Hepatitis B virus X protein sensitizes cells to starvation-induced autophagy via up-regulation of beclin 1 expression

Tang, Hong; Da, Liu; Mao, Yi; Li, Ying; Dong, Li; Xu, Zhenhua; Li, Feng; Wang, Yifei; Tiollais, Pierre; Li, Tsaiping; Zhao, Ming

doi:10.1002/hep.22581

Cited by 212 publications

(205 citation statements)

References 48 publications

(30 reference statements)

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“…The two major hepatitis viruses, both of which are significant causes of chronic human liver disease, alter host cell autophagic function by unknown mechanisms. The RNA hepatitis C virus (HCV) 60,61 and the DNA hepatitis B virus 62,63 upregulate autophagy, which acts to promote rather than to block viral replication. HCV has a well-established association with LDs and the core protein of HCV attaches to LD for the apparent purpose of promoting viral assembly through a mechanism that is unknown.…”

Section: Viruses Utilize Lipophagy For Replicationmentioning

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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Section: Viruses Utilize Lipophagy For Replicationmentioning

confidence: 99%

Regulation of lipid stores and metabolism by lipophagy

2012

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“…Beclin 1 is one of the essential components involved in autophagosome formation, and its level usually increases during autophagy. For example, in HBV (hepatitis B virus)-infected hepatocytes, the HBV x protein increases autophagy by up-regulating the expression of Beclin 1 [160]. In human monocytes and human myeloid leukemia cells, vitamin D3 has been shown to induce autophagy by up-regulating both Beclin 1 and Atg5 [161,162].…”

Section: Nf-κbmentioning

confidence: 99%

Overview of macroautophagy regulation in mammalian cells

et al. 2010

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Macroautophagy is a multistep, vacuolar, degradation pathway terminating in the lysosomal compartment, and it is of fundamental importance in tissue homeostasis. In this review, we consider macroautophagy in the light of recent advances in our understanding of the formation of autophagosomes, which are double-membrane-bound vacuoles that sequester cytoplasmic cargos and deliver them to lysosomes. In most cases, this final step is preceded by a maturation step during which autophagosomes interact with the endocytic pathway. The discovery of AuTophaGyrelated genes has greatly increased our knowledge about the mechanism responsible for autophagosome formation, and there has also been progress in the understanding of molecular aspects of autophagosome maturation. Finally, the regulation of autophagy is now better understood because of the discovery that the activity of Atg complexes is targeted by protein kinases, and owing to the importance of nuclear regulation via transcription factors in regulating the expression of autophagy genes.

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“…Autophagy enhances viral replication at most steps of HBV replication. 72 Since autophagy promotes the replication of both HBV and HCV, it is possible that pharmacological suppression of autophagy may suppress viral replication.…”

Section: Targeting Autophagy In Infective Diseases: Hepatitis B Virusmentioning

confidence: 99%

Autophagy Modulation As a Potential Therapeutic Target for Liver Diseases

Puri

Chandra

2014

Journal of Clinical and Experimental Hepatology

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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

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Hepatitis B virus X protein sensitizes cells to starvation-induced autophagy via up-regulation of beclin 1 expression

Cited by 212 publications

References 48 publications

Regulation of lipid stores and metabolism by lipophagy

Regulation of lipid stores and metabolism by lipophagy

Overview of macroautophagy regulation in mammalian cells

Autophagy Modulation As a Potential Therapeutic Target for Liver Diseases

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