Intestinal bacteria contribute to the pathogenesis of non-alcoholic fatty liver disease(NAFLD).Recently developed microbial profiling techniques are beginning to shed light on the nature of the changes in the gut micr...Intestinal bacteria contribute to the pathogenesis of non-alcoholic fatty liver disease(NAFLD).Recently developed microbial profiling techniques are beginning to shed light on the nature of the changes in the gut microbiota that accompany NAFLD and non-alcoholic steatohepatitis(NASH).In this review,we summarize the role of gut microbiota in the development of NAFLD,NASH,and hepatocellular carcinoma(HCC).We highlight the mechanisms by which gut microbiota contribute to NAFLD/NASH,including through alterations in gut epithelial permeability,choline metabolism,endogenous alcohol production,release of inflammatory cytokines,regulation of hepatic Toll-like receptor(TLR),and bile acid metabolism.In addition,we analyze possible mechanisms for enhanced hepatic carcinogenesis,including alterations in bile acid metabolism,release of inflammatory cytokines,and expression of TLR-4.Finally,we describe therapeutic approaches for NAFLD/NASH and preventive strategies for HCC involving modulation of the intestinal microbiota or affected host pathways.Although recent studies have provided useful information,large-scale prospective studies are required to better characterize the intestinal microbiota and metabolome,in order to demonstrate a causative role for changes in the gut microbiota in the etiology of NAFLD/NASH,to identify new therapeutic strategies for NAFLD/NASH,and to develop more effective methods of preventing HCC.展开更多
Non-alcoholic fatty liver disease(NAFLD)and non-alcoholic steatohepatitis(NASH)are national and global epidemics.The disease is characterized by a spectrum of liver steatosis(fat deposition),inflammation(in NASH)and f...Non-alcoholic fatty liver disease(NAFLD)and non-alcoholic steatohepatitis(NASH)are national and global epidemics.The disease is characterized by a spectrum of liver steatosis(fat deposition),inflammation(in NASH)and fibrosis.NAFLD and specifically NASH can lead to cirrhosis,which carry risks of progression to portal hypertension and hepatocellular carcinoma(HCC).NASH is also associated with higher mortality from cardiovascular causes.Most of the data for NAFLD has been obtained from the perspective of developed nations,although the disease is increasing and threatening to reach epidemic proportions across the world.Emerging data is notable for high prevalence of NAFLD in South Asian populations,presumably resulting from a combination of underlying genetic polymorphisms and changes in socio-economic status.It is also notable that an‘Asian Paradox'has been defined for NAFLD based upon the observation of lower than predefined body mass index(BMI),otherwise termed as"lean NAFLD",among this population.Yet,data remains limited in regards to the characteristics of NAFLD/NASH in this population.In this article,we present a review of the literature and discuss the prevalence,associated risk factors and burden of HCC in South Asians with NAFLD.展开更多
Liver cancer is the sixth most common cancer worldwide,and the third most common cause of cancer-related death.Hepatocellular carcinoma(HCC),which accounts for more than 90%of primary liver cancers,is an important pub...Liver cancer is the sixth most common cancer worldwide,and the third most common cause of cancer-related death.Hepatocellular carcinoma(HCC),which accounts for more than 90%of primary liver cancers,is an important public health problem.In addition to cirrhosis caused by hepatitis B viral(HBV)or hepatitis C viral(HCV)infection,non-alcoholic fatty liver disease(NAFLD)is becoming a major risk factor for liver cancer because of the prevalence of obesity.Non-alcoholic steatohepatitis(NASH)will likely become the leading indication for liver transplantation in the future.It is well recognized that gut microbiota is a key environmental factor in the pathogenesis of liver disease and cancer.The interplay between gut microbiota and liver disease has been investigated in animal and clinical studies.In this article,we summarize the roles of gut microbiota in the development of liver disease as well as gut microbiota-targeted therapies.展开更多
Bile acids are synthesized from cholesterol only in hepatocytes.Bile acids circulating in the enterohepatic system act as physiological detergent molecules to help solubilize biliary cholesterol and emulsify dietary l...Bile acids are synthesized from cholesterol only in hepatocytes.Bile acids circulating in the enterohepatic system act as physiological detergent molecules to help solubilize biliary cholesterol and emulsify dietary lipids and fat-soluble vitamins in small intestine.Bile acids are signaling molecules that activate nuclear receptor farnesoid X receptor(FXR)and cell surface G protein-coupled receptor TGR5.FXR critically regulates bile acid homeostasis by mediating bile acid feedback inhibition of hepatic bile acid synthesis.In addition,bile acid-activated cellular signaling pathways regulate metabolic homeostasis,immunity,and cell proliferation in various metabolically active organs.In the small and large intestine,gut bacterial enzymes modify primary bile acids to generate secondary bile acids to help shape the bile acid pool composition and subsequent biological effects.In turn,bile acids exhibit anti-microbial properties and modulate gut microbiota to influence host metabolism and immunity.Currently,bile acid-based therapies including systemic and intestine-restricted FXR agonists,TGR5 agonists,fibroblast growth factor 19 analogue,intestine FXR antagonists,and intestine apical sodium-bile acid transporter(ASBT)inhibitors have been developed as promising treatments for non-alcoholic steatohepatitis(NASH).These pharmacological agents improved metabolic and inflammatory disorders via distinct mechanisms of action that are subjects of extensive research interest.More recently,human and experimental alcoholic liver disease(ALD)has been associated with disrupted bile acid homeostasis.In additional,new findings showed that targeting bile acid metabolism and signaling may be promising therapeutic approaches for treating ALD.展开更多
Objective:To observe the effects of Yinchenhao Decoction(茵陈蒿汤) for non-alcoholic steatohepatitis(NASH) in rats and study the mechanism.Methods:Total 18 male SD rats were randomly divided into a normal control grou...Objective:To observe the effects of Yinchenhao Decoction(茵陈蒿汤) for non-alcoholic steatohepatitis(NASH) in rats and study the mechanism.Methods:Total 18 male SD rats were randomly divided into a normal control group,a model group and a treatment group,6 rats in each group.Rats in the model and treatment groups were fed with high-fat forage for 10 weeks to prepare the NASH model,and the rats in the treatment group were administrated with Yinchenhao Decoction from the 6th week for 5 weeks.All rats were sacrificed at the end of the10th week and the samples were collected.Serum alanine aminotransferase(ALT) activity,tumor necrosis factor-α(TNF-α) level,and hepatic triglyceride(TG) and free fatty acid(FFA) contents were determined.Hepatic pathological changes were detected by HE staining.Results:Serum ALT activity,TNF-α level,hepatic TG and FFA contents,and the fatty deposition in hepatocytes were significantly reduced in the rats of the treatment group.Conclusion:Yinchenhao Decoction has good therapeutic effects for NASH,protecting the liver function and reducing the fatty deposition in liver,which are possibly related with reduction of FFA content and inhibition of TNF-α expression.展开更多
Fatty liver diseases,non-alcoholic fatty liver disease(NAFLD)and alcoholic liver disease(ALD)are the most common causes of chronic liver diseases around the world.NAFLD and ALD can progress towards a more severe form ...Fatty liver diseases,non-alcoholic fatty liver disease(NAFLD)and alcoholic liver disease(ALD)are the most common causes of chronic liver diseases around the world.NAFLD and ALD can progress towards a more severe form of the disease,including as non-alcoholic steatohepatitis(NASH)and alcoholic steatohepatitis(ASH).In both instances central pathogenic events include hepatocyte death,liver inflammation,pathological angiogenesis,and fibrosis,followed by cirrhosis and cancer.Over the last few years,extracellular vesicles(EVs)have been identified as effective cell-to-cell communicators that contain a cell-and stressspecific cargo from the cell of origin and are capable of transferring this cargo to a target or acceptor cell.In this review,we focus on the growing evidence supporting a role for EVs in the pathophysiology of NASH and ASH as well as their potential roles as targets for novel biomarkers for these conditions.展开更多
Galectins(Gals)are evolutionarily conserved proteins that bind to b-galactoside containing glycans.Abnormal expression of Gals is associated with the development,progression,and metastasis of different types of cancer...Galectins(Gals)are evolutionarily conserved proteins that bind to b-galactoside containing glycans.Abnormal expression of Gals is associated with the development,progression,and metastasis of different types of cancer.Among the 11 Gals identified in humans,the roles of Gal-1 and Gal-3 have been extensively investigated in various tumors.Here,we summarize the roles of overly expressed Gal-1 and Gal-3 in the pathogenesis of hepatocellular carcinoma(HCC).The overexpression of Gal-1 and Gal-3 correlates with tumor growth,HCC cell migration and invasion,tumor aggressiveness,metastasis,and poor prognosis.A potentially promising future treatment strategy for HCC may include the combination of immunotherapy with Gal-1 inhibition.Additional research is warranted to investigate targeting Gal-1 and Gal-3 for HCC treatment.展开更多
Background:There is an unmet need for accurate non-invasive methods to diagnose non-alcoholic steatohepatitis(NASH).Since impedance-based measurements of body composition are simple,repeatable and have a strong associ...Background:There is an unmet need for accurate non-invasive methods to diagnose non-alcoholic steatohepatitis(NASH).Since impedance-based measurements of body composition are simple,repeatable and have a strong association with non-alcoholic fatty liver disease(NAFLD)severity,we aimed to develop a novel and fully automatic machine learning algorithm,consisting of a deep neural network based on impedance-based measurements of body composition to identify NASH[the bioeLectrical impEdance Analysis foR Nash(LEARN)algorithm].Methods:A total of 1,259 consecutive subjects with suspected NAFLD were screened from six medical centers across China,of which 766 patients with biopsy-proven NAFLD were included in final analysis.These patients were randomly subdivided into the training and validation groups,in a ratio of 4:1.The LEARN algorithm was developed in the training group to identify NASH,and subsequently,tested in the validation group.Results:The LEARN algorithm utilizing impedance-based measurements of body composition along with age,sex,pre-existing hypertension and diabetes,was able to predict the likelihood of having NASH.This algorithm showed good discriminatory ability for identifying NASH in both the training and validation groups[area under the receiver operating characteristics(AUROC):0.81,95%CI:0.77-0.84 and AUROC:0.80,95%CI:0.73-0.87,respectively].This algorithm also performed better than serum cytokeratin-18 neoepitope M30(CK-18 M30)level or other non-invasive NASH scores(including HAIR,ION,NICE)for identifying NASH(P value<0.001).Additionally,the LEARN algorithm performed well in identifying NASH in different patient subgroups,as well as in subjects with partial missing body composition data.Conclusions:The LEARN algorithm,utilizing simple easily obtained measures,provides a fully automated,simple,non-invasive method for identifying NASH.展开更多
Non-alcoholic fatty liver disease (NAFLD) has become a global issue and a severe threat to public health.However, to date, no approved therapeutic drugs have been developed. Dietary interventions with naturalproducts ...Non-alcoholic fatty liver disease (NAFLD) has become a global issue and a severe threat to public health.However, to date, no approved therapeutic drugs have been developed. Dietary interventions with naturalproducts have shown promise in preventing and treating NAFLD. Sulforaphane (SFN) is a phytocompoundwith antioxidant and anti-inflammatory properties, and previous research has demonstrated that SFN canameliorate hepatic lipid accumulation and inflammation. However, the molecular mechanisms underlying thesebeneficial effects remain unclear. In this study, we confirmed the protective effects of SFN on excessive lipidaccumulation and inflammatory injury in a high-fat, high-fructose diet-induced non-alcoholic steatohepatitis(NASH) mouse model. We found that SFN attenuates the inflammatory injury in a macrophage cell line andthe liver of NASH mice, owing to the promotion of M1-type macrophage polarization toward the M2-type andthe regulation of inflammatory mediators. Further analysis demonstrated that this SFN-induced macrophageM2-type polarization occurs in a Krüppel-like factor 4 (KLF4)-dependent manner. In summary, we uncovereda new mechanism of action underlying SFN activity and provide evidence that dietary intervention with SFNmight be protective against NASH.展开更多
基金This study was supported by the USA National Institutes of Health(NIH)grant R01 AA020703,and by Award Number I01BX002213 from the Biomedical Laboratory Research&Development Service of the VA Office of Research and Development to B.Schnab.
文摘Intestinal bacteria contribute to the pathogenesis of non-alcoholic fatty liver disease(NAFLD).Recently developed microbial profiling techniques are beginning to shed light on the nature of the changes in the gut microbiota that accompany NAFLD and non-alcoholic steatohepatitis(NASH).In this review,we summarize the role of gut microbiota in the development of NAFLD,NASH,and hepatocellular carcinoma(HCC).We highlight the mechanisms by which gut microbiota contribute to NAFLD/NASH,including through alterations in gut epithelial permeability,choline metabolism,endogenous alcohol production,release of inflammatory cytokines,regulation of hepatic Toll-like receptor(TLR),and bile acid metabolism.In addition,we analyze possible mechanisms for enhanced hepatic carcinogenesis,including alterations in bile acid metabolism,release of inflammatory cytokines,and expression of TLR-4.Finally,we describe therapeutic approaches for NAFLD/NASH and preventive strategies for HCC involving modulation of the intestinal microbiota or affected host pathways.Although recent studies have provided useful information,large-scale prospective studies are required to better characterize the intestinal microbiota and metabolome,in order to demonstrate a causative role for changes in the gut microbiota in the etiology of NAFLD/NASH,to identify new therapeutic strategies for NAFLD/NASH,and to develop more effective methods of preventing HCC.
文摘Non-alcoholic fatty liver disease(NAFLD)and non-alcoholic steatohepatitis(NASH)are national and global epidemics.The disease is characterized by a spectrum of liver steatosis(fat deposition),inflammation(in NASH)and fibrosis.NAFLD and specifically NASH can lead to cirrhosis,which carry risks of progression to portal hypertension and hepatocellular carcinoma(HCC).NASH is also associated with higher mortality from cardiovascular causes.Most of the data for NAFLD has been obtained from the perspective of developed nations,although the disease is increasing and threatening to reach epidemic proportions across the world.Emerging data is notable for high prevalence of NAFLD in South Asian populations,presumably resulting from a combination of underlying genetic polymorphisms and changes in socio-economic status.It is also notable that an‘Asian Paradox'has been defined for NAFLD based upon the observation of lower than predefined body mass index(BMI),otherwise termed as"lean NAFLD",among this population.Yet,data remains limited in regards to the characteristics of NAFLD/NASH in this population.In this article,we present a review of the literature and discuss the prevalence,associated risk factors and burden of HCC in South Asians with NAFLD.
文摘Liver cancer is the sixth most common cancer worldwide,and the third most common cause of cancer-related death.Hepatocellular carcinoma(HCC),which accounts for more than 90%of primary liver cancers,is an important public health problem.In addition to cirrhosis caused by hepatitis B viral(HBV)or hepatitis C viral(HCV)infection,non-alcoholic fatty liver disease(NAFLD)is becoming a major risk factor for liver cancer because of the prevalence of obesity.Non-alcoholic steatohepatitis(NASH)will likely become the leading indication for liver transplantation in the future.It is well recognized that gut microbiota is a key environmental factor in the pathogenesis of liver disease and cancer.The interplay between gut microbiota and liver disease has been investigated in animal and clinical studies.In this article,we summarize the roles of gut microbiota in the development of liver disease as well as gut microbiota-targeted therapies.
基金This work was supported in part by NIH grants 1R01DK102487-01 and R01 DK117965-01A1 to T Li,and DK44442 and DK58379 to JYL Chiang.
文摘Bile acids are synthesized from cholesterol only in hepatocytes.Bile acids circulating in the enterohepatic system act as physiological detergent molecules to help solubilize biliary cholesterol and emulsify dietary lipids and fat-soluble vitamins in small intestine.Bile acids are signaling molecules that activate nuclear receptor farnesoid X receptor(FXR)and cell surface G protein-coupled receptor TGR5.FXR critically regulates bile acid homeostasis by mediating bile acid feedback inhibition of hepatic bile acid synthesis.In addition,bile acid-activated cellular signaling pathways regulate metabolic homeostasis,immunity,and cell proliferation in various metabolically active organs.In the small and large intestine,gut bacterial enzymes modify primary bile acids to generate secondary bile acids to help shape the bile acid pool composition and subsequent biological effects.In turn,bile acids exhibit anti-microbial properties and modulate gut microbiota to influence host metabolism and immunity.Currently,bile acid-based therapies including systemic and intestine-restricted FXR agonists,TGR5 agonists,fibroblast growth factor 19 analogue,intestine FXR antagonists,and intestine apical sodium-bile acid transporter(ASBT)inhibitors have been developed as promising treatments for non-alcoholic steatohepatitis(NASH).These pharmacological agents improved metabolic and inflammatory disorders via distinct mechanisms of action that are subjects of extensive research interest.More recently,human and experimental alcoholic liver disease(ALD)has been associated with disrupted bile acid homeostasis.In additional,new findings showed that targeting bile acid metabolism and signaling may be promising therapeutic approaches for treating ALD.
基金supported by Natural Science Fund Plan of Fujian Province (No.2009J05089)Key Science and Technique Innovation Platform of Xiamen City Science and Technique Bureau (No. 3502Z20100006)Headmaster Grant of Medical College of Xiamen University
文摘Objective:To observe the effects of Yinchenhao Decoction(茵陈蒿汤) for non-alcoholic steatohepatitis(NASH) in rats and study the mechanism.Methods:Total 18 male SD rats were randomly divided into a normal control group,a model group and a treatment group,6 rats in each group.Rats in the model and treatment groups were fed with high-fat forage for 10 weeks to prepare the NASH model,and the rats in the treatment group were administrated with Yinchenhao Decoction from the 6th week for 5 weeks.All rats were sacrificed at the end of the10th week and the samples were collected.Serum alanine aminotransferase(ALT) activity,tumor necrosis factor-α(TNF-α) level,and hepatic triglyceride(TG) and free fatty acid(FFA) contents were determined.Hepatic pathological changes were detected by HE staining.Results:Serum ALT activity,TNF-α level,hepatic TG and FFA contents,and the fatty deposition in hepatocytes were significantly reduced in the rats of the treatment group.Conclusion:Yinchenhao Decoction has good therapeutic effects for NASH,protecting the liver function and reducing the fatty deposition in liver,which are possibly related with reduction of FFA content and inhibition of TNF-α expression.
基金This work was partially supported by the USA National Institutes Health(NIH)grants U01 AA022489 to A.E.Feldstein and R21 AA023574 to A.Eguchi and A.E.Feldstein.
文摘Fatty liver diseases,non-alcoholic fatty liver disease(NAFLD)and alcoholic liver disease(ALD)are the most common causes of chronic liver diseases around the world.NAFLD and ALD can progress towards a more severe form of the disease,including as non-alcoholic steatohepatitis(NASH)and alcoholic steatohepatitis(ASH).In both instances central pathogenic events include hepatocyte death,liver inflammation,pathological angiogenesis,and fibrosis,followed by cirrhosis and cancer.Over the last few years,extracellular vesicles(EVs)have been identified as effective cell-to-cell communicators that contain a cell-and stressspecific cargo from the cell of origin and are capable of transferring this cargo to a target or acceptor cell.In this review,we focus on the growing evidence supporting a role for EVs in the pathophysiology of NASH and ASH as well as their potential roles as targets for novel biomarkers for these conditions.
基金This manuscript is supported by grants funded by the USA National Institutes of Health(NIH)U01CA179582,R01CA222490,T32 CA108459-15UC Davis Comprehensive Cancer Center seed grant.
文摘Galectins(Gals)are evolutionarily conserved proteins that bind to b-galactoside containing glycans.Abnormal expression of Gals is associated with the development,progression,and metastasis of different types of cancer.Among the 11 Gals identified in humans,the roles of Gal-1 and Gal-3 have been extensively investigated in various tumors.Here,we summarize the roles of overly expressed Gal-1 and Gal-3 in the pathogenesis of hepatocellular carcinoma(HCC).The overexpression of Gal-1 and Gal-3 correlates with tumor growth,HCC cell migration and invasion,tumor aggressiveness,metastasis,and poor prognosis.A potentially promising future treatment strategy for HCC may include the combination of immunotherapy with Gal-1 inhibition.Additional research is warranted to investigate targeting Gal-1 and Gal-3 for HCC treatment.
基金supported by grants from the National Natural Science Foundation of China(82070588)High Level Creative Talents from Department of Public Health in Zhejiang Province(S2032102600032)+2 种基金Project of New Century 551 Talent Nurturing in Wenzhousupported in part by grants from the University School of Medicine of Verona,Verona,Italysupported in part by the Southampton NIHR Biomedical Research Centre(IS-BRC-20004),UK.
文摘Background:There is an unmet need for accurate non-invasive methods to diagnose non-alcoholic steatohepatitis(NASH).Since impedance-based measurements of body composition are simple,repeatable and have a strong association with non-alcoholic fatty liver disease(NAFLD)severity,we aimed to develop a novel and fully automatic machine learning algorithm,consisting of a deep neural network based on impedance-based measurements of body composition to identify NASH[the bioeLectrical impEdance Analysis foR Nash(LEARN)algorithm].Methods:A total of 1,259 consecutive subjects with suspected NAFLD were screened from six medical centers across China,of which 766 patients with biopsy-proven NAFLD were included in final analysis.These patients were randomly subdivided into the training and validation groups,in a ratio of 4:1.The LEARN algorithm was developed in the training group to identify NASH,and subsequently,tested in the validation group.Results:The LEARN algorithm utilizing impedance-based measurements of body composition along with age,sex,pre-existing hypertension and diabetes,was able to predict the likelihood of having NASH.This algorithm showed good discriminatory ability for identifying NASH in both the training and validation groups[area under the receiver operating characteristics(AUROC):0.81,95%CI:0.77-0.84 and AUROC:0.80,95%CI:0.73-0.87,respectively].This algorithm also performed better than serum cytokeratin-18 neoepitope M30(CK-18 M30)level or other non-invasive NASH scores(including HAIR,ION,NICE)for identifying NASH(P value<0.001).Additionally,the LEARN algorithm performed well in identifying NASH in different patient subgroups,as well as in subjects with partial missing body composition data.Conclusions:The LEARN algorithm,utilizing simple easily obtained measures,provides a fully automated,simple,non-invasive method for identifying NASH.
基金supported by the Science and Technology project of Henan Province(202102310142)the National Natural Science Foundation of China(32001806)。
文摘Non-alcoholic fatty liver disease (NAFLD) has become a global issue and a severe threat to public health.However, to date, no approved therapeutic drugs have been developed. Dietary interventions with naturalproducts have shown promise in preventing and treating NAFLD. Sulforaphane (SFN) is a phytocompoundwith antioxidant and anti-inflammatory properties, and previous research has demonstrated that SFN canameliorate hepatic lipid accumulation and inflammation. However, the molecular mechanisms underlying thesebeneficial effects remain unclear. In this study, we confirmed the protective effects of SFN on excessive lipidaccumulation and inflammatory injury in a high-fat, high-fructose diet-induced non-alcoholic steatohepatitis(NASH) mouse model. We found that SFN attenuates the inflammatory injury in a macrophage cell line andthe liver of NASH mice, owing to the promotion of M1-type macrophage polarization toward the M2-type andthe regulation of inflammatory mediators. Further analysis demonstrated that this SFN-induced macrophageM2-type polarization occurs in a Krüppel-like factor 4 (KLF4)-dependent manner. In summary, we uncovereda new mechanism of action underlying SFN activity and provide evidence that dietary intervention with SFNmight be protective against NASH.
