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
Sterile inflammation is a ubiquitous response of tissues to stress and injury,and occurs to a high degree in the liver.This results in high levels of tissue damage after development of the metabolic syndrome,and with ...Sterile inflammation is a ubiquitous response of tissues to stress and injury,and occurs to a high degree in the liver.This results in high levels of tissue damage after development of the metabolic syndrome,and with alcohol excess.Inflammatory cytokines such as interleukin(IL)-1βare key in the initiation and propagation of inflammation and tissue damage.IL-1βis activated by a cytosolic machinery collectively termed the inflammasome,and by proteases released by neutrophils.Most of the inflammatory response is driven by macrophages,but hepatocytes,stellate and sinusoidal endothelial cells also have key roles.Hepatocytes for example release acute phase reactants which have pro-and anti-inflammatory effects,and are also a major source of pro-inflammatory damage associated molecules.Stellate cells can regulate differentiation of regulatory T cells by the production of transforming growth factor(TGF)βand all-trans retinoic acid,but the overall effect seems to be context dependent.The strong hepatic inflammatory response is regulated in many ways,with epigenetic regulation playing a major role.This is seen most notably with the rapid development of non-alcoholic steatohepatitis(NASH)in pups of female mice kept on a high fat diet prior to conception,but is likely occurring in adults that have been under metabolic stress for extended periods of time.Epigenetic regulation is of key importance due to its clinical implications,and potential to reveal new pathways for liver inflammation.展开更多
Alcoholic liver disease(ALD)remains one of the leading causes of liver injury and death when left un-treated.The gut microbiota has been recognized as a key regulator of a number of pathologies,including ALD.The role ...Alcoholic liver disease(ALD)remains one of the leading causes of liver injury and death when left un-treated.The gut microbiota has been recognized as a key regulator of a number of pathologies,including ALD.The role of mast cells(MCs)during liver disease progression has been demonstrated in a number of animal models and in human liver diseases.The interaction between the gut microbiota and MCs has been investigated,and links between the gut and these immune cells are being uncovered.The interplay between the gut microbiota and MCs during ALD has been evaluated and studies suggest that there could be an important link between MCs,their mediators and gut inflammation during the progression of ALD.展开更多
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.
文摘Sterile inflammation is a ubiquitous response of tissues to stress and injury,and occurs to a high degree in the liver.This results in high levels of tissue damage after development of the metabolic syndrome,and with alcohol excess.Inflammatory cytokines such as interleukin(IL)-1βare key in the initiation and propagation of inflammation and tissue damage.IL-1βis activated by a cytosolic machinery collectively termed the inflammasome,and by proteases released by neutrophils.Most of the inflammatory response is driven by macrophages,but hepatocytes,stellate and sinusoidal endothelial cells also have key roles.Hepatocytes for example release acute phase reactants which have pro-and anti-inflammatory effects,and are also a major source of pro-inflammatory damage associated molecules.Stellate cells can regulate differentiation of regulatory T cells by the production of transforming growth factor(TGF)βand all-trans retinoic acid,but the overall effect seems to be context dependent.The strong hepatic inflammatory response is regulated in many ways,with epigenetic regulation playing a major role.This is seen most notably with the rapid development of non-alcoholic steatohepatitis(NASH)in pups of female mice kept on a high fat diet prior to conception,but is likely occurring in adults that have been under metabolic stress for extended periods of time.Epigenetic regulation is of key importance due to its clinical implications,and potential to reveal new pathways for liver inflammation.
基金Portions of this work were supported by(i)a VA Merit Award(1I01BX003031,HF)from the United States Department of Veter-an's AffairsBiomedical Laboratory Research and Development Service and(ii)the R01 grant from NIH NIDDK(DK108959,HF).
文摘Alcoholic liver disease(ALD)remains one of the leading causes of liver injury and death when left un-treated.The gut microbiota has been recognized as a key regulator of a number of pathologies,including ALD.The role of mast cells(MCs)during liver disease progression has been demonstrated in a number of animal models and in human liver diseases.The interaction between the gut microbiota and MCs has been investigated,and links between the gut and these immune cells are being uncovered.The interplay between the gut microbiota and MCs during ALD has been evaluated and studies suggest that there could be an important link between MCs,their mediators and gut inflammation during the progression of ALD.
