cholesterol cholelithiasis could result from a complex interaction of environmental factors and the effects of multiple undetermined genes. Quantitative trait locus (QTL) analysis is a powerful genetic method for identifying primary rate-limiting genetic defects and discriminating them from secondary downstream lithogenic effects caused by mutations of the primary genes, and the subsequent positional cloning of such genes responsible for QTLs, followed by the use of manufactured mouse strains with "knockout" or "knockin" of the genes, could lead to the discovery of lithogenic actions of gallstone (LITH) genes. The combined use of genomic strategies and phenotypic studies in inbred strains of mice has successfully resulted in the identification of many candidate LITH genes. Because there is exceptionally close homology between mouse and human genomes, the orthologous human LITH genes can be identified from the mouse study. The discovery of LITH genes and more fundamental knowledge concerning the genetic determinants and molecular mechanisms underlying the formation of cholesterol gallstones in humans will pave the way for critical diagnostic and prelithogenic preventive measures for this exceptionally prevalent digestive disease.
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Affiliation(s)
- Helen H Wang
- Liver Center and Gastroenterology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
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16
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Wang HH, Lammert F, Schmitz A, Wang DQH. Transgenic overexpression of Abcb11 enhances biliary bile salt outputs, but does not affect cholesterol cholelithogenesis in mice. Eur J Clin Invest 2010; 40:541-51. [PMID: 20456485 PMCID: PMC2929639 DOI: 10.1111/j.1365-2362.2010.02300.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Cholesterol gallstone disease is a complex genetic trait and induced by multiple but as yet unknown genes. A major Lith gene, Lith1 was first identified on chromosome 2 in gallstone-susceptible C57L mice compared with resistant AKR mice. Abcb11, encoding the canalicular bile salt export pump in the hepatocyte, co-localizes with the Lith1 QTL region and its hepatic expression is significantly higher in C57L mice than in AKR mice. MATERIAL AND METHODS To investigate whether Abcb11 influences cholesterol gallstone formation, we created an Abcb11 transgenic strain on the AKR genetic background and fed these mice with a lithogenic diet for 56 days. RESULT We excluded functionally relevant polymorphisms of the Abcb11 gene and its promoter region between C57L and AKR mice. Overexpression of Abcb11 significantly promoted biliary bile salt secretion and increased circulating bile salt pool size and bile salt-dependent bile flow rate. However, biliary cholesterol and phospholipid secretion, as well as gallbladder size and contractility were comparable in transgenic and wild-type mice. At 56 days on the lithogenic diet, cholesterol saturation indexes of gallbladder biles and gallstone prevalence rates were essentially similar in these two groups of mice. CONCLUSION Overexpression of Abcb11 augments biliary bile salt secretion, but does not affect cholelithogenesis in mice.
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Affiliation(s)
- Helen H. Wang
- Department of Medicine, Liver Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard Digestive Diseases Center, Boston, MA
| | - Frank Lammert
- Department of Medicine II, Saarland University Hospital, Saarland University, Homburg, Germany
| | - Anne Schmitz
- Department of Medicine II, Saarland University Hospital, Saarland University, Homburg, Germany
| | - David Q.-H. Wang
- Department of Medicine, Liver Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard Digestive Diseases Center, Boston, MA
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17
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Liu FL, Lu WB, Niu WX. XbaI polymorphisms of apolipoprotein B gene: Another risk factor of gallstone formation after radical gastrectomy. World J Gastroenterol 2010; 16:2549-53. [PMID: 20503456 PMCID: PMC2877186 DOI: 10.3748/wjg.v16.i20.2549] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To prospectively investigate the association between the XbaI polymorphisms of apolipoprotein B (APOB) gene and gallstone formation following gastrectomy.
METHODS: The study was conducted between January 2005 and December 2006. A total of 186 gastric cancer patients who had undergone radical gastrectomy were grouped according to XbaI polymorphisms of APOB gene (X+X- group, n = 24 and X-X- group, n = 162) and compared. The XbaI polymorphisms of APOB gene were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).
RESULTS: The incidence of gallstone was significantly higher in the X+X- group than in the X-X- group [54.2% vs 9.3%, RR = 5.85 (2.23-15.32), P < 0.001]. The serum levels of total cholesterol (TC) and low-density lipoprotein (LDL) were higher in the X+X- than in the X-X- group (4.02 ± 1.12 vs 3.48 ± 0.88, P = 0.004 before surgery and 3.88 ± 1.09 vs 3.40 ± 0.86, P = 0.008 after surgery). LDL was 2.21 ± 0.96 vs 1.89 ± 0.84 (P = 0.042) before surgery and 2.09 ± 0.95 vs 1.72 ± 0.85 (P = 0.029) after surgery in the two groups. No relationship was found between XbaI polymorphisms and gallbladder motility.
CONCLUSION: In Chinese patients after radical gastrectomy, X+ allele of APOB gene is another risk factor for the development of gallstone besides the gallbladder motility disorder after surgery.
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Abstract
Cholesterol gallstone disease is a common disorder with an incidence rate of about 10%. In recent years, the research on metabolic disorders involving the gut-liver axis and the relation between gallstone disease and metabolic syndrome is attracting more attention. This article focuses on the origin of biliary cholesterol, intestinal cholesterol absorption, regulation of gallbladder motility, cholesterol transporters and metabolic syndromes and their role in the pathogenesis of gallstone disease.
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19
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Xie Y, Blanc V, Kerr TA, Kennedy S, Luo J, Newberry EP, Davidson NO. Decreased expression of cholesterol 7alpha-hydroxylase and altered bile acid metabolism in Apobec-1-/- mice lead to increased gallstone susceptibility. J Biol Chem 2009; 284:16860-16871. [PMID: 19386592 PMCID: PMC2719322 DOI: 10.1074/jbc.m109.010173] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Quantitative trait mapping in mice identified a susceptibility locus for gallstones (Lith6) spanning the Apobec-1 locus, the structural gene encoding the RNA-specific cytidine deaminase responsible for production of apolipoprotein B48 in mammalian small intestine and rodent liver. This observation prompted us to compare dietary gallstone susceptibility in Apobec-1(-/-) mice and congenic C57BL/6 wild type controls. When fed a lithogenic diet (LD) for 2 weeks, 90% Apobec-1(-/-) mice developed solid gallstones in comparison with 16% wild type controls. LD-fed Apobec-1(-/-) mice demonstrated increased biliary cholesterol secretion as well as increased cholesterol saturation and bile acid hydrophobicity indices. These changes occurred despite a relative decrease in cholesterol absorption in LD-fed Apobec-1(-/-) mice. Among the possible mechanisms to account for this phenotype, expression of Cyp7a1 mRNA and protein were significantly decreased in chow-fed Apobec-1(-/-) mice, decreasing further in LD-fed animals. Cyp7a1 transcription in hepatocyte nuclei, however, was unchanged in Apobec-1(-/-) mice, excluding transcriptional repression as a potential mechanism for decreased Cyp7a1 expression. We demonstrated that APOBEC-1 binds to AU-rich regions of the 3'-untranslated region of the Cyp7a1 transcript, containing the UUUN(A/U)U consensus motif, using both UV cross-linking to recombinant APOBEC-1 and in vivo RNA co-immunoprecipitation. In vivo Apobec-1-dependent modulation of Cyp7a1 expression was further confirmed following adenovirus-Apobec-1 administration to chow-fed Apobec-1(-/-) mice, which rescued Cyp7a1 gene expression. Taken together, the findings suggest that the AU-rich RNA binding-protein Apobec-1 mediates post-transcriptional regulation of murine Cyp7a1 expression and influences susceptibility to diet-induced gallstone formation.
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Affiliation(s)
- Yan Xie
- From the Departments of Medicine, St. Louis, Missouri 63110
| | - Valerie Blanc
- From the Departments of Medicine, St. Louis, Missouri 63110
| | - Thomas A Kerr
- From the Departments of Medicine, St. Louis, Missouri 63110
| | - Susan Kennedy
- From the Departments of Medicine, St. Louis, Missouri 63110
| | - Jianyang Luo
- From the Departments of Medicine, St. Louis, Missouri 63110
| | | | - Nicholas O Davidson
- From the Departments of Medicine, St. Louis, Missouri 63110; Pharmacology and Developmental Biology, Washington University School of Medicine, St. Louis, Missouri 63110.
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20
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Jiang ZY, Jiang CY, Wang L, Wang JC, Zhang SD, Einarsson C, Eriksson M, Han TQ, Parini P, Eggertsen G. Increased NPC1L1 and ACAT2 expression in the jejunal mucosa from Chinese gallstone patients. Biochem Biophys Res Commun 2009; 379:49-54. [PMID: 19071091 DOI: 10.1016/j.bbrc.2008.11.131] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2008] [Accepted: 11/30/2008] [Indexed: 11/24/2022]
Abstract
The incidence of cholesterol gallstones is a very common disease. The aim of this study is to probe for underlying intestinal molecular defects associated with development of gallstones. Twelve Chinese patients with cholesterol gallstone disease (GS) and 31 gallstone-free (GSF) patients were investigated. Quantitation of mRNA levels for individual genes in mucosal biopsies from jejunum was carried out with real-time PCR. The frequency of two SNPs in the ABCG8 gene (Y54C and T400K) was determined by allelic discrimination. The intestinal mRNA expression of NPC1L1 and ACAT2 were significantly higher in GS than GSF (P<0.05). No differences were observed concerning the levels for plasma lipids, plant sterols and 7alpha-hydroxy-4-cholesten-3-one between GS and GSF. No correlations were observed between patients carrying the different genotypes for Y54C or T400K and their mRNA levels for ABCG5 or ABCG8. The increased NPC1L1 and ACAT2 mRNA levels in gallstone patients might indicate an upregulated absorption and esterification of cholesterol in the small intestine.
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Affiliation(s)
- Zhao-Yan Jiang
- Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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21
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Reshetnyak TM, Saparin GV, Ivannikov PV, Reshetnyak VI. Corticosteroids and Cholelithiasis in Systemic Lupus Erythematosus. SCHOLARLY RESEARCH EXCHANGE 2009; 2009:1-9. [DOI: 10.3814/2009/123481] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Valasek MA, Repa JJ, Quan G, Dietschy JM, Turley SD. Inhibiting intestinal NPC1L1 activity prevents diet-induced increase in biliary cholesterol in Golden Syrian hamsters. Am J Physiol Gastrointest Liver Physiol 2008; 295:G813-22. [PMID: 18718997 PMCID: PMC2575918 DOI: 10.1152/ajpgi.90372.2008] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Niemann-Pick C1-like 1 (NPC1L1) facilitates the uptake of sterols into the enterocyte and is the target of the novel cholesterol absorption inhibitor, ezetimibe. These studies used the Golden Syrian hamster as a model to delineate the changes in the relative mRNA expression of NPC1L1 and other proteins that regulate sterol homeostasis in the enterocyte during and following cessation of ezetimibe treatment and also to address the clinically important question of whether the marked inhibition of cholesterol absorption alters biliary lipid composition. In hamsters fed a low-cholesterol, low-fat basal diet, the abundance of mRNA for NPC1L1 in the small intestine far exceeded that in other regions of the gastrointestinal tract, liver, and gallbladder. In the first study, female hamsters were fed the basal diet containing ezetimibe at doses up to 2.0 mg.day(-1).kg body wt(-1). At this dose, cholesterol absorption fell by 82%, fecal neutral sterol excretion increased by 5.3-fold, and hepatic and intestinal cholesterol synthesis increased more than twofold, but there were no significant changes in either fecal bile acid excretion or biliary lipid composition. The ezetimibe-induced changes in intestinal cholesterol handling were reversed when treatment was withdrawn. In a second study, male hamsters were given a diet enriched in cholesterol and safflower oil without or with ezetimibe. The lipid-rich diet raised the absolute and relative cholesterol levels in bile more than fourfold. This increase was largely prevented by ezetimibe. These data are consistent with the recent finding that ezetimibe treatment significantly reduced biliary cholesterol saturation in patients with gallstones.
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Affiliation(s)
- Mark A. Valasek
- Departments of Internal Medicine and Physiology, University of Texas Southwestern Medical School, Dallas, Texas
| | - Joyce J. Repa
- Departments of Internal Medicine and Physiology, University of Texas Southwestern Medical School, Dallas, Texas
| | - Gang Quan
- Departments of Internal Medicine and Physiology, University of Texas Southwestern Medical School, Dallas, Texas
| | - John M. Dietschy
- Departments of Internal Medicine and Physiology, University of Texas Southwestern Medical School, Dallas, Texas
| | - Stephen D. Turley
- Departments of Internal Medicine and Physiology, University of Texas Southwestern Medical School, Dallas, Texas
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23
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Zúñiga S, Molina H, Azocar L, Amigo L, Nervi F, Pimentel F, Jarufe N, Arrese M, Lammert F, Miquel JF. Ezetimibe prevents cholesterol gallstone formation in mice. Liver Int 2008; 28:935-47. [PMID: 18783541 DOI: 10.1111/j.1478-3231.2008.01808.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
BACKGROUND Intestinal cholesterol absorption may influence gallstone formation and its modulation could be a useful therapeutic strategy for gallstone disease (GSD). Ezetimibe (EZET) is a cholesterol-lowering agent that specifically inhibits intestinal cholesterol absorption. AIMS To test whether EZET can prevent gallstone formation in mice. METHODS/RESULTS Gallstone-susceptible C57BL/6 inbred mice were fed control and lithogenic diets with or without simultaneous EZET administration. Lithogenic diet increased biliary cholesterol content and secretion, and induced sludge or gallstone formation in 100% of the animals. EZET administration reduced intestinal cholesterol absorption by 90% in control animals and by 35% in mice receiving the lithogenic diet. EZET prevented the appearance of cholesterol crystals and gallstones. In addition, mice fed the lithogenic diet plus EZET exhibited a 60% reduction in biliary cholesterol saturation index. Of note, EZET treatment caused a significant increase in bile flow (+50%, P<0.01) as well as bile salt, phospholipid and glutathione secretion rates (+60%, +44% and +100%, respectively, P<0.01), which was associated with a moderately increased expression of hepatic bile salt transporters. In addition, relative expression levels of Nieman-Pick C1 like 1 (NPC1L1) in the enterohepatic axis in humans were assessed. Expression levels of NPC1L1 were 15- to 30-fold higher in the duodenum compared with the liver at transcript and protein levels, respectively, suggesting preferential action of EZET on intestinal cholesterol absorption in humans. CONCLUSIONS In a murine model of GSD, EZET prevented gallstone formation by reducing intestinal cholesterol absorption and increasing bile salt-dependent and -independent bile flow. EZET could be useful in preventing GSD disease in susceptible patients.
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Affiliation(s)
- Silvia Zúñiga
- Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
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24
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Wang HH, Portincasa P, Mendez-Sanchez N, Uribe M, Wang DQH. Effect of ezetimibe on the prevention and dissolution of cholesterol gallstones. Gastroenterology 2008; 134:2101-10. [PMID: 18442485 PMCID: PMC2741499 DOI: 10.1053/j.gastro.2008.03.011] [Citation(s) in RCA: 126] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2007] [Revised: 02/26/2008] [Accepted: 03/06/2008] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Cholesterol cholelithiasis is one of the most prevalent and most costly digestive diseases in developed countries and its incidence has increased markedly in Asian countries owing to the adoption of Western-type dietary habits. Because animal experiments showed that high efficiency of intestinal cholesterol absorption contributes to gallstone formation, we explored whether the potent cholesterol absorption inhibitor ezetimibe could prevent gallstones and promote gallstone dissolution in mice and reduce biliary cholesterol content in human beings. METHODS Male gallstone-susceptible C57L mice were fed a lithogenic diet and concomitantly administered with ezetimibe at 0, 0.8, 4, or 8 mg/kg/day for 8 or 12 weeks. Gallbladder biles and gallstones were examined by microscopy. Gallbladder emptying in response to cholecystokinin octapeptide was measured gravimetrically. Biliary lipid outputs were analyzed by physical-chemical methods. Cholesterol absorption efficiency was determined by fecal dual-isotope ratio and mass balance methods. Lipid changes in gallbladder biles of gallstone patients vs overweight subjects without gallstones were examined before (day 0) and at 30 days after ezetimibe treatment (20 mg/day). RESULTS Ezetimibe prevented gallstones by effectively reducing intestinal cholesterol absorption and biliary cholesterol secretion, and protected gallbladder motility function by desaturating bile in mice. Treatment with ezetimibe promoted the dissolution of gallstones by forming an abundance of unsaturated micelles. Furthermore, ezetimibe significantly reduced biliary cholesterol saturation and retarded cholesterol crystallization in biles of patients with gallstones. CONCLUSIONS Ezetimibe is a novel approach to reduce biliary cholesterol content and a promising strategy for preventing or treating cholesterol gallstones by inhibiting intestinal cholesterol absorption.
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Affiliation(s)
- Helen H. Wang
- Department of Medicine, Liver Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard Digestive Diseases Center, Boston, Massachusetts
| | - Piero Portincasa
- Department of Internal Medicine and Public Medicine, Section of Internal Medicine, University Medical School, Bari, Italy
| | - Nahum Mendez-Sanchez
- Departments of Biomedical Research, Gastroenterology and Liver Unit, Medica Sur Clinic and Foundation, Mexico City, Mexico
| | - Misael Uribe
- Departments of Biomedical Research, Gastroenterology and Liver Unit, Medica Sur Clinic and Foundation, Mexico City, Mexico
| | - David Q.-H. Wang
- Department of Medicine, Liver Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard Digestive Diseases Center, Boston, Massachusetts
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Uppal H, Zhai Y, Gangopadhyay A, Khadem S, Ren S, Moser JA, Xie W. Activation of liver X receptor sensitizes mice to gallbladder cholesterol crystallization. Hepatology 2008; 47:1331-42. [PMID: 18318438 DOI: 10.1002/hep.22175] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
UNLABELLED Gallstone disease is a hepatobiliary disorder due to biochemical imbalances in the gallbladder bile. In this report, we show that activation of nuclear receptor liver X receptor (LXR) sensitized mice to lithogenic diet-induced gallbladder cholesterol crystallization, which was associated with dysregulation of several hepatic transporters that efflux cholesterol, phospholipids, and bile salts. The combined effect of increased biliary concentrations of cholesterol and phospholipids and decreased biliary concentrations of bile salts in LXR-activated mice led to an increased cholesterol saturation index and the formation of cholesterol crystals. Interestingly, the lithogenic effect of LXR was completely abolished in the low-density lipoprotein receptor (Ldlr) null background or when the mice were treated with Ezetimibe, a cholesterol-lowering drug that blocks intestinal dietary cholesterol absorption. These results suggest that LDLR-mediated hepatic cholesterol uptake and intestinal cholesterol absorption play an essential role in LXR-promoted lithogenesis. CONCLUSION The current study has revealed a novel lithogenic role of LXR as well as a functional interplay between LXR and LDLR in gallbladder cholesterol crystallization and possibly cholesterol gallstone disease (CGD). We propose that LXR is a lithogenic factor and that the LXR transgenic mice may offer a convenient CGD model to develop therapeutic interventions for this disease.
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Affiliation(s)
- Hirdesh Uppal
- Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261, USA
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26
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Kurzawski M, Juzyszyn Z, Modrzejewski A, Pawlik A, Wiatr M, Czerny B, Adamcewicz R, Droździk M. Apolipoprotein B (APOB) Gene Polymorphism in Patients with Gallbladder Disease. Arch Med Res 2007; 38:360-3. [PMID: 17350490 DOI: 10.1016/j.arcmed.2006.11.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2006] [Accepted: 11/16/2006] [Indexed: 10/23/2022]
Abstract
Cholelithiasis is one of the most prevalent gastroenterological diseases, precipitated mainly by environmental factors. However, twin studies provided strong evidence for a role of genetic factors in the disease pathogenesis. An association between plasma lipoprotein levels and gallstone disease (GSD) was presented. Apolipoprotein B is an essential structural component of triglyceride-rich lipoprotein particles and plays an important role in the maintenance of cholesterol homeostasis in mammals. Various studies have shown a relationship between APOB gene polymorphisms and lipoprotein levels, but only few investigated a potential association between APOB polymorphism and GSD, giving contrary results. In the current study, an association between common polymorphisms in APOB gene (T2488T and E4154K) and cholesterol gallstone disease was examined. Two hundred and forty patients of Caucasian origin suffering from cholelithiasis, as well as 217 healthy individuals, were included in the study. Patients were genotyped for two single nucleotide polymorphisms (SNPs) in APOB gene: 2488C>T (XbaI), and 4154G>A (EcoRI) using PCR-RLFP method. The resulting analysis has shown that polymorphic loci in positions 2488 and 4154 in APOB gene are in full linkage in a Polish population and form only three haplotypes: 2488C-4154G, 2488T-4154G and 2488C-4154A. Frequency and distribution of 2488C>T alleles did not differ significantly between patients and controls. The 4154G allele has been found to be associated with GSD (p=0.001). A risk of gallstone formation was reduced in 4154AA homozygotes (OR=0.25, p=0.009) and heterozygous individuals (OR=0.63, p=0.03) as compared to 4154GG homozygotes. Additionally, 2488C-4154A haplotype was identified as a protective factor against GSD (p=0.04). Our results suggest that SNPs in APOB, potentially considered as one of lith genes as well as certain haplotypes, may be risk factors for GSD.
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Affiliation(s)
- Mateusz Kurzawski
- Department of Pharmacology, Pomeranian Medical University, Szczecin, Poland
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Abstract
The identification of defective structures in the ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 in patients with sitosterolemia suggests that these two proteins are an apical sterol export pump promoting active efflux of cholesterol and plant sterols from enterocytes back into the intestinal lumen for excretion. The newly identified Niemann-Pick C1-like 1 (NPC1L1) protein is also expressed at the apical membrane of enterocytes and plays a crucial role in the ezetimibe-sensitive cholesterol absorption pathway. These findings indicate that cholesterol absorption is a multistep process that is regulated by multiple genes at the enterocyte level and that the efficiency of cholesterol absorption may be determined by the net effect between influx and efflux of intraluminal cholesterol molecules crossing the brush border membrane of the enterocyte. Combination therapy using cholesterol absorption (NPC1L1) inhibitor (ezetimibe) and 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) provides a powerful novel strategy for the prevention and treatment of hypercholesterolemia.
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Affiliation(s)
- David Q-H Wang
- Department of Medicine, Liver Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard Digestive Diseases Center, Boston, Massachusetts 02115, USA.
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28
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Lyons MA, Wittenburg H. Cholesterol gallstone susceptibility loci: a mouse map, candidate gene evaluation, and guide to human LITH genes. Gastroenterology 2006; 131:1943-70. [PMID: 17087948 DOI: 10.1053/j.gastro.2006.10.024] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2006] [Accepted: 08/15/2006] [Indexed: 12/11/2022]
Affiliation(s)
- Malcolm A Lyons
- Centre for Medical Research, University of Western Australia, Western Australian Institute for Medical Research, Perth, Australia.
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Abstract
PURPOSE OF REVIEW With the completion of the human genome project and HapMap, previously unknown genetic polymorphisms associated with disease have been observed. This review highlights genetic polymorphisms that have provided insight into the pathophysiology underlying the many phenotypes of sickle cell disease. RECENT FINDINGS The phenotypes of sickle cell disease are likely to be modulated by polymorphisms in genes that are involved in inflammation, cell-cell interaction, and nitric oxide biology. Case-control studies are beginning to define the relationships between single-nucleotide polymorphisms in candidate genes and the many subphenotypes of sickle cell anemia. A common theme emerging from these studies is that single-nucleotide polymorphisms in genes of the transforming growth factor-beta/bone morphogenetic protein and a few other genes such as Klotho are associated with several subphenotypes of sickle cell disease. SUMMARY Genomic medicine is merging with clinical practice as our understanding of the structure and variability of the human genome increases. Patients with diseases caused by identical mutations in a single gene - sickle cell anemia is a prime example - can have clinical courses very different from one another, and when environmental influences are removed the phenotypic heterogeneity of mendelian single-gene disorders is best explained by single-nucleotide polymorphisms in genes that modulate the disease phenotype. As this field expands, insights will be gained into complex epistatic factors that influence the clinical presentation of sickle cell disease, enabling physicians to better predict and manage the many complications of this disease.
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Affiliation(s)
- Martin H Steinberg
- Department of Medicine, Boston University School of Medicine and the Center of Excellence in Sickle Cell Disease, Boston Medical Center, Boston, Massachussetts 02118, USA.
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Grünhage F, Lammert F. Gallstone disease. Pathogenesis of gallstones: A genetic perspective. Best Pract Res Clin Gastroenterol 2006; 20:997-1015. [PMID: 17127184 DOI: 10.1016/j.bpg.2006.05.007] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Cholelithiasis is one of the most prevalent gastroenterological diseases, imposing a huge economic burden on health-care systems. Gallbladder stones form when the concentration of cholesterol or bilirubin exceeds the solubility in the bile salt and phospholipid-rich bile. The physiology of biliary lipid secretion by a number of specialized transport proteins has recently been elucidated, and underlying genetic defects in these proteins have been identified as susceptibility factors for gallstone disease. Recent studies of identical twins and family strongly support the idea of a genetic component to gallstone disease. Epidemiological studies in high-risk populations indicate that gallstone formation is caused by multiple environmental influences and common genetic factors and their interactions. Monogenic subtypes of cholelithiasis, such as biliary lipid transporter deficiencies, appear to be rare. The characterization of lithogenic genes in knockout and transgenic mice, and the identification of many gallstone susceptibility loci in inbred mice, provide the basis for studies of the corresponding genes in patients with gallstones. The transfer of findings from mouse genetics to the bedside might lead to new strategies for individual risk assessment and reveal molecular targets for the development of new treatment strategies.
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Affiliation(s)
- Frank Grünhage
- Department of Internal Medicine I, University Hospital Bonn, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany
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Wang HH, Afdhal NH, Wang DQH. Overexpression of estrogen receptor alpha increases hepatic cholesterogenesis, leading to biliary hypersecretion in mice. J Lipid Res 2005; 47:778-86. [PMID: 16380638 DOI: 10.1194/jlr.m500454-jlr200] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
We explored whether there is an "estrogen-ERalpha-SREBP-2" (for estrogen-estrogen receptor subtype alpha-sterol-regulatory element binding protein-2) pathway for regulating hepatic cholesterol biosynthesis in ovariectomized AKR mice treated with 17beta-estradial (E2) at 6 microg/day or E2 plus the antiestrogenic agent ICI 182,780 at 125 microg/day and on chow or fed a high-cholesterol (1%) diet for 14 days. To monitor changes in cholesterol biosynthesis and newly synthesized cholesterol secreted into bile, incorporation into digitonin-precipitable sterols in mice treated with 25 mCi of [3H]water was measured in extracts of liver and extrahepatic organs 1 h later and in hepatic biles 6 h later. ERalpha upregulated SREBP-2, with resulting activation of SREBP-2-responsive genes in the cholesterol biosynthetic pathway. The E2-treated mice continued to synthesize cholesterol in spite of its excess availability from high dietary cholesterol, which reflects a loss in controlling the negative feedback regulation of cholesterol synthesis. These alterations augmented biliary cholesterol secretion and enhanced the lithogenicity of bile. However, these lithogenic effects of E2 were fully blocked by ICI 182,780. We conclude that during estrogen treatment, more newly synthesized cholesterol determined by the estrogen-ERalpha-SREBP-2 pathway is secreted into bile, leading to biliary cholesterol hypersecretion. These studies provide insights into therapeutic approaches to cholesterol gallstones in high-risk subjects, especially those exposed to high levels of estrogen.
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Affiliation(s)
- Helen H Wang
- Department of Medicine, Liver Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard Digestive Diseases Center, Boston, MA, USA
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