Endoplasmic reticulum stress-mediated cell death in liver injury

Cell Death and Disease, Год журнала: 2022, Номер 13(12)

Опубликована: Дек. 19, 2022

The endoplasmic reticulum is an important intracellular organelle that plays role in maintaining cellular homeostasis. Endoplasmic stress (ERS) and unfolded protein response (UPR) are induced when the body exposed to adverse external stimuli. It has been established ERS can induce different cell death modes, including autophagy, apoptosis, ferroptosis, pyroptosis, through three major transmembrane receptors on ER membrane, inositol requirement enzyme 1α, kinase-like kinase activating transcription factor 6. These modes of play occurrence development various diseases, such as neurodegenerative inflammation, metabolic liver injury. As largest organ, rich enzymes, carries out functions metabolism secretion, body's main site synthesis. Accordingly, a well-developed system present hepatocytes help perform its physiological functions. Current evidence suggests closely related stages injury, caused by may be key In addition, increasing modulating great potential for treating This article provided comprehensive overview relationship between four types death. Moreover, we discussed mechanism UPR injuries their therapeutic strategies.

Язык: Английский

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ER stress and UPR in Alzheimer’s disease: mechanisms, pathogenesis, treatments

Cell Death and Disease, Год журнала: 2022, Номер 13(8)

Опубликована: Авг. 15, 2022

Abstract Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by gradual loss of memory and cognitive function, which constitutes heavy burden on the healthcare system globally. Current therapeutics to interfere with underlying process in AD still under development. Although many efforts have centered toxic forms Aβ effectively tackle AD, considering unsatisfactory results so far it vital examine other targets therapeutic approaches as well. The endoplasmic reticulum (ER) stress refers build-up unfolded or misfolded proteins within ER, thus, perturbing ER cellular homeostasis. Emerging evidence indicates that contributes onset development AD. A thorough elucidation machinery pathology may help open up new avenues management this condition relieve dementia symptoms. Herein, we aim at deciphering unique role pathogenesis, reviewing key findings, existing controversy an attempt summarize plausible interventions pathophysiology.

Язык: Английский

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PPAR-γ signaling in nonalcoholic fatty liver disease: Pathogenesis and therapeutic targets

Pharmacology & Therapeutics, Год журнала: 2023, Номер 245, С. 108391 - 108391

Опубликована: Март 22, 2023

Язык: Английский

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Aging, oxidative stress and degenerative diseases: mechanisms, complications and emerging therapeutic strategies

Biogerontology, Год журнала: 2023, Номер 24(5), С. 609 - 662

Опубликована: Июль 30, 2023

Язык: Английский

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Updated mechanisms of MASLD pathogenesis

Lipids in Health and Disease, Год журнала: 2024, Номер 23(1)

Опубликована: Апрель 22, 2024

Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) has garnered considerable attention globally. Changing lifestyles, over-nutrition, and physical inactivity have promoted its development. MASLD is typically accompanied by obesity strongly linked to metabolic syndromes. Given that prevalence on the rise, there an urgent need elucidate pathogenesis. Hepatic lipid accumulation generally triggers lipotoxicity induces or progress steatohepatitis (MASH) mediating endoplasmic reticulum stress, oxidative organelle dysfunction, ferroptosis. Recently, significant been directed towards exploring role of gut microbial dysbiosis in development MASLD, offering a novel therapeutic target for MASLD. Considering are no recognized pharmacological therapies due diversity mechanisms involved difficulty associated with undertaking clinical trials, potential targets remain elusive. Thus, this article aimed summarize evaluate prominent roles lipotoxicity, ferroptosis, microbes underlying their effects. Furthermore, existing advances challenges treatment were outlined.

Язык: Английский

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Polystyrene nanoplastics-induced lung apoptosis and ferroptosis via ROS-dependent endoplasmic reticulum stress

The Science of The Total Environment, Год журнала: 2023, Номер 912, С. 169260 - 169260

Опубликована: Дек. 10, 2023

Язык: Английский

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Cellular stress in the pathogenesis of nonalcoholic steatohepatitis and liver fibrosis

Nature Reviews Gastroenterology & Hepatology, Год журнала: 2023, Номер 20(10), С. 662 - 678

Опубликована: Сен. 7, 2023

Язык: Английский

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The Interconnection between Hepatic Insulin Resistance and Metabolic Dysfunction-Associated Steatotic Liver Disease—The Transition from an Adipocentric to Liver-Centric Approach

Current Issues in Molecular Biology, Год журнала: 2023, Номер 45(11), С. 9084 - 9102

Опубликована: Ноя. 14, 2023

The central mechanism involved in the pathogenesis of MAFLD is insulin resistance with hyperinsulinemia, which stimulates triglyceride synthesis and accumulation liver. On other side, free fatty acid hepatocytes promotes via oxidative stress, endoplasmic reticulum lipotoxicity, increased secretion hepatokines. Cytokines adipokines cause resistance, thus promoting lipolysis adipose tissue ectopic fat deposition muscles Free acids along cytokines contribute to liver activation numerous signaling pathways. hepatokines, hormone-like proteins, primarily by disturbed impairs pathways, causing metabolic dysregulation ER stress unfolded protein response play significant roles aggravation through apoptosis, inflammatory response, impairment mediated IRE1/PERK/ATF6 pathways upregulation SREBP 1c. Circadian rhythm derangement biological clock desynchronization are related disorders, NAFLD, suggesting genes as a potential target for new therapeutic strategies. This review aims summarize mechanisms hepatic NAFLD development progression.

Язык: Английский

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The functions and mechanisms of post-translational modification in protein regulators of RNA methylation: Current status and future perspectives

International Journal of Biological Macromolecules, Год журнала: 2023, Номер 253, С. 126773 - 126773

Опубликована: Сен. 9, 2023

Язык: Английский

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The Role of Endoplasmic Reticulum in Lipotoxicity during Metabolic Dysfunction–Associated Steatotic Liver Disease (MASLD) Pathogenesis

American Journal Of Pathology, Год журнала: 2023, Номер 193(12), С. 1887 - 1899

Опубликована: Сен. 7, 2023

Perturbations in lipid and protein homeostasis induce endoplasmic reticulum (ER) stress metabolic dysfunction–associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty disease. Lipotoxic proteotoxic can activate the unfolded response (UPR) transducers: inositol requiring enzyme1α, PKR-like ER kinase, activating transcription factor 6α. Collectively, these pathways expression of genes that encode functions to resolve folding defect by increasing capacity degradation misfolded proteins. The is also intimately connected with metabolism, including de novo ceramide synthesis, phospholipid cholesterol droplet formation. Following their activation, UPR transducers regulate lipogenic liver. With persistent stress, cellular adaptation fails, resulting hepatocyte apoptosis, a pathological marker In addition ER–nucleus signaling activated UPR, interact other organelles via membrane contact sites. Modulating intracellular communication between endosomes, droplets, mitochondria restore could have therapeutic efficacy ameliorating Recent studies demonstrated cells convey release extracellular vesicles. This review discusses lipotoxic central role communicating MASLD pathogenesis. Metabolic disease, or MASLD, earlier most common chronic worldwide an overall prevalence 32.4%.1Riazi K. Azhari H. Charette J.H. Underwood F.E. King J.A. Afshar E.E. Swain M.G. Congly S.E. Kaplan G.G. Shaheen A.A. incidence NAFLD worldwide: systematic meta-analysis.Lancet Gastroenterol Hepatol. 2022; 7: 851-861Abstract Full Text PDF PubMed Scopus (440) Google Scholar background consistently rising obesity, affects up 48% US population foremost cause liver-related mortality morbidity.1Riazi encompasses clinico-pathological spectrum includes liver, benign, nonprogressive macrovesicular accumulation lipids steatohepatitis (MASH), more severe progressive condition evidence cell injury, inflammation, degeneration, fibrosis. MASH has potential progress cirrhosis, antecedent end-stage hepatocellular carcinoma.2Parthasarathy G. Revelo X. Malhi Pathogenesis steatohepatitis: overview.Hepatol Commun. 2020; 4: 478-492Crossref (222) primary insult hepatic lipotoxicity occurs when hepatocyte's handle export free acids (FA) exceeded either due excessive FA influx lipogenesis. Several molecular mechanisms orchestrate lipotoxicity, oxidative autophagy, lipoapoptosis.3Rada P. Gonzalez-Rodriguez A. Garcia-Monzon C. Valverde A.M. Understanding pathogenesis: CD36 key driver?.Cell Death Dis. 11: 802Crossref (201) organelle whose folding, modification, trafficking been well studied. It plays vital synthesizing glycoproteins, cholesterol, phospholipids, while maintaining calcium homeostasis.4Malhotra J.D. Kaufman R.J. Endoplasmic stress: vicious cycle double-edged sword?.Antioxid Redox Signal. 2007; 9: 2277-2293Crossref (1285) Scholar,5Xu Bailly-Maitre B. Reed J.C. life death decisions.J Clin Invest. 2005; 115: 2656-2664Crossref (1969) When perturbed, occurs, which implicated various conditions diabetes mellitus, atherosclerosis, disorders, cancers.6Hotamisligil G.S. atherosclerosis.Nat Med. 2010; 16: 396-399Crossref (240) Scholar, 7Hotamisligil inflammatory basis disease.Cell. 140: 900-917Abstract (2196) 8Hummasti S. Hotamisligil inflammation obesity diabetes.Circ Res. 107: 579-591Crossref (343) Cellular impacts membranous organelles, mitochondria, lysosomes, functional contacts ER, turn exert direct indirect effects on outcome signaling.9Xiong Kuang Ansari Liu T. Gong J. Wang Zhao X.-Y. Ji Y. Li Guo L. Zhou Chen Z. Leon-Mimila Chung M.T. Kurabayashi Opp Campos-Pérez F. Villamil-Ramirez Canizales-Quinteros Lyons R. Lumeng C.N. Qi Huertas-Vazquez Lusis A.J. Xu X.Z.S. Yu J.Z. Lin Landscape intercellular crosstalk healthy NASH revealed single-cell secretome gene analysis.Mol Cell. 2019; 75: 644-660.e5Abstract (396) this article, authors offer succinct insights into processes underlie particular emphasis its evolution MASLD/MASH. addition, global landscape mediators show promise targets reviewed. interconnected network largely made three main structures: nuclear envelope, peripheral consisting smooth tubules rough sheets, cortical abuts plasma membrane. envelope composed two bilayers, inner outer membrane, numerous pores facilitate transport RNAs continuous sheets cisternae through shared lumen. Sheets are flat structures stacked appearance parallel arrangement layers consistent luminal spacing. curved regions edges connect them one another.10Terasaki M. Shemesh Kasthuri N. Klemm R.W. Schalek Hayworth K.J. Hand A.R. Yankova Huber Lichtman J.W. Rapoport T.A. Kozlov M.M. Stacked helicoidal motifs.Cell. 2013; 154: 285-296Abstract (168) Rough possess ribosomes cytosolic surface, thus allowing partake synthesis folding. Smooth dynamic constantly remodeling characterized scant ribosome attachment binding. Cortical abutting combination tubules, signaling.11Schwarz D.S. Blower M.D. reticulum: structure, function signaling.Cell Mol Life Sci. 2016; 73: 79-94Crossref (841) distinctions subcellular architecture differences ratio across types diverse functions.12Staehelin L.A. plant ER: large number discrete domains.Plant 1997; 1151-1165Crossref For instance, high secretory demand such B (antibody secretion) pancreatic acinar (insulin amounts whereas involved hepatocytes Leydig ER. difference identified because different shaping proteins, prominent being reticulon family vivo change structure respect tubule formation alter changes normal metabolism leading increase droplets (LDs) triglyceride content, up-regulation enzymes Primary from obese mice models shown enriching sheet ER-shaping proteins 63-kDa cytoskeleton-linking (Climp-63) decrease lipogenesis glucose production.13Parlakgul Arruda A.P. Pang Cagampan E. Min Guney Lee G.Y. Inouye Hess H.F. C.S. Regulation controls homeostasis.Nature. 603: 736-742Crossref (35) Thus, spatial organization provides flexibility diversity cell. Structural complexity components aid meeting complex demands maximizing efficiency multicellular organisms. Numerous extensively relation homeostasis, revealing structural critical influencing respective functions.13Parlakgul A biosynthetic ensure cotranslational nascent polypeptides, whether they secreted intended for within Golgi, lysosomes. Translation begins cytosol, where ribosome–mRNA formed. topogenic signal sequence polypeptide recognition particle, SRP.14Walter Blobel Translocation reticulum. II. Signal (SRP) mediates selective binding microsomal membranes in-vitro-assembled polysomes protein.J Cell Biol. 1981; 91: 551-556Crossref (282) Scholar,15Walter Ibrahimi I. binds 545-550Crossref (433) encounters polypeptide–SRP complex, four-component ribosome, mRNA, polypeptide, SRP recruited it docks receptor.16Meyer D.I. Krause Dobberstein Secretory translocation membranes-the 'docking protein.Nature. 1982; 297: 647-650Crossref (365) continues Depending directed be integral secreted, will pause embedding transported completely lumen, respectively. event aggregates, remain lumen enter ER-associated degradation. quality control prevent secretion anomalous proteins.17Ruggiano Foresti O. Carvalho Quality control: degradation: beyond.J 2014; 204: 869-879Crossref Apart second process biogenesis, reviewed elsewhere detail.18Jacquemyn Cascalho Goodchild R.E. ins outs reticulum-controlled biosynthesis.EMBO Rep. 2017; 18: 1905-1921Crossref (142) hepatocytes, abundant site almost all classes. Most transmembrane located both membranes, some focused subdomains ER–organelle sites.18Jacquemyn Phospholipids synthesized cytosol-facing bilayer Ceramides formed exported Golgi further enzymatically modified generate glycosphingolipids sphingomyelin lumen-facing bilayer.19Promlek Ishiwata-Kimata Shido Sakuramoto Kohno Kimata Membrane aberrancy sensor Ire1 ways.Mol Biol 2011; 22: 3520-3532Crossref (195) sphingolipid LD lipoprotein occur membrane.20Olzmann Dynamics droplets.Nat Rev 20: 137-155Crossref (1185) double Due continuity, share many Like metabolism. Mutations may pathogenic, multisystem lipodystrophies susceptibility MASH. These genetic links demonstrate at envelope. connections chromatin, affect programs.21Östlund Hernandez-Ono Shin J.Y. pathogenesis NAFLD.Biology (Basel). 338PubMed Lastly, crucial rule employing pumping Ca2+ cytosol against electrochemical gradient, storing way sequestering using releasing back channels along gradient. Calcium maintained ATPase (SERCA) transporters, pump 1,4,5-triphosphate (IP3) receptor activation–mediated stored cytosol.11Schwarz aforementioned underscore organismal homeostasis. homeostatic conditions, several checks balances place ER.22Ajoolabady Kaplowitz Lebeaupin Kroemer Ren diseases.Hepatology. 2023; 77: 619-639Crossref (51) accumulate and/or undergo stress. this, maintain compensatory translation inhibition, chaperones unfolded/misfolded Failure recover triggers death. mammals, mediated proximal sensors: enzyme 1α (IRE1α), kinase-like kinase (PERK), 6α (ATF6α). sensors inactive basally, configuration, domains bound chaperone 78-kDa glucose-regulated (GRP78)/binding immunoglobulin (BiP) (Figure 1). Misfolded trigger activation GRP78/BiP interactions sensors. There described sensing IRE1α. association model, postulated conformational changes, result stabilization IRE1α homodimers peptide pocket created domain dimers, endoribonuclease activities.19Promlek Scholar,23Credle J.J. Finer-Moore J.S. Papa F.R. Stroud R.M. Walter On mechanism reticulum.Proc Natl Acad Sci U S 102: 18773-18784Crossref (422) competition prevents dimerization domain.24Amin-Wetzel Saunders R.A. Kamphuis M.J. Rato Preissler Harding H.P. Ron D. J-protein co-chaperone recruits BiP monomerize IRE1 repress response.Cell. 171: 1625-1637.e13Abstract (157) dissociation facilitated nucleotide exchange factors.25Behnke Feige Hendershot L.M. factors Grp170 Sil1: action biological functions.J 2015; 427: 1589-1608Crossref (135) allosteric substrate (SBD) causes change.26Santiago Goncalves D.L. Morano K.A. Mechanisms stress.Exp 395112240Crossref (16) undergoes autophosphorylation, RNase activity, then splices X-box 1 (XBP1) mRNA sXBP1 encodes soluble active (sXBP1). transcriptionally encoding Although spliced unspliced forms XBP1 potent factor. PERK, like IREα, protein, N-terminal BiP. PERK autotransphosphorylation leads phosphorylation eukaryotic initiation 2-α (eIF2α).27Harding Zhang Protein coupled endoplasmic-reticulum-resident kinase.Nature. 1999; 397: 271-274Crossref (2650) eIF2α results attenuation 4 (ATF4). ATF4 thereafter up-regulate C/EBP homologous (CHOP), proapoptotic negative feedback loop, CHOP induces GADD34, phosphatase (PP1) dephosphorylates eIF2α, proceed.28Malhi disease.J 54: 795-809Abstract (918) third sensor, ATF6α, translocates apparatus, cleaved sequentially site-1 protease site-2 fragment (ATF6f) factor.29Ye Rawson R.B. Komuro Dave U.P. Prywes Brown M.S. Goldstein J.L. cleavage membrane-bound ATF6 same proteases SREBPs.Mol 2000; 6: 1355-1364Abstract (1454) Overall, work concert proteostasis. If restoration proteostasis sustained apoptosis. stress–induced apoptosis CHOP, mitogen c-Jun (JNK), 5, Bcl-2 calcium, redox caspase activation.30Brancolini Iuliano Proteotoxic cancer cells.Cancers 12: 2385Crossref (32) Lipotoxicity defined dysregulation environment composition transient generation toxic lipids, injury death, β-cells.31Malhi Gores G.J. Molecular disease.Semin Liver 2008; 28: 360-369Crossref (447) induced species saturated (SFA) palmitate, sphingolipids (C16:0 ceramide), lysophosphatidylcholine (LPC), cholesterol. By contrast, monosaturated FAs, oleate palmitoleate, protect SFA-induced toxicity. excess palmitate incorporated triglycerides serve LPC Ceramide C16 causing disturbance PERK/ATF4 ATF6α arms induction expression.32Aflaki Doddapattar Radovic Povoden Kolb Vujic Wegscheider Koefeler Hornemann Graier W.F. Malli Madeo Kratky triacylglycerol-induced macrophages.Cell 2012; 3e280Crossref (50) 33Epstein Kirkpatrick C.L. Castillon G.A. Muñiz Riezman David F.P.A. 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ER–lipid composition, stiffness function.38Cao Dai D.-L. Yao H.-H. Ning Cheng W.-H. Shen W. Yang Z.-X. Saturated acid human PERK/ATF4/CHOP pathway.Mol Biochem. 364: 115-129Crossref (189) Sterol content determinant fluidity normally low membrane.39Pineau Colas Dupont Beney Fleurat-Lessard Berjeaud Berges Ferreira Lipid-induced synergistic sterols acids.Traffic. 2009; 10: 673-690Crossref (159) Abnormally increased sterol SFA concentrations stretch stiffness, triggering oligomerization 2) UPR.40Radanovic Ernst guardian pathway.Cells. 2021; 2965Crossref (23) Exploring how detect might elicit physical reveal potentially druggable targets. important mediator MASH.41Han Park S.Y. Shinzawa Kim K.W. J.-H. Kwon C.H. K.-W. C.K. W.J. Hwang Yan J.-J. Song D.-K. Tsujimoto M.-S. Lysophosphatidylcholine effector lipoapoptosis hepatocytes.J 49: 84-97Abstract (198) Scholar,42Song non alcoholic disease.Pharmacol Ther. 203107401Crossref (79) monolayers, very density (VLDL).43Neuschwander-Tetri B.A. Hepatic nontriglyceride metabolites.Hepatology. 52: 774-788Crossref (818) intracellularly phospholipase A2 (PLA2) phosphatidylcholine (PC) extracellularly lecithin-cholesterol acyltransferase. PLA2 palmitate-induced apoptosis.44Kakisaka Cazanave S.C. Fingas C.D. Guicciardi M.E. Bronk S.F. Werneburg N.W. Mott lysophosphatidylcholine-induced lipoapoptosis.Am J Physiol Gastrointest Physiol. 302: G77-84Crossref (166) depletes PC loss integrity, vesicle (EV) release, apoptosis.42Song Additionally, phosphorylation, expression, JNK BH3-only PUMA (p53 upregulated modulator apoptosis). Increased Bax caspa

Язык: Английский

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