Endoplasmic reticulum stress and autophagy dysregulation in alcoholic and non-alcoholic liver diseases

Clinical and Molecular Hepatology - Tập 26 Số 4 - Trang 715-727 - 2020
Yun Seok Kim1, Sang Geon Kim1
1College of Pharmacy, Seoul National University, Seoul, Korea

Tóm tắt

Alcoholic and non-alcoholic liver diseases begin from an imbalance in lipid metabolism in hepatocytes as the earliest response. Both liver diseases share common disease features and stages (i.e., steatosis, hepatitis, cirrhosis, and hepatocellular carcinoma). However, the two diseases have differential pathogenesis and clinical symptoms. Studies have elucidated the molecular basis underlying similarities and differences in the pathogenesis of the diseases; the factors contributing to the progression of liver diseases include depletion of sulfhydryl pools, enhanced levels of reactive oxygen and nitrogen intermediates, increased sensitivity of hepatocytes to toxic cytokines, mitochondrial dysfunction, and insulin resistance. Endoplasmic reticulum (ER) stress, which is caused by the accumulation of misfolded proteins and calcium depletion, contributes to the pathogenesis, often causing catastrophic cell death. Several studies have demonstrated a mechanism by which ER stress triggers liver disease progression. Autophagy is an evolutionarily conserved process that regulates organelle turnover and cellular energy balance through decomposing damaged organelles including mitochondria, misfolded proteins, and lipid droplets. Autophagy dysregulation also exacerbates liver diseases. Thus, autophagy-related molecules can be potential therapeutic targets for liver diseases. Since ER stress and autophagy are closely linked to each other, an understanding of the molecules, gene clusters, and networks engaged in these processes would be of help to find new remedies for alcoholic and non-alcoholic liver diseases. In this review, we summarize the recent findings and perspectives in the context of the molecular pathogenesis of the liver diseases.

Từ khóa


Tài liệu tham khảo

10.1080/10915810490502069

10.1016/j.jhep.2015.03.006

10.1002/hep.22010

10.1152/ajpcell.00295.2016

10.1002/hep.30251

10.5772/19403

10.1101/gad.13.10.1211

10.1146/annurev.biochem.73.011303.074134

10.1023/A:1016175429877

10.1016/S0092-8674(00)80855-7

10.1038/nrm829

10.1177/153537020322801018

10.1172/JCI26373

10.1111/j.1530-0277.1991.tb00563.x

10.1111/j.1530-0277.1986.tb05182.x

10.1002/hep4.1066

10.1016/j.tem.2016.09.002

10.1002/hep.27420

10.1007/s00535-013-0758-5

10.1194/jlr.M031716

10.1016/j.ebiom.2019.03.046

10.1016/0741-8329(93)90067-X

10.1002/hep.23280

10.1007/s00018-003-3216-3

10.1016/j.ejphar.2014.01.035

10.1172/JCI97831

10.1016/j.mam.2018.06.003

10.12688/f1000research.14841.1

10.1146/annurev.pharmtox.45.120403.095906

10.1053/j.gastro.2011.09.002

10.2174/13816128113199990344

10.1038/nrm4024

10.1053/j.gastro.2015.09.042

10.1111/tra.12617

10.1038/ncb2788

10.1038/nature06639

10.1002/hep4.1056

10.1016/j.cmet.2011.04.004

10.1038/nri3532

10.1038/nrd3802

10.1053/j.gastro.2010.07.041

10.1016/j.livres.2019.11.001

Li, 2014, Autophagy in alcoholinduced multiorgan injury: mechanisms and potential therapeutic targets, 498491

10.1111/acer.12904

10.1155/2014/120179

10.1016/j.bbrc.2009.03.039

10.1016/j.cmet.2010.04.005

10.1002/hep.28820

10.1016/j.jhep.2013.01.011

Kim, 2020, LXRα activation inhibits autophagy and lipophagy in hepatocytes by dysregulating ATG4B and Rab-8B, reducing mitochondrial fuel oxidation, 10.1002/hep.31423

10.1016/j.jhep.2017.09.015

10.1038/nrgastro.2017.38

10.1016/j.jhep.2017.10.011

10.1016/j.clinre.2012.07.005

10.1038/s41419-018-1036-5

10.1016/j.jhep.2011.07.010

10.1136/jech.46.3.197

10.1097/00004872-200301000-00019

10.1016/j.tics.2010.11.001

10.1111/j.1530-0277.2000.tb01992.x

10.1016/S0016-5085(19)33655-8

10.1016/0168-8278(91)90846-4

10.1074/jbc.M111.333534

10.1002/hep.25543

10.1053/j.gastro.2012.05.048

Junge, 1987, Megamitochondria as a diagnostic marker for alcohol induced centrilobular and periportal fibrosis in the liver, 553

10.1016/j.ajpath.2018.11.008

10.1194/jlr.R066514

10.1038/nrm4074

10.1152/ajpgi.00108.2015

10.1038/nature07976

10.1007/s00018-018-2860-6

10.1016/S0140-6736(95)91685-7

10.1016/S0270-9139(03)80963-1

10.1155/2012/978136

10.1016/j.alcohol.2004.07.005

10.1016/j.bpg.2011.02.010

10.1093/alcalc/agl025

10.1136/gut.2007.145573

10.1152/ajpendo.00011.2008

10.1016/S0272-2712(18)30270-1

10.1111/j.1530-0277.1993.tb05673.x

10.1055/s-2008-1040525

10.1055/s-2008-1040605

10.1111/j.1530-0277.2006.00181.x

Osna, 2017, Alcoholic liver disease: pathogenesis and current management, 147

10.1038/nprot.2006.375

10.1073/pnas.87.23.9383

10.1016/S0735-1097(00)01040-8

10.1042/BJ20081386

10.1136/gutjnl-2017-315123

10.1038/srep29743

10.1001/jama.2015.5370

10.1136/gutjnl-2016-312891

10.1053/j.gastro.2016.03.004

2016, EASL-EASD-EASO clinical practice Guidelines for the management of non-alcoholic fatty liver disease, 1388

10.1172/JCI25604

10.1016/j.jhep.2018.06.022

10.1136/gutjnl-2016-313379

10.1002/hep.31046

10.1093/ecco-jcc/jjy213

10.1016/j.phrs.2017.08.001

10.1172/JCI60777

10.1002/hep4.1256

10.1016/j.bbr.2016.12.016

10.2174/1574887113666180227100217

10.1016/j.drugalcdep.2016.03.022

10.1016/j.cmet.2019.08.001

10.1074/jbc.M114.552141

10.1016/j.jhep.2019.06.018

10.1002/hep.31041

10.3389/fimmu.2018.02133

Cho, 2019, Fructose promotes leaky gut, endotoxemia, and liver fibrosis through ethanolinducible cytochrome P450-2E1-mediated oxidative and nitrative stress

10.1016/j.jhep.2018.05.021

10.1016/j.alcohol.2008.12.009

10.1002/hep.29676

10.1016/j.jhep.2018.03.031

10.1016/j.chom.2016.01.003

10.1089/thy.2019.0007

10.1021/acs.jmedchem.7b01285

10.1021/acs.jmedchem.7b00907

10.1111/dom.13654

10.1096/fj.201801699R

10.1016/j.jhep.2020.03.024

10.1016/S0140-6736(18)31785-9

10.1111/liv.12570

10.1111/apt.13816

10.1080/13543784.2018.1442436

10.1002/hep4.1107

10.1016/S0140-6736(19)32517-6

10.1053/j.gastro.2016.01.038

10.1016/S0140-6736(19)33041-7

10.1038/nrgastro.2017.42

10.1002/hep4.1019

10.1016/j.cell.2018.09.053

10.1016/j.cmet.2020.05.012

10.1126/scitranslmed.aan4735

10.1016/j.cmet.2020.03.010

10.1016/j.cmet.2020.03.007

10.2139/ssrn.3219265

10.1016/j.celrep.2020.01.028