Autophagy Reduces Acute Ethanol-Induced Hepatotoxicity and Steatosis in Mice

Ding, Wen–Xing; Li, Min; Chen, Xiaoyun; Ni, Hong‐Min; Lin, Chih‐Wen; Gao, Wentao; Lu, Binfeng; Stolz, Donna B.; Clemens, Dahn L.; Yin, Xiao‐Ming

doi:10.1053/j.gastro.2010.07.041

Cited by 450 publications

(584 citation statements)

References 28 publications

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“…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

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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.

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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

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“…It is also possible that a decline in autophagy of mitochondria (mitophagy) could be contributing to the increased mitochondria number caused by intragastric alcohol feeding. With acute alcohol feeding, mitophagy seems to increase in the liver (45). However, the impact of chronic alcohol feeding on the clearance of mitochondria remains to be determined.…”

Section: Increased Mitochondrial Respiration and Increased Componentsmentioning

confidence: 99%

Dynamic Adaptation of Liver Mitochondria to Chronic Alcohol Feeding in Mice

Han

Ybanez

Johnson

et al. 2012

Journal of Biological Chemistry

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“…74 Autophagy has been shown to protect against ethanol-induced fatty liver injury. 75 Autophagy was found to be increased both in the livers of binge alcohol-fed mice and cultured hepatocytes treated with ethanol. Autophagic degradation of long-lived proteins was not increased, but findings of increased numbers of autophagosomes containing LDs and mitochondria suggested that selective increases in lipophagy and mitophagy occurred in response to alcohol.…”

Section: Lipophagy Mediates Resistance To Cell Deathmentioning

confidence: 99%

Regulation of lipid stores and metabolism by lipophagy

2012

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Intracellular lipids are stored in lipid droplets (LDs) and metabolized by cytoplasmic neutral hydrolases to supply lipids for cell use. Recently, an alternative pathway of lipid metabolism through the lysosomal degradative pathway of autophagy has been described and termed lipophagy. In this form of lipid metabolism, LD triglycerides (TGs) and cholesterol are taken up by autophagosomes and delivered to lysosomes for degradation by acidic hydrolases. Free fatty acids generated by lipophagy from the breakdown of TGs fuel cellular rates of mitochondrial b-oxidation. Lipophagy therefore functions to regulate intracellular lipid stores, cellular levels of free lipids such as fatty acids and energy homeostasis. The amount of lipid metabolized by lipophagy varies in response to the extracellular supply of nutrients. The ability of the cell to alter the amount of lipid targeted for autophagic degradation depending on nutritional status demonstrates that this process is selective. Intracellular lipids themselves regulate levels of autophagy by unclear mechanisms. Impaired lipophagy can lead to excessive tissue lipid accumulation such as hepatic steatosis, alter hypothalamic neuropeptide release to affect body mass, block cellular transdifferentiation and sensitize cells to death stimuli. Future studies will likely identify additional mechanisms by which lipophagy regulates cellular physiology, making this pathway a potential therapeutic target in a variety of diseases. Open QuestionsHow does the autophagic machinery selectively target stored lipids for degradation in response to changes in nutrient levels? What are the relative contributions of cytosolic lipolysis and lipophagy to lipid metabolism in different cell types, and is there cross-talk between the two pathways? What are the mechanisms by which intracellular lipids and other factors regulate levels of lipophagy? Do defects in lipophagy underlie human disease and can lipophagy be a therapeutic target? Intracellular lipids are essential to cells as an energy source, structural components for membranes, synthetic building blocks for other molecules, such as hormones, and as mediators of cell signaling. The ability to safely store adequate, but not excessive, amounts of lipids and to metabolize them when needed is critical for cell function and survival. The recent finding that lipids can be selectively degraded by the lysosomal pathway of macroautophagy through a process termed lipophagy 1 has opened up a new understanding of how lipid metabolism regulates cellular physiology and pathophysiology. Many new functions for autophagic lipid metabolism have now been defined in diverse cellular processes ranging from transdifferentiation to resistance to death. Intracellular Lipids are Degraded by LipophagyTGs and cholesterol are safely stored as neutral lipids in specialized cellular organelles called LDs. 2,3 Until recently, the breakdown of LD-stored TG and cholesterol was attributed exclusively to the actions of cytosolic hydrolytic enzymes or lipases. The role of l...

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Autophagy Reduces Acute Ethanol-Induced Hepatotoxicity and Steatosis in Mice

Cited by 450 publications

References 28 publications

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

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

Dynamic Adaptation of Liver Mitochondria to Chronic Alcohol Feeding in Mice

Regulation of lipid stores and metabolism by lipophagy

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