Autophagy and Liver Disease (2013)

Abstract 1Amir M1, Zhao E1, Fontana L2, Rosenberg H1, Tanaka K3, Gao G4 and Czaja MJ1. Inhibition of hepatocyte autophagy increases tumor necrosis factor-dependent liver injury by promoting caspase-8 activation. Cell Death Differ. 2013; 20: 878-887.1Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA; 2Department of Biochemistry and Molecular Biology II, School of Pharmacy, Institute of Nutrition and Food Technology, Center of Biomedical Research, University of Granada, Granada, Spain; 3Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA; 4Department of Microbiology and Physiological Systems, Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA.Recent investigations have demonstrated a complex interrelationship between autophagy and cell death. A common mechanism of cell death in liver injury is tumor necrosis factor (TNF) cytotoxicity. To better delineate the in vivo function of autophagy in cell death, we examined the role of autophagy in TNF-induced hepatic injury. Atg7Δhep mice with a hepatocyte-specific knockout of the autophagy gene Atg7 were generated and cotreated with d-galactosamine (GalN) and lipopolysaccharide (LPS). GalN/LPS treated Atg7Δhep mice had increased serum alanine aminotransferase levels, histological injury, numbers of TUNEL (terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling)-positive cells and mortality as compared with littermate controls. Loss of hepatocyte autophagy similarly sensitized to GalN/TNF liver injury. GalN/LPS injury in knockout animals did not result from altered production of TNF or other cytokines. Atg7Δhep mice had accelerated activation of the mitochondrial death pathway and caspase-3 and -7 cleavage. Increased cell death did not occur from direct mitochondrial toxicity or a lack of mitophagy, but rather from increased activation of initiator caspase-8 causing Bid cleavage. GalN blocked LPS induction of hepatic autophagy, and increased autophagy from beclin1 overexpression prevented GalN/LPS injury. Autophagy, therefore, mediates cellular resistance to TNF toxicity in vivo by blocking activation of caspase-8 and the mitochondrial death pathway, suggesting that autophagy is a therapeutic target in TNF-dependent tissue injury.Abstract 2Sinha RA1, Farah BL1, Singh BK1, Siddique MM1, Li Y1, Wu Y2, Ilkayeva OR3, Gooding J3, Ching J1, Zhou J1, Martinez L1, Xie S1, Bay BH2, Summers SA1,3, Newgard CB3, Yen PM1,3. Caffeine stimulates hepatic lipid metabolism via autophagy-lysosomal pathway. Hepatology. 2013; http://dx.doi.org/10.1002/hep.26667.1Program of Cardiovascular and Metabolic Disorders, Duke-NUS Graduate Medical School, Singapore; 2Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 3Sarah W. Stedman Nutrition and Metabolism Center, Departments of Medicine and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.Caffeine is one of the world's most consumed drugs. Recently, several studies showed that its consumption is associated with lower risk for non-alcoholic fatty liver disease (NAFLD), an obesity-related condition that recently has become the major cause of liver disease worldwide. Although caffeine is known to stimulate hepatic fat oxidation, its mechanism of action on lipid metabolism is still not clear. Here, we show that caffeine surprisingly is a potent stimulator of hepatic autophagic flux. Using genetic, pharmacological, and metabolomic approaches, we demonstrate that caffeine reduces intra-hepatic lipid content and stimulates β-oxidation in hepatic cells and liver via an autophagy-lysosomal pathway. Furthermore, caffeine induced autophagy involved down regulation of mTOR signaling and alteration in hepatic amino acids and sphingolipid levels. In mice fed a high fat diet, caffeine markedly reduces hepatosteatosis and concomitantly increases autophagy and lipid uptake in lysosomes. Conclusion: Taken together, these results provide novel insight into caffeine's lipolytic actions through autophagy in mammalian liver and its potential beneficial effects in NAFLD.Abstract 3Lan SH1, Wu SY1, Zuchini R 2,3, Lin XZ 3, Su IJ6, Tsai TF7, Lin YJ8, Wu CT8 and Liu HS1,4,5. Autophagy suppresses tumorigenesis of hepatitis B virus-associated hepatocellular carcinoma through degradation of miR-224. Hepatology. 2013; http://dx.doi.org/10.1002/hep.26659.1Institute of Basic Medical Sciences; 2Graduate Institute of Clinical Medicine; 3Department of Internal Medicine; 4Department of Microbiology and Immunology; 5Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 6National Health Research Institutes, Division of Clinical Research, Tainan, Taiwan; 7Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan; 8Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan.In hepatocellular carcinoma (HCC), dysregulated expression of microRNA-224 (miR-224) and impaired autophagy have been reported separately. However, the relationship between them has not been explored. In this study, we determine that autophagy is down-regulated and inversely correlated with miR-224 expression in hepatitis B virus (HBV)-associated HCC patient specimens. These results were confirmed in liver tumors of HBV X gene transgenic mice. Furthermore, miR-224 was preferentially recruited and degraded during autophagic progression demonstrated by real-time PCR and miRNA in situ hybridization electron microscopy after extraction of autophagosomes. Our in vitro study demonstrated that miR-224 played an oncogenic role in hepatoma cell migration and tumor formation through silencing its target gene Smad4. In HCC patients, the expression of low-Atg5, high-miR-224 and low-Smad4 shows significant correlation with HBV infection and poor overall survival rate. Autophagy mediated miR-224 degradation and liver tumor suppression were further confirmed by the autophagy inducer amiodarone and miR-224 antagonist using an orthotopic SD rat model. Conclusion: we reveal a non-canonical pathway which links autophagy, miR-224, Smad4 and HBV-associated HCC. Our novel findings open a new avenue for the treatment of HCC.CommentsIn ancient roman mythology, is as the of and and is as to the and to the Autophagy is in that is a survival in to cell death. In most hepatic autophagy is in hepatitis B and virus of autophagy is the of cellular in which degraded in the lysosomes. In autophagy, a of the in the formation of by a autophagosomes. of formation with the of mammalian target of complex from is with the Autophagy is during of as in the from the complex in with the complex and results in the of the which to the of the with the an in degradation of the Autophagy and the 2013; Liver and Autophagy in liver studies show that autophagy to rather cell cell the of a Cell Autophagy is to on the liver through of and autophagy is associated with hepatic and of autophagy with the cellular and to which is by hepatitis and Liver and is for cell survival as of or Atg7 in the liver results in increased cell death, and liver injury. Inhibition of the autophagy gene the of liver Autophagy and the 2013; role of and autophagy in has been known a the of autophagy has been by of is with on the role of autophagy in liver role of autophagy has been by Zhao Fontana of hepatocyte autophagy increases tumor necrosis factor-dependent liver injury by promoting caspase-8 Death Differ. 2013; 20: have that of hepatocyte autophagy increases tumor necrosis factor liver injury by promoting caspase-8 activation. the in vivo of TNF-dependent hepatocyte and liver injury using of mice with lipopolysaccharide and the hepatocyte-specific d-galactosamine in mice with knockout of the autophagy gene and littermate mice. mice in serum aminotransferase levels, histological hepatocyte injury and mortality the littermate mice. GalN/LPS injury in the knockout mice did not result from altered production of TNF or other but to increased activation of is the initiator of the TNF death pathway activation and the Bid into Bid which in mitochondrial death and Farah Singh stimulates hepatic lipid metabolism via autophagy-lysosomal 2013; have the role of caffeine in promoting through autophagy in non-alcoholic fatty liver disease Although have beneficial of in with fatty liver of and caffeine consumption with fatty liver and of hepatic Caffeine is in with non-alcoholic fatty liver its mechanism of action on lipid metabolism has not been beneficial of in with has been to its Caffeine as an of lipid induced by Farah Singh stimulates hepatic lipid metabolism via autophagy-lysosomal 2013; have that caffeine is a potent stimulator of hepatic autophagy by down regulation of mTOR to in the intra-hepatic lipid content and of β-oxidation in the to an role in tumor an of of the of autophagy in the of hepatocellular carcinoma to hepatitis B hepatitis virus and liver role of autophagy in liver and potential therapeutic 2013; Wu Zuchini suppresses tumorigenesis of hepatitis B virus-associated hepatocellular carcinoma through degradation of 2013; have a of autophagy correlated with an inversely high miR-224 expression in hepatitis B virus (HBV)-associated HCC and tumors in mice. miR-224 played an oncogenic role in hepatoma cell migration and tumor formation through silencing its target gene Smad4. have a role of autophagy in HCC by that most HCC cell and HCC with disease lower autophagic cell or expression of several autophagic and and autophagic is in HCC cell and mice with of have a high of hepatocellular a known inducer of autophagy has been associated with better survival in with HCC liver Autophagy in liver is a for cell survival and has a role in most hepatic A of autophagy to hepatocellular injury and Caffeine and autophagy have a on the A better of the mechanism of autophagy and its role in liver disease result in new therapeutic Abstract 1Amir M1, Zhao E1, Fontana L2, Rosenberg H1, Tanaka K3, Gao G4 and Czaja MJ1. Inhibition of hepatocyte autophagy increases tumor necrosis factor-dependent liver injury by promoting caspase-8 activation. Cell Death Differ. 2013; 20: 878-887.1Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA; 2Department of Biochemistry and Molecular Biology II, School of Pharmacy, Institute of Nutrition and Food Technology, Center of Biomedical Research, University of Granada, Granada, Spain; 3Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA; 4Department of Microbiology and Physiological Systems, Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA.Recent investigations have demonstrated a complex interrelationship between autophagy and cell death. A common mechanism of cell death in liver injury is tumor necrosis factor (TNF) cytotoxicity. To better delineate the in vivo function of autophagy in cell death, we examined the role of autophagy in TNF-induced hepatic injury. Atg7Δhep mice with a hepatocyte-specific knockout of the autophagy gene Atg7 were generated and cotreated with d-galactosamine (GalN) and lipopolysaccharide (LPS). GalN/LPS treated Atg7Δhep mice had increased serum alanine aminotransferase levels, histological injury, numbers of TUNEL (terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling)-positive cells and mortality as compared with littermate controls. Loss of hepatocyte autophagy similarly sensitized to GalN/TNF liver injury. GalN/LPS injury in knockout animals did not result from altered production of TNF or other cytokines. Atg7Δhep mice had accelerated activation of the mitochondrial death pathway and caspase-3 and -7 cleavage. Increased cell death did not occur from direct mitochondrial toxicity or a lack of mitophagy, but rather from increased activation of initiator caspase-8 causing Bid cleavage. GalN blocked LPS induction of hepatic autophagy, and increased autophagy from beclin1 overexpression prevented GalN/LPS injury. Autophagy, therefore, mediates cellular resistance to TNF toxicity in vivo by blocking activation of caspase-8 and the mitochondrial death pathway, suggesting that autophagy is a therapeutic target in TNF-dependent tissue injury. M1, Zhao E1, Fontana L2, Rosenberg H1, Tanaka K3, Gao G4 and Czaja MJ1. Inhibition of hepatocyte autophagy increases tumor necrosis factor-dependent liver injury by promoting caspase-8 activation. Cell Death Differ. 2013; 20: of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA; 2Department of Biochemistry and Molecular Biology II, School of Pharmacy, Institute of Nutrition and Food Technology, Center of Biomedical Research, University of Granada, Granada, Spain; 3Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA; 4Department of Microbiology and Physiological Systems, Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, investigations have demonstrated a complex interrelationship between autophagy and cell death. A common mechanism of cell death in liver injury is tumor necrosis factor (TNF) cytotoxicity. To better delineate the in vivo function of autophagy in cell death, we examined the role of autophagy in TNF-induced hepatic injury. Atg7Δhep mice with a hepatocyte-specific knockout of the autophagy gene Atg7 were generated and cotreated with d-galactosamine (GalN) and lipopolysaccharide (LPS). GalN/LPS treated Atg7Δhep mice had increased serum alanine aminotransferase levels, histological injury, numbers of TUNEL (terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling)-positive cells and mortality as compared with littermate controls. Loss of hepatocyte autophagy similarly sensitized to GalN/TNF liver injury. GalN/LPS injury in knockout animals did not result from altered production of TNF or other cytokines. Atg7Δhep mice had accelerated activation of the mitochondrial death pathway and caspase-3 and -7 cleavage. Increased cell death did not occur from direct mitochondrial toxicity or a lack of mitophagy, but rather from increased activation of initiator caspase-8 causing Bid cleavage. GalN blocked LPS induction of hepatic autophagy, and increased autophagy from beclin1 overexpression prevented GalN/LPS injury. Autophagy, therefore, mediates cellular resistance to TNF toxicity in vivo by blocking activation of caspase-8 and the mitochondrial death pathway, suggesting that autophagy is a therapeutic target in TNF-dependent tissue injury. Abstract 2Sinha RA1, Farah BL1, Singh BK1, Siddique MM1, Li Y1, Wu Y2, Ilkayeva OR3, Gooding J3, Ching J1, Zhou J1, Martinez L1, Xie S1, Bay BH2, Summers SA1,3, Newgard CB3, Yen PM1,3. Caffeine stimulates hepatic lipid metabolism via autophagy-lysosomal pathway. Hepatology. 2013; http://dx.doi.org/10.1002/hep.26667.1Program of Cardiovascular and Metabolic Disorders, Duke-NUS Graduate Medical School, Singapore; 2Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 3Sarah W. Stedman Nutrition and Metabolism Center, Departments of Medicine and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.Caffeine is one of the world's most consumed drugs. Recently, several studies showed that its consumption is associated with lower risk for non-alcoholic fatty liver disease (NAFLD), an obesity-related condition that recently has become the major cause of liver disease worldwide. Although caffeine is known to stimulate hepatic fat oxidation, its mechanism of action on lipid metabolism is still not clear. Here, we show that caffeine surprisingly is a potent stimulator of hepatic autophagic flux. Using genetic, pharmacological, and metabolomic approaches, we demonstrate that caffeine reduces intra-hepatic lipid content and stimulates β-oxidation in hepatic cells and liver via an autophagy-lysosomal pathway. Furthermore, caffeine induced autophagy involved down regulation of mTOR signaling and alteration in hepatic amino acids and sphingolipid levels. In mice fed a high fat diet, caffeine markedly reduces hepatosteatosis and concomitantly increases autophagy and lipid uptake in lysosomes. Conclusion: Taken together, these results provide novel insight into caffeine's lipolytic actions through autophagy in mammalian liver and its potential beneficial effects in RA1, Farah BL1, Singh BK1, Siddique MM1, Li Y1, Wu Y2, Ilkayeva OR3, Gooding J3, Ching J1, Zhou J1, Martinez L1, Xie S1, Bay BH2, Summers SA1,3, Newgard CB3, Yen PM1,3. Caffeine stimulates hepatic lipid metabolism via autophagy-lysosomal pathway. Hepatology. 2013; of Cardiovascular and Metabolic Disorders, Duke-NUS Graduate Medical School, Singapore; 2Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 3Sarah W. Stedman Nutrition and Metabolism Center, Departments of Medicine and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, Caffeine is one of the world's most consumed drugs. Recently, several studies showed that its consumption is associated with lower risk for non-alcoholic fatty liver disease (NAFLD), an obesity-related condition that recently has become the major cause of liver disease worldwide. Although caffeine is known to stimulate hepatic fat oxidation, its mechanism of action on lipid metabolism is still not clear. Here, we show that caffeine surprisingly is a potent stimulator of hepatic autophagic flux. Using genetic, pharmacological, and metabolomic approaches, we demonstrate that caffeine reduces intra-hepatic lipid content and stimulates β-oxidation in hepatic cells and liver via an autophagy-lysosomal pathway. Furthermore, caffeine induced autophagy involved down regulation of mTOR signaling and alteration in hepatic amino acids and sphingolipid levels. In mice fed a high fat diet, caffeine markedly reduces hepatosteatosis and concomitantly increases autophagy and lipid uptake in lysosomes. Conclusion: Taken together, these results provide novel insight into caffeine's lipolytic actions through autophagy in mammalian liver and its potential beneficial effects in Abstract 3Lan SH1, Wu SY1, Zuchini R 2,3, Lin XZ 3, Su IJ6, Tsai TF7, Lin YJ8, Wu CT8 and Liu HS1,4,5. Autophagy suppresses tumorigenesis of hepatitis B virus-associated hepatocellular carcinoma through degradation of miR-224. Hepatology. 2013; http://dx.doi.org/10.1002/hep.26659.1Institute of Basic Medical Sciences; 2Graduate Institute of Clinical Medicine; 3Department of Internal Medicine; 4Department of Microbiology and Immunology; 5Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 6National Health Research Institutes, Division of Clinical Research, Tainan, Taiwan; 7Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan; 8Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan.In hepatocellular carcinoma (HCC), dysregulated expression of microRNA-224 (miR-224) and impaired autophagy have been reported separately. However, the relationship between them has not been explored. In this study, we determine that autophagy is down-regulated and inversely correlated with miR-224 expression in hepatitis B virus (HBV)-associated HCC patient specimens. These results were confirmed in liver tumors of HBV X gene transgenic mice. Furthermore, miR-224 was preferentially recruited and degraded during autophagic progression demonstrated by real-time PCR and miRNA in situ hybridization electron microscopy after extraction of autophagosomes. Our in vitro study demonstrated that miR-224 played an oncogenic role in hepatoma cell migration and tumor formation through silencing its target gene Smad4. In HCC patients, the expression of low-Atg5, high-miR-224 and low-Smad4 shows significant correlation with HBV infection and poor overall survival rate. Autophagy mediated miR-224 degradation and liver tumor suppression were further confirmed by the autophagy inducer amiodarone and miR-224 antagonist using an orthotopic SD rat model. Conclusion: we reveal a non-canonical pathway which links autophagy, miR-224, Smad4 and HBV-associated HCC. Our novel findings open a new avenue for the treatment of HCC. SH1, Wu SY1, Zuchini R 2,3, Lin XZ 3, Su IJ6, Tsai TF7, Lin YJ8, Wu CT8 and Liu HS1,4,5. Autophagy suppresses tumorigenesis of hepatitis B virus-associated hepatocellular carcinoma through degradation of miR-224. Hepatology. 2013; of Basic Medical Sciences; 2Graduate Institute of Clinical Medicine; 3Department of Internal Medicine; 4Department of Microbiology and Immunology; 5Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 6National Health Research Institutes, Division of Clinical Research, Tainan, Taiwan; 7Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan; 8Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, In hepatocellular carcinoma (HCC), dysregulated expression of microRNA-224 (miR-224) and impaired autophagy have been reported separately. However, the relationship between them has not been explored. In this study, we determine that autophagy is down-regulated and inversely correlated with miR-224 expression in hepatitis B virus (HBV)-associated HCC patient specimens. These results were confirmed in liver tumors of HBV X gene transgenic mice. Furthermore, miR-224 was preferentially recruited and degraded during autophagic progression demonstrated by real-time PCR and miRNA in situ hybridization electron microscopy after extraction of autophagosomes. Our in vitro study demonstrated that miR-224 played an oncogenic role in hepatoma cell migration and tumor formation through silencing its target gene Smad4. In HCC patients, the expression of low-Atg5, high-miR-224 and low-Smad4 shows significant correlation with HBV infection and poor overall survival rate. Autophagy mediated miR-224 degradation and liver tumor suppression were further confirmed by the autophagy inducer amiodarone and miR-224 antagonist using an orthotopic SD rat model. Conclusion: we reveal a non-canonical pathway which links autophagy, miR-224, Smad4 and HBV-associated HCC. Our novel findings open a new avenue for the treatment of HCC. ancient roman mythology, is as the of and and is as to the and to the Autophagy is in that is a survival in to cell death. In most hepatic autophagy is in hepatitis B and virus of autophagy is the of cellular in which degraded in the lysosomes. In autophagy, a of the in the formation of by a autophagosomes. of formation with the of mammalian target of complex from is with the Autophagy is during of as in the from the complex in with the complex and results in the of the which to the of the with the an in degradation of the Autophagy and the 2013; Liver and Autophagy in liver studies show that autophagy to rather cell cell the of a Cell Autophagy is to on the liver through of and autophagy is associated with hepatic and of autophagy with the cellular and to which is by hepatitis and Liver and is for cell survival as of or Atg7 in the liver results in increased cell death, and liver injury. Inhibition of the autophagy gene the of liver Autophagy and the 2013; role of and autophagy in has been known a the of autophagy has been by of is with on the role of autophagy in liver role of autophagy has been by Zhao Fontana of hepatocyte autophagy increases tumor necrosis factor-dependent liver injury by promoting caspase-8 Death Differ. 2013; 20: have that of hepatocyte autophagy increases tumor necrosis factor liver injury by promoting caspase-8 activation. the in vivo of TNF-dependent hepatocyte and liver injury using of mice with lipopolysaccharide and the hepatocyte-specific d-galactosamine in mice with knockout of the autophagy gene and littermate mice. mice in serum aminotransferase levels, histological hepatocyte injury and mortality the littermate mice. GalN/LPS injury in the knockout mice did not result from altered production of TNF or other but to increased activation of is the initiator of the TNF death pathway activation and the Bid into Bid which in mitochondrial death and Farah Singh stimulates hepatic lipid metabolism via autophagy-lysosomal 2013; have the role of caffeine in promoting through autophagy in non-alcoholic fatty liver disease Although have beneficial of in with fatty liver of and caffeine consumption with fatty liver and of hepatic Caffeine is in with non-alcoholic fatty liver its mechanism of action on lipid metabolism has not been beneficial of in with has been to its Caffeine as an of lipid induced by Farah Singh stimulates hepatic lipid metabolism via autophagy-lysosomal 2013; have that caffeine is a potent stimulator of hepatic autophagy by down regulation of mTOR to in the intra-hepatic lipid content and of β-oxidation in the to an role in tumor an of of the of autophagy in the of hepatocellular carcinoma to hepatitis B hepatitis virus and liver role of autophagy in liver and potential therapeutic 2013; Wu Zuchini suppresses tumorigenesis of hepatitis B virus-associated hepatocellular carcinoma through degradation of 2013; have a of autophagy correlated with an inversely high miR-224 expression in hepatitis B virus (HBV)-associated HCC and tumors in mice. miR-224 played an oncogenic role in hepatoma cell migration and tumor formation through silencing its target gene Smad4. have a role of autophagy in HCC by that most HCC cell and HCC with disease lower autophagic cell or expression of several autophagic and and autophagic is in HCC cell and mice with of have a high of hepatocellular a known inducer of autophagy has been associated with better survival in with HCC liver Autophagy in liver is a for cell survival and has a role in most hepatic A of autophagy to hepatocellular injury and Caffeine and autophagy have a on the A better of the mechanism of autophagy and its role in liver disease result in new therapeutic In ancient roman mythology, is as the of and and is as to the and to the Autophagy is in that is a survival in to cell death. In most hepatic autophagy is in hepatitis B and virus of autophagy Autophagy is the of cellular in which degraded in the lysosomes. In autophagy, a of the in the formation of by a autophagosomes. of formation with the of mammalian target of complex from is with the Autophagy is during of as in the from the complex in with the complex and results in the of the which to the of the with the an in degradation of the Autophagy and the 2013; Liver and Autophagy in liver studies show that autophagy to rather cell cell the of a Cell Autophagy is to on the liver through of and autophagy is associated with hepatic and of autophagy with the cellular and to which is by hepatitis and Liver and is for cell survival as of or Atg7 in the liver results in increased cell death, and liver injury. Inhibition of the autophagy gene the of liver Autophagy and the 2013; role of and autophagy in has been known a the of autophagy has been by of is with on the role of autophagy in liver role of autophagy has been by Zhao Fontana of hepatocyte autophagy increases tumor necrosis factor-dependent liver injury by promoting caspase-8 Death Differ. 2013; 20: have that of hepatocyte autophagy increases tumor necrosis factor liver injury by promoting caspase-8 activation. the in vivo of TNF-dependent hepatocyte and liver injury using of mice with lipopolysaccharide and the hepatocyte-specific d-galactosamine in mice with knockout of the autophagy gene and littermate mice. mice in serum aminotransferase levels, histological hepatocyte injury and mortality the littermate mice. GalN/LPS injury in the knockout mice did not result from altered production of TNF or other but to increased activation of is the initiator of the TNF death pathway activation and the Bid into Bid which in mitochondrial death and Farah Singh stimulates hepatic lipid metabolism via autophagy-lysosomal 2013; have the role of caffeine in promoting through autophagy in non-alcoholic fatty liver disease Although have beneficial of in with fatty liver of and caffeine consumption with fatty liver and of hepatic Caffeine is in with non-alcoholic fatty liver its mechanism of action on lipid metabolism has not been beneficial of in with has been to its Caffeine as an of lipid induced by Farah Singh stimulates hepatic lipid metabolism via autophagy-lysosomal 2013; have that caffeine is a potent stimulator of hepatic autophagy by down regulation of mTOR to in the intra-hepatic lipid content and of β-oxidation in the Autophagy to an role in tumor an of of the of autophagy in the of hepatocellular carcinoma to hepatitis B hepatitis virus and liver role of autophagy in liver and potential therapeutic 2013; Wu Zuchini suppresses tumorigenesis of hepatitis B virus-associated hepatocellular carcinoma through degradation of 2013; have a of autophagy correlated with an inversely high miR-224 expression in hepatitis B virus (HBV)-associated HCC and tumors in mice. miR-224 played an oncogenic role in hepatoma cell migration and tumor formation through silencing its target gene Smad4. have a role of autophagy in HCC by that most HCC cell and HCC with disease lower autophagic cell or expression of several autophagic and and autophagic is in HCC cell and mice with of have a high of hepatocellular a known inducer of autophagy has been associated with better survival in with HCC liver Autophagy in liver Autophagy is a for cell survival and has a role in most hepatic A of autophagy to hepatocellular injury and Caffeine and autophagy have a on the A better of the mechanism of autophagy and its role in liver disease result in new therapeutic