Functions of Autophagy in Hepatic and Pancreatic Physiology and Disease

Czaja, Mark J.

doi:10.1053/j.gastro.2011.04.038

Cited by 158 publications

(148 citation statements)

References 103 publications

(139 reference statements)

Supporting

Mentioning

137

Contrasting

Unclassified

Order By: Relevance

“…12,13 Conversely, HFD and alcohol-induced steatosis may also suppress hepatocyte autophagy. 38,39 An underlying mechanism for this observed iron effect remains unclear, but may relate to a synergistic effect on ethanolinduced reduction in AMPKa activity in the liver via the mTOR pathway, or a decrease in fusion efficiency between autophagosomes and lysosomes because of diet-induced membrane lipid alterations. 40,41 The role of iron in modulating autophagy is unclear, but iron-induced lyosomal damage and fragility could lead to impaired formation of the functioning of autophagosome function.…”

Section: Discussionmentioning

confidence: 99%

Excess iron modulates endoplasmic reticulum stress-associated pathways in a mouse model of alcohol and high-fat diet-induced liver injury

Tan

Crawford

Jaskowski

et al. 2013

Laboratory Investigation

View full text Add to dashboard Cite

Endoplasmic reticulum (ER) stress is an important pathogenic mechanism for alcoholic (ALD) and nonalcoholic fatty liver disease (NAFLD). Iron overload is an important cofactor for liver injury in ALD and NAFLD, but its role in ER stress and associated stress signaling pathways is unclear. To investigate this, we developed a murine model of combined liver injury by co-feeding the mildly iron overloaded, the hemochromatosis gene-null (Hfe À / ) mouse ad libitum with ethanol and a high-fat diet (HFD) for 8 weeks. This co-feeding led to profound steatohepatitis, significant fibrosis, and increased apoptosis in the Hfe À / À mice as compared with wild-type (WT) controls. Iron overload also led to induction of unfolded protein response (XBP1 splicing, activation of IRE-1a and PERK, as well as sequestration of GRP78) and ER stress (increased CHOP protein expression) following HFD and ethanol. This is associated with a muted autophagic response including reduced LC3-I expression and impaired conjugation to LC3-II, reduced beclin-1 protein, and failure of induction of autophagy-related proteins (Atg) 3, 5, 7, and 12. As a result of the impaired autophagy, levels of the sequestosome protein p62 were most elevated in the Hfe À / À group co-fed ethanol and HFD. Iron overload reduces the activation of adenosine monophosphate protein kinase associated with ethanol and HFD feeding. We conclude that iron toxicity may modulate hepatic stress signaling pathways by impairing adaptive cellular compensatory mechanisms in alcohol-and obesity-induced liver injury.

show abstract

Section: Discussionmentioning

confidence: 99%

Excess iron modulates endoplasmic reticulum stress-associated pathways in a mouse model of alcohol and high-fat diet-induced liver injury

Tan

Crawford

Jaskowski

et al. 2013

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

“…On the one hand, autophagy has been shown to protect against liver injury from alcohol and oxidative stress. 26,27 On the other, autophagy contributes to activation of HSC, a key process leading to hepatic fibrosis in HSC. 28 In our system, activation of GCN by histidine deprivation failed to induce autophagy in HSC and had a protective effect, counteracting the loss of viability caused by autophagy inhibitors.…”

Section: Discussionmentioning

confidence: 99%

GCN2 kinase is a key regulator of fibrogenesis and acute and chronic liver injury induced by carbon tetrachloride in mice

Arriazu

López-Zabalza

Leung

et al. 2013

Laboratory Investigation

View full text Add to dashboard Cite

General control nonderepresible 2 (GCN2) is a highly conserved cytosolic kinase that modulates a complex response for coping with the stress owing to lack of amino acids. GCN2 has been recently shown to be involved in the regulation of metabolic balance and lipid degradation rate in the liver. We hypothesized that GCN2 could have a role in in hepatic fibrogenesis and in the response to acute or chronic liver injury. Activation of GCN2 in primary or immortalized human hepatic stellate cells by incubation with medium lacking the essential amino acid histidine correlated with decreased levels of collagen type I protein and mRNA, suggesting an antifibrogenic effect of GCN2. In vivo studies with Gcn2 knockout mice (Gcn2 À / À ) showed increased susceptibility to both acute or chronic liver damage induced by CCl 4 , as shown by higher alanine aminotransferase and aspartate aminotransferase activities, increased necrosis and higher inflammatory infiltrates compared with wild-type mice (WT). Chronic CCl 4 treatment increased deposition of interstitial collagen type I more in Gcn2 À / À mice than in WT mice. Col1a1 and col1a2 mRNA levels also increased in CCl 4 -treated Gcn2 À / À mice compared with WT mice. These results suggest that GCN2 is a key regulator of the fibrogenic response to liver injury.

show abstract

“…51 Liver triglyceride (TG) content is increased in Atg7 deficient mice, suggesting an important role of autophagy in its regulation. 52 Inhibition of autophagy by pharmacological inhibition of Atg5 in cultured hepatocytes show an abnormal increase in cellular TG content on challenge with a lipid load. Experimental mice with obesity and consequently increased hepatocyte lipid content demonstrated a decrease in indicators of autophagy.…”

Section: Autophagy Modulation In Therapy For Liver Diseasesmentioning

confidence: 99%

Autophagy Modulation As a Potential Therapeutic Target for Liver Diseases

Puri

Chandra

2014

Journal of Clinical and Experimental Hepatology

View full text Add to dashboard Cite

Autophagy is a critical intracellular pathway which maintains cellular function by lysosomal degradation of damaged proteins and organelles besides elimination of invading pathogens. Its primary function is to prevent cell death. Autophagy has diverse physiological functions namely; starvation adaptation, prevention of tumorigenesis, energy homeostasis, intracellular quality control and degradation of abnormal intracellular protein aggregates. Understanding the molecular mechanisms of autophagy has given key insights into the pathogenesis of various diseases like Non Alcoholic Steato-Hepatitis, Hepatitis B and C infections, Alpha-1 antitrypsin deficiency and hepatocellular carcinoma. Pharmacological modulation of autophagy may have a therapeutic potential in management of these liver diseases. ( J CLIN EXP HEPATOL 2014;4:51-59) O urobros or Urobros is an ancient symbol depicting a serpent or a dragon eating its own tail, which symbolizes cyclicality in the sense of something recreating itself. In living organisms, cells and intracellular organelles need to be constantly remodeled and renewed. Autophagy is a term derived from Greek terminology for self-eating and signifies the process of cellular selfdigestion in which cytoplasmic components are degraded in lysosomes. Reminiscent of the serpent eating its own tail in the symbol of Ourobros, the cells are able to survive by using autophagy to remove damaged proteins and organelles, eliminate invading microbes and generate nutrients during starvation.After Metchnicoff, a Russian zoologist, first described phagocytosis, the role of lysosomes and autophagy in degrading cytoplasmic components has been elucidated. 1,2 The control of autophagy has been recently delineated by identification of over 30 Autophagy-related (ATG) genes. 3 Autophagy functions to prevent rather than promote cell death. Autophagy has effects of increased cytoprotection, decreased stem cell attrition, decreased oncogenic transformation, decreased dysfunctional mitochondria and decrease in dysfunctional aggregate prone proteins. 4

show abstract

Functions of Autophagy in Hepatic and Pancreatic Physiology and Disease

Cited by 158 publications

References 103 publications

Excess iron modulates endoplasmic reticulum stress-associated pathways in a mouse model of alcohol and high-fat diet-induced liver injury

Excess iron modulates endoplasmic reticulum stress-associated pathways in a mouse model of alcohol and high-fat diet-induced liver injury

GCN2 kinase is a key regulator of fibrogenesis and acute and chronic liver injury induced by carbon tetrachloride in mice

Autophagy Modulation As a Potential Therapeutic Target for Liver Diseases

Contact Info

Product

Resources

About