Advances in Endoplasmic Reticulum Stress in Liver Diseases

doi:10.12114/j.issn.1007-9572.2023.0545

Abstract

Abstract:

A large number of studies have confirmed that endoplasmic reticulum stress (ERS) is closely related to the development and progression of liver diseases, but the mechanism of the association between ERS and liver disease progression has not been clarified and needs to be further explored. Numerous studies have found that moderate ERS can activate the unfolded protein response (UPR) to protect cells, while severe or persistent ERS can induce apoptosis. Therefore, exploring the role of ERS in the pathogenesis of liver diseases may help to discover new therapeutic strategies. This paper describes the current research status and potential therapeutic strategies of ERS and UPR in various liver diseases.

Key words: Liver disease, Endoplasmic reticulum stress, Unfolded protein reaction, Cell apoptosis, Inflammation

摘要：

大量研究证实内质网应激（ERS）与肝脏疾病的发生、发展密切相关，但ERS与肝脏疾病进展的关联机制目前尚未明确，还需进一步探索。诸多研究发现，适度的ERS能激活未折叠蛋白反应（UPR）以保护细胞，而严重或持续的ERS将诱导细胞凋亡。因此，探讨ERS在肝脏疾病发病机制中的作用可能有助于发现新的治疗策略。故本文就ERS和UPR在多种肝脏疾病中的研究现状及其潜在治疗策略进行阐述。

关键词: 肝病, 内质网应激, 未折叠蛋白反应, 细胞凋亡, 炎症

CLC Number:

R 256.4

LI Chuan,WU Yunchong,YANG Yanyan, et al. Advances in Endoplasmic Reticulum Stress in Liver Diseases[J]. Chinese General Practice, 2024, 27(21): 2679-2684. DOI: 10.12114/j.issn.1007-9572.2023.0545.
李川,吴云冲,杨颜颜等. 内质网应激在肝脏疾病中的研究进展[J]. 中国全科医学, 2024, 27(21): 2679-2684. DOI: 10.12114/j.issn.1007-9572.2023.0545.

Figures/Tables 1

References 51

[1]	WALTER P，RON D. The unfolded protein response：from stress pathway to homeostatic regulation[J]. Science，2011，334（6059）：1081-1086. DOI：10.1126/science.1209038.
[2]	CHEN X，CUBILLOS-RUIZ J R. Endoplasmic reticulum stress signals in the tumour and its microenvironment[J]. Nat Rev Cancer，2021，21（2）：71-88. DOI：10.1038/s41568-020-00312-2.
[3]	ZHANG J，GUO J F，YANG N N，et al. Endoplasmic reticulum stress-mediated cell death in liver injury[J]. Cell Death Dis，2022，13（12）：1051. DOI：10.1038/s41419-022-05444-x.
[4]	HETZ C. The unfolded protein response：controlling cell fate decisions under ER stress and beyond[J]. Nat Rev Mol Cell Biol，2012，13（2）：89-102. DOI：10.1038/nrm3270.
[5]	AJOOLABADY A，KAPLOWITZ N，LEBEAUPIN C，et al. Endoplasmic reticulum stress in liver diseases[J]. Hepatology，2023，77（2）：619-639. DOI：10.1002/hep.32562.
[6]	ZHANG Z Y，QIAN Q W，LI M，et al. The unfolded protein response regulates hepatic autophagy by sXBP1-mediated activation of TFEB[J]. Autophagy，2021，17（8）：1841-1855. DOI：10.1080/15548627.2020.1788889.
[7]	AJOOLABADY A，WANG S Y，KROEMER G，et al. ER stress in cardiometabolic diseases：from molecular mechanisms to therapeutics[J]. Endocr Rev，2021，42（6）：839-871. DOI：10.1210/endrev/bnab006.
[8]	HETZ C，CHEVET E，OAKES S A. Proteostasis control by the unfolded protein response[J]. Nat Cell Biol，2015，17（7）：829-838. DOI：10.1038/ncb3184.
[9]	LUCHETTI F，CRINELLI R，CESARINI E，et al. Endothelial cells，endoplasmic reticulum stress and oxysterols[J]. Redox Biol，2017，13：581-587. DOI：10.1016/j.redox.2017.07.014.
[10]	GREY M J，CLOOTS E，SIMPSON M S，et al. IRE1β negatively regulates IRE1α signaling in response to endoplasmic reticulum stress[J]. J Cell Biol，2020，219（2）：e201904048. DOI：10.1083/jcb.201904048.
[11]	KARAGÖZ G E，ACOSTA-ALVEAR D，NGUYEN H T，et al. An unfolded protein-induced conformational switch activates mammalian IRE1[J]. eLife，2017，6：e30700. DOI：10.7554/eLife.30700.
[12]	MAUREL M，CHEVET E，TAVERNIER J，et al. Getting RIDD of RNA：IRE1 in cell fate regulation[J]. Trends Biochem Sci，2014，39（5）：245-254. DOI：10.1016/j.tibs.2014.02.008.
[13]	陈顺宏，黄汉飞，林杰，等. 人参皂苷调节内质网应激影响细胞凋亡研究进展[J]. 临床医药实践，2020，29（10）：777-780.
[14]	REN J，BI Y G，SOWERS J R，et al. Endoplasmic reticulum stress and unfolded protein response in cardiovascular diseases[J].Nat Rev Cardiol，2021，18（7）：499-521. DOI：10.1038/s41569-021-00511-w.
[15]	SONG Q，CHEN Y L，WANG J，et al. ER stress-induced upregulation of NNMT contributes to alcohol-related fatty liver development[J]. J Hepatol，2020，73（4）：783-793. DOI：10.1016/j.jhep.2020.04.038.
[16]	HE E Q，MA Y R，KONG L，et al. Suppression of endoplasmic reticulum stress-associated pathways and hepatocyte apoptosis participates in the attenuation of betulinic acid on alcohol-provoked liver injury in mice[J]. Food Funct，2022，13（22）：11489-11502. DOI：10.1039/d2fo01042a.
[17]	WREE A，BRODERICK L，CANBAY A，et al. From NAFLD to NASH to cirrhosis-new insights into disease mechanisms[J]. Nat Rev Gastroenterol Hepatol，2013，10（11）：627-636. DOI：10.1038/nrgastro.2013.149.
[18]	ABDELMALEK M F. Nonalcoholic fatty liver disease：another leap forward[J]. Nat Rev Gastroenterol Hepatol，2021，18（2）：85-86. DOI：10.1038/s41575-020-00406-0.
[19]	HORWATH J A，HURR C，BUTLER S D，et al. Obesity-induced hepatic steatosis is mediated by endoplasmic reticulum stress in the subfornical organ of the brain[J]. JCI Insight，2017，2（8）：e90170. DOI：10.1172/jci.insight.90170.
[20]	DASGUPTA D，NAKAO Y，MAUER A S，et al. IRE1A stimulates hepatocyte-derived extracellular vesicles that promote inflammation in mice with steatohepatitis[J]. Gastroenterology，2020，159（4）：1487-1503.e17. DOI：10.1053/j.gastro.2020.06.031.
[21]	MAIERS J L，MALHI H. Endoplasmic reticulum stress in metabolic liver diseases and hepatic fibrosis[J]. Semin Liver Dis，2019，39（2）：235-248. DOI：10.1055/s-0039-1681032.
[22]	WANG J M，QIU Y N，YANG Z，et al. IRE1α prevents hepatic steatosis by processing and promoting the degradation of select microRNAs[J]. Sci Signal，2018，11（530）：eaao4617. DOI：10.1126/scisignal.aao4617.
[23]	XU Y，HUANG X H，HUANGFU B X，et al. Sulforaphane ameliorates nonalcoholic fatty liver disease induced by high-fat and high-fructose diet via LPS/TLR4 in the gut-liver axis[J]. Nutrients，2023，15（3）：743. DOI：10.3390/nu15030743.
[24]	NASIRI-ANSARI N，NIKOLOPOULOU C，PAPOUTSI K，et al. Empagliflozin attenuates non-alcoholic fatty liver disease （NAFLD） in high fat diet fed ApoE （-/-） mice by activating autophagy and reducing ER stress and apoptosis[J]. Int J Mol Sci，2021，22（2）：818. DOI：10.3390/ijms22020818.
[25]	AO N，YANG J，WANG X C，et al. Glucagon-like peptide-1 preserves non-alcoholic fatty liver disease through inhibition of the endoplasmic reticulum stress-associated pathway[J]. Hepatol Res，2016，46（4）：343-353. DOI：10.1111/hepr.12551.
[26]	LATIF M U，SCHMIDT G E，MERCAN S，et al. NFATc1 signaling drives chronic ER stress responses to promote NAFLD progression[J]. Gut，2022，71（12）：2561-2573. DOI：10.1136/gutjnl-2021-325013.
[27]	HAN H，XUE T L，LI J，et al. Plant sterol ester of α-linolenic acid improved non-alcoholic fatty liver disease by attenuating endoplasmic reticulum stress-triggered apoptosis via activation of the AMPK[J]. J Nutr Biochem，2022，107：109072. DOI：10.1016/j.jnutbio.2022.109072.
[28]	丁文斌，戴佳敏，张峰，等. 内质网应激在肝脏相关疾病中的研究进展[J]. 基础医学与临床，2018，38（2）：260-264. DOI：10.16352/j.issn.1001-6325.2018.02.025.
[29]	WANG J C，DING L L，WANG K，et al. Role of endoplasmic reticulum stress in cadmium-induced hepatocyte apoptosis and the protective effect of quercetin[J]. Ecotoxicol Environ Saf，2022，241：113772. DOI：10.1016/j.ecoenv.2022.113772.
[30]	QIU T，SHI J X，CHENG C，et al. Avicularin attenuates lead-induced impairment of hepatic glucose metabolism by inhibiting the ER stress-mediated inflammatory pathway[J]. Nutrients，2022，14（22）：4806. DOI：10.3390/nu14224806.
[31]	BAUDI I，ISOGAWA M，MOALLI F，et al. Interferon signaling suppresses the unfolded protein response and induces cell death in hepatocytes accumulating hepatitis B surface antigen[J]. PLoS Pathog，2021，17（5）：e1009228. DOI：10.1371/journal.ppat.1009228.
[32]	LEE H，INN K S，KIM H，et al. Upregulation of endoplasmic reticulum stress and reactive oxygen species by naturally occurring mutations in hepatitis B virus core antigen[J]. J Gen Virol，2015，96（7）：1850-1854. DOI：10.1099/vir.0.000134.
[33]	WANG J，KANG R Y，HUANG H，et al. Hepatitis C virus core protein activates autophagy through EIF2AK3 and ATF6 UPR pathway-mediated MAP1LC3B and ATG12 expression[J]. Autophagy，2014，10（5）：766-784. DOI：10.4161/auto.27954.
[34]	WANG X Y，WEI Z Q，LAN T Y，et al. CCDC88A/GIV promotes HBV replication and progeny secretion via enhancing endosomal trafficking and blocking autophagic degradation[J]. Autophagy，2022，18（2）：357-374. DOI：10.1080/15548627.2021.1934271.
[35]	RÍOS-OCAMPO W A，NAVAS M C，BUIST-HOMAN M，et al. Hepatitis C virus proteins core and NS5A are highly sensitive to oxidative stress-induced degradation after eIF2α/ATF4 pathway activation[J]. Viruses，2020，12（4）：425. DOI：10.3390/v12040425.
[36]	WU S X，YE S S，HONG Y X，et al. Hepatitis B virus small envelope protein promotes hepatocellular carcinoma angiogenesis via endoplasmic reticulum stress signaling to upregulate the expression of vascular endothelial growth factor A[J]. J Virol，2022，96（4）：e0197521. DOI：10.1128/JVI.01975-21.
[37]	LV X R，KONG J，CHEN W D，et al. The role of the apelin/APJ system in the regulation of liver disease[J]. Front Pharmacol，2017，8：221. DOI：10.3389/fphar.2017.00221.
[38]	MAIERS J L，KOSTALLARI E，MUSHREF M，et al. The unfolded protein response mediates fibrogenesis and collagen I secretion through regulating TANGO1 in mice[J]. Hepatology，2017，65（3）：983-998. DOI：10.1002/hep.28921.
[39]	HARRIS T R，BETTAIEB A，KODANI S，et al. Inhibition of soluble epoxide hydrolase attenuates hepatic fibrosis and endoplasmic reticulum stress induced by carbon tetrachloride in mice[J]. Toxicol Appl Pharmacol，2015，286（2）：102-111. DOI：10.1016/j.taap.2015.03.022.
[40]	SU W，TAI Y，TANG S H，et al. Celecoxib attenuates hepatocyte apoptosis by inhibiting endoplasmic reticulum stress in thioacetamide-induced cirrhotic rats[J]. World J Gastroenterol，2020，26（28）：4094-4107. DOI：10.3748/wjg.v26.i28.4094.
[41]	MARAS J S，MAIWALL R，HARSHA H C，et al. Dysregulated iron homeostasis is strongly associated with multiorgan failure and early mortality in acute-on-chronic liver failure[J]. Hepatology，2015，61（4）：1306-1320. DOI：10.1002/hep.27636.
[42]	HU X W，LI X M，WANG A M，et al. Caffeine alleviates acute liver injury by inducing the expression of NEDD4L and deceasing GRP78 level via ubiquitination[J]. Inflamm Res，2022，71（10/11）：1213-1227. DOI：10.1007/s00011-022-01603-0.
[43]	TORRES S，BAULIES A，INSAUSTI-URKIA N，et al. Endoplasmic reticulum stress-induced upregulation of STARD1 promotes acetaminophen-induced acute liver failure[J]. Gastroenterology，2019，157（2）：552-568. DOI：10.1053/j.gastro.2019.04.023.
[44]	SHUDA M，KONDOH N，IMAZEKI N，et al. Activation of the ATF6，XBP1 and grp78 genes in human hepatocellular carcinoma：a possible involvement of the ER stress pathway in hepatocarcinogenesis[J]. J Hepatol，2003，38（5）：605-614. DOI：10.1016/s0168-8278(03)00029-1.
[45]	VANDEWYNCKEL Y P，LAUKENS D，BOGAERTS E，et al. Modulation of the unfolded protein response impedes tumor cell adaptation to proteotoxic stress：a PERK for hepatocellular carcinoma therapy[J]. Hepatol Int，2015，9（1）：93-104. DOI：10.1007/s12072-014-9582-0.
[46]	LEE E J，CHIANG W C J，KROEGER H，et al. Multiexon deletion alleles of ATF6 linked to Achromatopsia[J]. JCI Insight，2020，5（7）：e136041. DOI：10.1172/jci.insight.136041.
[47]	CHIANG W C，CHAN P，WISSINGER B，et al. Achromatopsia mutations target sequential steps of ATF6 activation[J]. Proc Natl Acad Sci USA，2017，114（2）：400-405. DOI：10.1073/pnas.1606387114.
[48]	WU Y，SHAN B，DAI J L，et al. Dual role for inositol-requiring enzyme 1α in promoting the development of hepatocellular carcinoma during diet-induced obesity in mice[J]. Hepatology，2018，68（2）：533-546. DOI：10.1002/hep.29871.
[49]	LEE S H，MOON H J，LEE Y S，et al. Potentiation of TRAIL-induced cell death by nonsteroidal anti-inflammatory drug in human hepatocellular carcinoma cells through the ER stress-dependent autophagy pathway[J]. Oncol Rep，2020，44（3）：1136-1148. DOI：10.3892/or.2020.7662.
[50]	DING Y M，CHEN X Y，WANG B，et al. Deubiquitinase inhibitor b-AP15 activates endoplasmic reticulum（ER）stress and inhibits Wnt/Notch1 signaling pathway leading to the reduction of cell survival in hepatocellular carcinoma cells[J]. Eur J Pharmacol，2018，825：10-18. DOI：10.1016/j.ejphar.2018.02.020.
[51]	YANG Z B，BIAN M L，LV L，et al. Tumor-targeting NHC-Au（I） complex induces immunogenic cell death in hepatocellular carcinoma[J]. J Med Chem，2023，66（6）：3934-3952. DOI：10.1021/acs.jmedchem.2c01798.