Bile acids (BAs) are not only digestive surfactants but also important cell signaling molecules, which stimulate several signaling pathways to regulate some important biological processes. The bile-acid-activated nucl...Bile acids (BAs) are not only digestive surfactants but also important cell signaling molecules, which stimulate several signaling pathways to regulate some important biological processes. The bile-acid-activated nuclear receptor, farnesoid X receptor (FXR), plays a pivotal role in regulating bile acid, lipid and glucose homeostasis as well as in regulating the inflammatory responses, harrier function and prevention of bacterial manslocation in the intestinal tract. As expected, FXR is involved in the pathophysiology of a wide, range of diseases of gastrointestinal tract, including inflammatory bowel disease, colorectal cancer and type 2 diabetes. In this review, we discuss current knowledge of the roles of FXR in physiology of the digestive system and the related diseases. Better understanding of the roles of FXR in digestive system will accelerate the development of FXR ligands/modulators for the treatment of digestive system diseases. (C) 2015 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. All rights reserved展开更多
The liver is unique in regenerative potential, which could recover the lost mass and function after injury from ischemia and resection. The underlying molecular mechanisms of liver regeneration have been extensively s...The liver is unique in regenerative potential, which could recover the lost mass and function after injury from ischemia and resection. The underlying molecular mechanisms of liver regeneration have been extensively studied in the past using the partial hepatectomy(PH) model in rodents, where 2/3 PH is carried out by removing two lobes. The whole process of liver regeneration is complicated, orchestrated event involving a network of connected interactions, which still remain fully elusive. Bile acids(BAs) are ligands of farnesoid X receptor(FXR), a nuclear receptor of ligand-activated transcription factor. FXR has been shown to be highly involved in liver regeneration. BAs and FXR not only interact with each other but also regulate various downstream targets independently during liver regeneration. Moreover, recent findings suggest that tissue-specific FXR also contributes to liver regeneration significantly. These novel findings suggest that FXR has much broader role than regulating BA, cholesterol, lipid and glucose metabolism. Therefore, these researches highlight FXR as an important pharmaceutical target for potentialuse of FXR ligands to regulate liver regeneration in clinic. This review focuses on the roles of BAs and FXR in liver regeneration and the current underlying molecular mechanisms which contribute to liver regeneration.展开更多
With the high prevalence of obesity, diabetes, and otherfeatures of the metabolic syndrome in United States, nonalcoholic fatty liver disease(NAFLD) has inevitably become a very prevalent chronic liver disease and is ...With the high prevalence of obesity, diabetes, and otherfeatures of the metabolic syndrome in United States, nonalcoholic fatty liver disease(NAFLD) has inevitably become a very prevalent chronic liver disease and is now emerging as one of the leading indications for liver transplantation. Insulin resistance and derangement of lipid metabolism, accompanied by activation of the pro-inflammatory response and fibrogenesis, are essential pathways in the development of the more clinically significant form of NAFLD, known as nonalcoholic steatohepatitis(NASH). Recent advances in the functional characterization of bile acid receptors, such as farnesoid X receptor(FXR) and transmembrane G protein-coupled receptor(TGR) 5, have provided further insight in the pathophysiology of NASH and have led to the development of potential therapeutic targets for NAFLD and NASH. Beyond maintaining bile acid metabolism, FXR and TGR5 also regulate lipid metabolism, maintain glucose homeostasis, increase energy expenditure, and ameliorate hepatic inflammation. These intriguing features have been exploited to develop bile acid analogues to target pathways in NAFLD and NASH pathogenesis. This review provides a brief overview of the pathogenesis of NAFLD and NASH, and then delves into the biological functions of bile acid receptors, particularly with respect to NASH pathogenesis, with a description of the associated experimental data, and, finally, we discuss the prospects of bile acid analogues in the treatment of NAFLD and NASH.展开更多
目的探讨黄芪总黄酮(total flavonoids of astragalus,TFA)改善四氯化碳(CCl4)诱导的大鼠肝纤维化效果及抗炎抗氧化作用机制。方法大鼠分为正常组、模型组、TFA低剂量组和TFA高剂量组。除正常组外,其余各组给予CCl4橄榄油皮下注射,每周2...目的探讨黄芪总黄酮(total flavonoids of astragalus,TFA)改善四氯化碳(CCl4)诱导的大鼠肝纤维化效果及抗炎抗氧化作用机制。方法大鼠分为正常组、模型组、TFA低剂量组和TFA高剂量组。除正常组外,其余各组给予CCl4橄榄油皮下注射,每周2次,共8周。造模4周后,模型组给予生理盐水灌胃,TFA低剂量组和TFA高剂量组给15mg/kg和30mg/kg的TFA灌胃,1次/d,治疗4周后分别取血清及肝组织标本。血清检测ALT、AST、ALB水平;肝组织做病理学检查;qPCR法检测相关炎症因子和法尼酯衍生物X受体(farnesoid X receptor,FXR)的mRNA表达水平;Western blot检测NF-κB、FXR等蛋白表达变化;试剂盒检测丙二醛(MDA)、超氧化物歧化酶(SOD)、谷胱甘肽(GSH)水平。结果与模型组相比,TFA低剂量组和TFA高剂量组中肝脏脂肪变性明显减轻、炎症细胞浸润减少及肝纤维化减轻;肝功能相关指标AST、ALT、ALB明显好转;相关炎症因子的mRNA和蛋白下降;FXR的表达明显上调;肝组织中MDA水平明显降低,GSH、SOD表达水平增高。结论TFA具有抗炎、抗氧化作用,能够有效地延缓四氯化碳诱导的肝纤维化进程,其机制可能与调控FXR的表达相关。展开更多
Portal hypertension(PHT)in advanced chronic liver disease(ACLD)results from increased intrahepatic resistance caused by pathologic changes of liver tissue composition(structural component)and intrahepatic vasoconstric...Portal hypertension(PHT)in advanced chronic liver disease(ACLD)results from increased intrahepatic resistance caused by pathologic changes of liver tissue composition(structural component)and intrahepatic vasoconstriction(functional component).PHT is an important driver of hepatic decompensation such as development of ascites or variceal bleeding.Dysbiosis and an impaired intestinal barrier in ACLD facilitate translocation of bacteria and pathogen-associated molecular patterns(PAMPs)that promote disease progression via immune system activation with subsequent induction of proinflammatory and profibrogenic pathways.Congestive portal venous blood flow represents a critical pathophysiological mechanism linking PHT to increased intestinal permeability:The intestinal barrier function is affected by impaired microcirculation,neoangiogenesis,and abnormal vascular and mucosal permeability.The close bidirectional relationship between the gut and the liver has been termed“gut-liver axis”.Treatment strategies targeting the gut-liver axis by modulation of microbiota composition and function,intestinal barrier integrity,as well as amelioration of liver fibrosis and PHT are supposed to exert beneficial effects.The activation of the farnesoid X receptor in the liver and the gut was associated with beneficial effects in animal experiments,however,further studies regarding efficacy and safety of pharmacological FXR modulation in patients with ACLD are needed.In this review,we summarize the clinical impact of PHT on the course of liver disease,discuss the underlying pathophysiological link of PHT to gut-liver axis signaling,and provide insight into molecular mechanisms that may represent novel therapeutic targets.展开更多
Obeticholic acid(OCA), the first FXR-targeting drug, has been claimed effective in the therapy of liver fibrosis. However, recent clinical trials indicated that OCA might not be effective against liver fibrosis, possi...Obeticholic acid(OCA), the first FXR-targeting drug, has been claimed effective in the therapy of liver fibrosis. However, recent clinical trials indicated that OCA might not be effective against liver fibrosis, possibly due to the lower dosage to reduce the incidence of the side-effect of pruritus. Here we propose a combinatory therapeutic strategy of OCA and apoptosis inhibitor for combating against liver fibrosis. CCl4-injured mice, D-galactosamine/LPS(GalN/LPS)-treated mice and cycloheximide/TNFα(CHX/TNFα)-treated HepG2 cells were employed to assess the effects of OCA, or together with IDN-6556, an apoptosis inhibitor. OCA treatment significantly inhibited hepatic stellate cell(HSC)activation/proliferation and prevented fibrosis. Elevated bile acid(BA) levels and hepatocyte apoptosis triggered the activation and proliferation of HSCs. OCA treatment reduced BA levels but could not inhibit hepatocellular apoptosis. An enhanced anti-fibrotic effect was observed when OCA was co-administrated with IDN-6556. Our study demonstrated that OCA inhibits HSCs activation/proliferation partially by regulating BA homeostasis and thereby inhibiting activation of HSCs. The findings in this study suggest that combined use of apoptosis inhibitor and OCA at lower dosage represents a novel therapeutic strategy for liver fibrosis.展开更多
Spontaneous bacterial peritonitis(SBP) is a frequent, life-threatening bacterial infection in patients with liver cirrhosis and ascites. Portal hypertension leads to increased bacterial translocation from the intestin...Spontaneous bacterial peritonitis(SBP) is a frequent, life-threatening bacterial infection in patients with liver cirrhosis and ascites. Portal hypertension leads to increased bacterial translocation from the intestine. Failure to eliminate invading pathogens due to immune defects associated with advanced liver disease on the background of genetic predisposition may result in SBP. The efficacy of antibiotic treatment and prophylaxis has declined due to the spread of multi-resistant bacteria. Patients with nosocomial SBP and with prior antibiotictreatment are at a particularly high risk for infection with resistant bacteria. Therefore, it is important to adapt empirical treatment to these risk factors and to the local resistance profile. Rifaximin, an oral, nonabsorbable antibiotic, has been proposed to prevent SBP, but may be useful only in a subset of patients. Since novel antibiotic classes are lacking, we have to develop prophylactic strategies which do not induce bacterial resistance. Farnesoid X receptor agonists may be a candidate, but so far, clinical studies are not available. New diagnostic tests which can be carried out quickly at the patient's site and provide additional prognostic information would be helpful. Furthermore, we need tools to predict antibiotic resistance in order to tailor first-line antibiotic treatment of spontaneous bacterial peritonitis to the individual patient and to reduce mortality.展开更多
Alcoholic liver disease(ALD) is one of the major causes of liver morbidity and mortality worldwide. Chronic alcohol consumption leads to development of liver pathogenesis encompassing steatosis, inflammation, fibrosis...Alcoholic liver disease(ALD) is one of the major causes of liver morbidity and mortality worldwide. Chronic alcohol consumption leads to development of liver pathogenesis encompassing steatosis, inflammation, fibrosis, cirrhosis, and in extreme cases, hepatocellular carcinoma. Moreover,ALD may also associate with cholestasis. Emerging evidence now suggests that farnesoid X receptor(FXR) and bile acids also play important roles in ALD. In this review, we discuss the effects of alcohol consumption on FXR, bile acids and gut microbiome as well as their impacts on ALD. Moreover, we summarize the findings on FXR, Fox O3a(forkhead box-containing protein class O3a) and PPARα(peroxisome proliferator-activated receptor alpha) in regulation of autophagy-related gene transcription program and liver injury in response to alcohol exposure.展开更多
Recent studies have revealed that bile acids(BAs)are not only facilitators of dietary lipid absorption but also important signaling molecules exerting multiple physiological functions.Some major signaling pathways inv...Recent studies have revealed that bile acids(BAs)are not only facilitators of dietary lipid absorption but also important signaling molecules exerting multiple physiological functions.Some major signaling pathways involving the nuclear BAs receptor farnesoid X receptor and the G protein-coupled BAs receptor TGR5/M-BAR have been identified to be the targets of BAs.BAs regulate their own homeostasis via signaling pathways.BAs also affect diverse metabolic pathways including glucose metabolism,lipid metabolism and energy expenditure.This paper suggests the mechanism of controlling metabolism via BA signaling and demonstrates that BA signaling is an attractive therapeutic target of the metabolic syndrome.展开更多
BACKGROUND: Parenteral nutrition-associated liver disease (PNALD) has been common in patients who require long-term parenteral nutrition. PNALD develops in 40%-60% of infants on long-term parenteral nutrition compared...BACKGROUND: Parenteral nutrition-associated liver disease (PNALD) has been common in patients who require long-term parenteral nutrition. PNALD develops in 40%-60% of infants on long-term parenteral nutrition compared with 15%-40% of adults on home parenteral nutrition for intestinal failure. The pathogenesis of PNALD is multifactorial and remains unclear There is no specific treatment. Management strategies for its prevention and treatment depend on an understanding of many risk factors. This review aims to provide an update on the pathogenesis and treatment of this disease. DATA SOURCES: A literature search was performed on the MEDLINE and Web of Science databases for articles published up to October 2011, using the keywords: parenteral nutrition associated liver disease, intestinal failure associated liver disease lipid emulsions and fish oil. The available data reported in the relevant literatures were analyzed. RESULTS: The literature search provided a huge amount of evidence about the pathogenesis and management strategies on PNALD. Currently, lack of enteral feeding, extended duration of parenteral nutrition, recurrent sepsis, and nutrient deficiency or excess may play important roles in the pathogenesis of PNALD. Recent studies found that phytosterols present as contaminants in soy-based lipid emulsions, are also an important factor in the pathogenesis. Moreover, the treatment of PNALD is discussed. CONCLUSIONS: The use of lipid emulsions, phytosterols in particular, is associated with PNALD. Management strategies for the prevention and treatment of PNALD include consideration of early enteral feeding, the use of specialized lipid emulsions such as fish oil emulsions, and isolated small bowel or combined liver and small bowel transplantation. A greater understanding of the pathogenesis of PNALD has led to promising interventions to prevent and treat this condition. Future work should aim to better understand the mechanisms of PNALD and the long-term outcomes of its treatment.展开更多
基金supported by National Cancer Institute of United States (No.1R01-CA139158,to Wendong Huang)National Natural Science Foundation of China (Nos.81303186 and ZYX-NSFC-016)China Postdoctoral Science Foundation (No.2013M531202)
文摘Bile acids (BAs) are not only digestive surfactants but also important cell signaling molecules, which stimulate several signaling pathways to regulate some important biological processes. The bile-acid-activated nuclear receptor, farnesoid X receptor (FXR), plays a pivotal role in regulating bile acid, lipid and glucose homeostasis as well as in regulating the inflammatory responses, harrier function and prevention of bacterial manslocation in the intestinal tract. As expected, FXR is involved in the pathophysiology of a wide, range of diseases of gastrointestinal tract, including inflammatory bowel disease, colorectal cancer and type 2 diabetes. In this review, we discuss current knowledge of the roles of FXR in physiology of the digestive system and the related diseases. Better understanding of the roles of FXR in digestive system will accelerate the development of FXR ligands/modulators for the treatment of digestive system diseases. (C) 2015 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. All rights reserved
基金supported by the National Institutes of Health Fund (Nos.DK081343,DK090036 and GM104037 to Grace L.Guo)the National Natural Science Foundation of China (No.81302059)+2 种基金the Natural Science Foundation of Heilongjiang Province of China (No.LC2013C35)the Foundation of Educational Committee of Heilongjiang Province of China (No.12541300)supported by the Scientific Research Foundation for the Returned Overseas Chinese Scholars,State Education Ministry and Science Foundation for The Excellent Youth Scholars of the Fourth Hospital of Harbin Medical University in China
文摘The liver is unique in regenerative potential, which could recover the lost mass and function after injury from ischemia and resection. The underlying molecular mechanisms of liver regeneration have been extensively studied in the past using the partial hepatectomy(PH) model in rodents, where 2/3 PH is carried out by removing two lobes. The whole process of liver regeneration is complicated, orchestrated event involving a network of connected interactions, which still remain fully elusive. Bile acids(BAs) are ligands of farnesoid X receptor(FXR), a nuclear receptor of ligand-activated transcription factor. FXR has been shown to be highly involved in liver regeneration. BAs and FXR not only interact with each other but also regulate various downstream targets independently during liver regeneration. Moreover, recent findings suggest that tissue-specific FXR also contributes to liver regeneration significantly. These novel findings suggest that FXR has much broader role than regulating BA, cholesterol, lipid and glucose metabolism. Therefore, these researches highlight FXR as an important pharmaceutical target for potentialuse of FXR ligands to regulate liver regeneration in clinic. This review focuses on the roles of BAs and FXR in liver regeneration and the current underlying molecular mechanisms which contribute to liver regeneration.
文摘With the high prevalence of obesity, diabetes, and otherfeatures of the metabolic syndrome in United States, nonalcoholic fatty liver disease(NAFLD) has inevitably become a very prevalent chronic liver disease and is now emerging as one of the leading indications for liver transplantation. Insulin resistance and derangement of lipid metabolism, accompanied by activation of the pro-inflammatory response and fibrogenesis, are essential pathways in the development of the more clinically significant form of NAFLD, known as nonalcoholic steatohepatitis(NASH). Recent advances in the functional characterization of bile acid receptors, such as farnesoid X receptor(FXR) and transmembrane G protein-coupled receptor(TGR) 5, have provided further insight in the pathophysiology of NASH and have led to the development of potential therapeutic targets for NAFLD and NASH. Beyond maintaining bile acid metabolism, FXR and TGR5 also regulate lipid metabolism, maintain glucose homeostasis, increase energy expenditure, and ameliorate hepatic inflammation. These intriguing features have been exploited to develop bile acid analogues to target pathways in NAFLD and NASH pathogenesis. This review provides a brief overview of the pathogenesis of NAFLD and NASH, and then delves into the biological functions of bile acid receptors, particularly with respect to NASH pathogenesis, with a description of the associated experimental data, and, finally, we discuss the prospects of bile acid analogues in the treatment of NAFLD and NASH.
文摘目的探讨黄芪总黄酮(total flavonoids of astragalus,TFA)改善四氯化碳(CCl4)诱导的大鼠肝纤维化效果及抗炎抗氧化作用机制。方法大鼠分为正常组、模型组、TFA低剂量组和TFA高剂量组。除正常组外,其余各组给予CCl4橄榄油皮下注射,每周2次,共8周。造模4周后,模型组给予生理盐水灌胃,TFA低剂量组和TFA高剂量组给15mg/kg和30mg/kg的TFA灌胃,1次/d,治疗4周后分别取血清及肝组织标本。血清检测ALT、AST、ALB水平;肝组织做病理学检查;qPCR法检测相关炎症因子和法尼酯衍生物X受体(farnesoid X receptor,FXR)的mRNA表达水平;Western blot检测NF-κB、FXR等蛋白表达变化;试剂盒检测丙二醛(MDA)、超氧化物歧化酶(SOD)、谷胱甘肽(GSH)水平。结果与模型组相比,TFA低剂量组和TFA高剂量组中肝脏脂肪变性明显减轻、炎症细胞浸润减少及肝纤维化减轻;肝功能相关指标AST、ALT、ALB明显好转;相关炎症因子的mRNA和蛋白下降;FXR的表达明显上调;肝组织中MDA水平明显降低,GSH、SOD表达水平增高。结论TFA具有抗炎、抗氧化作用,能够有效地延缓四氯化碳诱导的肝纤维化进程,其机制可能与调控FXR的表达相关。
文摘Portal hypertension(PHT)in advanced chronic liver disease(ACLD)results from increased intrahepatic resistance caused by pathologic changes of liver tissue composition(structural component)and intrahepatic vasoconstriction(functional component).PHT is an important driver of hepatic decompensation such as development of ascites or variceal bleeding.Dysbiosis and an impaired intestinal barrier in ACLD facilitate translocation of bacteria and pathogen-associated molecular patterns(PAMPs)that promote disease progression via immune system activation with subsequent induction of proinflammatory and profibrogenic pathways.Congestive portal venous blood flow represents a critical pathophysiological mechanism linking PHT to increased intestinal permeability:The intestinal barrier function is affected by impaired microcirculation,neoangiogenesis,and abnormal vascular and mucosal permeability.The close bidirectional relationship between the gut and the liver has been termed“gut-liver axis”.Treatment strategies targeting the gut-liver axis by modulation of microbiota composition and function,intestinal barrier integrity,as well as amelioration of liver fibrosis and PHT are supposed to exert beneficial effects.The activation of the farnesoid X receptor in the liver and the gut was associated with beneficial effects in animal experiments,however,further studies regarding efficacy and safety of pharmacological FXR modulation in patients with ACLD are needed.In this review,we summarize the clinical impact of PHT on the course of liver disease,discuss the underlying pathophysiological link of PHT to gut-liver axis signaling,and provide insight into molecular mechanisms that may represent novel therapeutic targets.
基金supported by National Natural Science Foundation of China (grants 81430091, 81720108032, 81421005, 91429308 and 81603194)the Project for Major New Drug Innovation and Development (grant 2015ZX09501010 and 2017ZX09101003-002-003, China)+3 种基金Overseas Expertise Introduction Project for Discipline Innovation (G20582017001, China)"Double First Class" Initiative Project (CPU2018GF01 and CPU2018GF09, China)State Key Laboratory of Natural Medicines at China Pharmaceutical University (SKLNMZZCX201610 and SKLNMZZCX201801, China)China Postdoctoral Science Foundation (grants 2016M600455 and 2017T100423)
文摘Obeticholic acid(OCA), the first FXR-targeting drug, has been claimed effective in the therapy of liver fibrosis. However, recent clinical trials indicated that OCA might not be effective against liver fibrosis, possibly due to the lower dosage to reduce the incidence of the side-effect of pruritus. Here we propose a combinatory therapeutic strategy of OCA and apoptosis inhibitor for combating against liver fibrosis. CCl4-injured mice, D-galactosamine/LPS(GalN/LPS)-treated mice and cycloheximide/TNFα(CHX/TNFα)-treated HepG2 cells were employed to assess the effects of OCA, or together with IDN-6556, an apoptosis inhibitor. OCA treatment significantly inhibited hepatic stellate cell(HSC)activation/proliferation and prevented fibrosis. Elevated bile acid(BA) levels and hepatocyte apoptosis triggered the activation and proliferation of HSCs. OCA treatment reduced BA levels but could not inhibit hepatocellular apoptosis. An enhanced anti-fibrotic effect was observed when OCA was co-administrated with IDN-6556. Our study demonstrated that OCA inhibits HSCs activation/proliferation partially by regulating BA homeostasis and thereby inhibiting activation of HSCs. The findings in this study suggest that combined use of apoptosis inhibitor and OCA at lower dosage represents a novel therapeutic strategy for liver fibrosis.
文摘Spontaneous bacterial peritonitis(SBP) is a frequent, life-threatening bacterial infection in patients with liver cirrhosis and ascites. Portal hypertension leads to increased bacterial translocation from the intestine. Failure to eliminate invading pathogens due to immune defects associated with advanced liver disease on the background of genetic predisposition may result in SBP. The efficacy of antibiotic treatment and prophylaxis has declined due to the spread of multi-resistant bacteria. Patients with nosocomial SBP and with prior antibiotictreatment are at a particularly high risk for infection with resistant bacteria. Therefore, it is important to adapt empirical treatment to these risk factors and to the local resistance profile. Rifaximin, an oral, nonabsorbable antibiotic, has been proposed to prevent SBP, but may be useful only in a subset of patients. Since novel antibiotic classes are lacking, we have to develop prophylactic strategies which do not induce bacterial resistance. Farnesoid X receptor agonists may be a candidate, but so far, clinical studies are not available. New diagnostic tests which can be carried out quickly at the patient's site and provide additional prognostic information would be helpful. Furthermore, we need tools to predict antibiotic resistance in order to tailor first-line antibiotic treatment of spontaneous bacterial peritonitis to the individual patient and to reduce mortality.
基金supported in part by the National Institutes of Health (Nos.R01 AA020518 and R01 DK102142)National Center for Research Resources (No.5P20RR021940)+1 种基金the National Institute of General Medical Sciences (Nos.8P20 GM103549 and T32 ES007079)an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health (No.P20 GM103418)
文摘Alcoholic liver disease(ALD) is one of the major causes of liver morbidity and mortality worldwide. Chronic alcohol consumption leads to development of liver pathogenesis encompassing steatosis, inflammation, fibrosis, cirrhosis, and in extreme cases, hepatocellular carcinoma. Moreover,ALD may also associate with cholestasis. Emerging evidence now suggests that farnesoid X receptor(FXR) and bile acids also play important roles in ALD. In this review, we discuss the effects of alcohol consumption on FXR, bile acids and gut microbiome as well as their impacts on ALD. Moreover, we summarize the findings on FXR, Fox O3a(forkhead box-containing protein class O3a) and PPARα(peroxisome proliferator-activated receptor alpha) in regulation of autophagy-related gene transcription program and liver injury in response to alcohol exposure.
基金国家自然科学基金，国家973计划前期研究专项，河南省科技厅重点攻关项目，郑州市创新型科技人才队伍建设工程基金，河南省科技创新杰出人才基金(134200510022)Fund program:National Natural Science Foundation of China，Special Prophase Research Project for National Program on Key Basic Research Project (973 Program)，Key Technolo-gies R&D Program of Henan Province of China，Zhengzhou Municipal Fund for Fostering In-novative Talents in Science and Technology，Henan Provincial Foundation for Outstanding In-novative Talents in Science and Technology
文摘Recent studies have revealed that bile acids(BAs)are not only facilitators of dietary lipid absorption but also important signaling molecules exerting multiple physiological functions.Some major signaling pathways involving the nuclear BAs receptor farnesoid X receptor and the G protein-coupled BAs receptor TGR5/M-BAR have been identified to be the targets of BAs.BAs regulate their own homeostasis via signaling pathways.BAs also affect diverse metabolic pathways including glucose metabolism,lipid metabolism and energy expenditure.This paper suggests the mechanism of controlling metabolism via BA signaling and demonstrates that BA signaling is an attractive therapeutic target of the metabolic syndrome.
文摘BACKGROUND: Parenteral nutrition-associated liver disease (PNALD) has been common in patients who require long-term parenteral nutrition. PNALD develops in 40%-60% of infants on long-term parenteral nutrition compared with 15%-40% of adults on home parenteral nutrition for intestinal failure. The pathogenesis of PNALD is multifactorial and remains unclear There is no specific treatment. Management strategies for its prevention and treatment depend on an understanding of many risk factors. This review aims to provide an update on the pathogenesis and treatment of this disease. DATA SOURCES: A literature search was performed on the MEDLINE and Web of Science databases for articles published up to October 2011, using the keywords: parenteral nutrition associated liver disease, intestinal failure associated liver disease lipid emulsions and fish oil. The available data reported in the relevant literatures were analyzed. RESULTS: The literature search provided a huge amount of evidence about the pathogenesis and management strategies on PNALD. Currently, lack of enteral feeding, extended duration of parenteral nutrition, recurrent sepsis, and nutrient deficiency or excess may play important roles in the pathogenesis of PNALD. Recent studies found that phytosterols present as contaminants in soy-based lipid emulsions, are also an important factor in the pathogenesis. Moreover, the treatment of PNALD is discussed. CONCLUSIONS: The use of lipid emulsions, phytosterols in particular, is associated with PNALD. Management strategies for the prevention and treatment of PNALD include consideration of early enteral feeding, the use of specialized lipid emulsions such as fish oil emulsions, and isolated small bowel or combined liver and small bowel transplantation. A greater understanding of the pathogenesis of PNALD has led to promising interventions to prevent and treat this condition. Future work should aim to better understand the mechanisms of PNALD and the long-term outcomes of its treatment.
