Autophagy, Metabolism, and Alcohol-Related Liver Disease: Novel Modulators and Functions
Abstract
:1. Introduction
2. General Interactions between Autophagy and Liver Diseases
2.1. Autophagy in Hepatic Lipid Metabolism
2.1.1. Autophagy as A Key Executor in Hepatic Steatosis
2.1.2. Crosstalk of Autophagy and the Nutrient-Sensing Nuclear Receptors
2.2. Regulation of Autophagy by Non-Coding RNAs in the Liver
2.3. Effects of Autophagy in Non-Parenchymal Hepatic Cells on Liver Diseases
3. Alcohol Modulates Autophagy in the Liver via Multiple Pathways
3.1. Novel Autophagy-Mediating Molecules in ALD
3.1.1. Novel Modulators of Alcohol-Induced Lipophagy
3.1.2. TFEB in ALD
3.1.3. Potential Involvement of Chaperone-Mediated Autophagy in ALD
3.2. Autophagy-Mediating miRNAs in ALD
4. Roles of Autophagy during Pathogenesis of ALD
4.1. Hepatocytes
4.2. Macrophages
4.3. Hepatic Stellate Cells
5. Conclusions and Perspectives
Author Contributions
Funding
Conflicts of Interest
Abbreviations
4E-BP1 | Eukaryotic translation initiation factor 4E-binding protein 1 |
ACC1 | Acetyl-CoA carboxylase 1 |
ADH | Alcohol dehydrogenase |
AKT | Protein kinase B |
ALD | Alcohol-related liver disease |
ALDH2 | Aldehyde dedydrogenase-2 |
ALR | Augmenter of liver regeneration |
AMPK | 5′ AMP-activated protein kinase |
ATGL | Adipose triglyceride lipase |
CAT | Catalase |
CCL4 | Carbon tetrachloride |
CD36 | Cluster of differentiation 36 |
CEBPβ | CCAAT/enhancer-binding protein beta |
CMA | Chaperone-mediated autophagy |
CREB | cAMP response element-binding protein |
CTSA | Cathepsin A |
Cyp2E1 | Cytochrome P450 family 2 subfamily E member 1 |
DEPTOR | DEP domain-containing mTOR-interacting protein |
DYN2 | Dynamin2 |
ER | Endoplasmic reticulum |
FXR | Farnesoid X receptor |
G6PC | Glucose-6-phosphatase α |
GABARAP | GABA type A receptor-associated protein |
GalN | D-galactosamine |
GSDIa | Glycogen storage diseases Ia |
HCC | Hepatocellular carcinoma |
HDAC3 | Histone deacetylase 3 |
HMGB1 | High mobility group box 1 |
HNF1A-AS1 | HNF1A antisense RNA 1 |
HOTAIR | HOX transcript antisense RNA |
HSC | Hepatic stellate cells |
HSC70 | Heat shock-cognate protein of 70 kDa |
HSL | Hormone-sensitive lipase |
HULC | Hepatocellular carcinoma up-regulated long non-coding RNA |
IL | Interleukin |
IRF1 | Interferon regulatory factor1 |
KC | Kupffer cells |
LAMP | Lysosome-associated membrane protein |
LC3 | Microtubule-associated proteins 1A/1B light chain 3 |
LDs | Lipid droplets |
lncRNA | Long non-coding RNAs |
LPS | Lipopolysaccharide |
LXRα | Liver X receptor alpha |
miRNA | MicroRNAs |
Mtor | The mammalian target of rapamycin |
NAD | Nicotinamide adenine dinucleotide |
NAFLD | Non-alcoholic fatty liver disease |
NCoR1 | Nuclear receptor corepressor 1 |
ncRNAs | Non-coding RNAs |
Nogo-B | Reticulon 4B |
NRF2 | Nuclear factor erythroid 2-related factor 2 |
oxLDL | Oxidized low-density lipoprotein |
PGC-1α | Peroxisome proliferator-activated receptor gamma coactivator 1-alpha |
PHLPP | PH domain and leucine rich repeat protein phosphatase |
PI3KC3 | Class III phosphatidylinositol-3 kinase |
PPARα | Peroxisome proliferator-activated receptor alpha |
PTEN | Phosphatase and tensin homolog |
PTENP1 | Phosphatase and tensin homolog pseudogene 1 |
RHEB | Ras homolog enriched in brain |
ROS | Reactive oxidative species |
S6 | Ribosomal protein S6 |
SIRT1 | Sirtuin 1 |
SNX | Sorting nexin |
SQSTM1 | Sequestosome-1 |
TFE3 | Transcription factor E3 |
TFEB | Transcription factor EB |
Vps34 | Vacuolar protein sorting 34 |
vtRNA1-1 | Vault RNA1-1 |
YAP | Yes-associated protein |
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Cell Types | General Functions | Functions in ALD |
---|---|---|
Hepatocytes | Autophagy in hepatocytes is critical to maintain homeostasis of liver functions. See other reviews for details [11,13,25,26,27,28]. | Generally, autophagy plays a protective role in ALD, whereas different status of autophagy deficiency can lead to diverse consequences [9,14,24,25,26,71,72]. |
Macrophages | Macrophage autophagy is important to maintain a normal immune response [64]. Macrophage-specific deletion of Atg5 can aggravate CCL4-induced liver fibrosis [67]. Impaired macrophage autophagy can promote proinflammatory macrophage polarization and increase the immune response in obese mice [69]. Inhibition of macrophage autophagy can also increase toxin-induced acute liver injury from GalN/LPS co-treatment through down-regulation of IL1β [70]. | Autophagy in macrophages is critical to protect the liver from alcohol-induced damage, either by mediating effects from other protectors or by directly protecting the liver from a “second hit” in the progression of liver injury [73,74,75]. |
Hepatic stellate cells | Activation of HSCs requires production of energy from autophagy-mediated lipid catabolism [64,65,66]. | An in vitro study using HSC-T6, an immortalized rat HSC line, shows that autophagy may contribute to alcohol-induced HSC activation [76]. |
Endothelial cells | Autophagy in endothelial cells is critical to maintain these cells homeostasis [64]. Impaired autophagy by deletion of Atg7 in endothelial cells does not affect liver homeostasis but amplifies liver fibrosis without increasing liver injury following CCL4-treatment [68]. | Unclear. |
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Yan, S.; Khambu, B.; Hong, H.; Liu, G.; Huda, N.; Yin, X.-M. Autophagy, Metabolism, and Alcohol-Related Liver Disease: Novel Modulators and Functions. Int. J. Mol. Sci. 2019, 20, 5029. https://doi.org/10.3390/ijms20205029
Yan S, Khambu B, Hong H, Liu G, Huda N, Yin X-M. Autophagy, Metabolism, and Alcohol-Related Liver Disease: Novel Modulators and Functions. International Journal of Molecular Sciences. 2019; 20(20):5029. https://doi.org/10.3390/ijms20205029
Chicago/Turabian StyleYan, Shengmin, Bilon Khambu, Honghai Hong, Gang Liu, Nazmul Huda, and Xiao-Ming Yin. 2019. "Autophagy, Metabolism, and Alcohol-Related Liver Disease: Novel Modulators and Functions" International Journal of Molecular Sciences 20, no. 20: 5029. https://doi.org/10.3390/ijms20205029