The Role of Endoplasmic Reticulum in Lipotoxicity during Metabolic Dysfunction–Associated Steatotic Liver Disease (MASLD) Pathogenesis
2023; Elsevier BV; Volume: 193; Issue: 12 Linguagem: Inglês
10.1016/j.ajpath.2023.08.007
ISSN1525-2191
AutoresNanditha Venkatesan, Luke C. Doskey, Harmeet Malhi,
Tópico(s)Alcohol Consumption and Health Effects
ResumoPerturbations in lipid and protein homeostasis induce endoplasmic reticulum (ER) stress in metabolic dysfunction–associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease. Lipotoxic and proteotoxic stress can activate the unfolded protein response (UPR) transducers: inositol requiring enzyme1α, PKR-like ER kinase, and activating transcription factor 6α. Collectively, these pathways induce expression of genes that encode functions to resolve the protein folding defect and ER stress by increasing the protein folding capacity of the ER and degradation of misfolded proteins. The ER is also intimately connected with lipid metabolism, including de novo ceramide synthesis, phospholipid and cholesterol synthesis, and lipid droplet formation. Following their activation, the UPR transducers also regulate lipogenic pathways in the liver. With persistent ER stress, cellular adaptation fails, resulting in hepatocyte apoptosis, a pathological marker of liver disease. In addition to the ER–nucleus signaling activated by the UPR, the ER can interact with other organelles via membrane contact sites. Modulating intracellular communication between ER and endosomes, lipid droplets, and mitochondria to restore ER homeostasis could have therapeutic efficacy in ameliorating liver disease. Recent studies have also demonstrated that cells can convey ER stress by the release of extracellular vesicles. This review discusses lipotoxic ER stress and the central role of the ER in communicating ER stress to other intracellular organelles in MASLD pathogenesis. Perturbations in lipid and protein homeostasis induce endoplasmic reticulum (ER) stress in metabolic dysfunction–associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease. Lipotoxic and proteotoxic stress can activate the unfolded protein response (UPR) transducers: inositol requiring enzyme1α, PKR-like ER kinase, and activating transcription factor 6α. Collectively, these pathways induce expression of genes that encode functions to resolve the protein folding defect and ER stress by increasing the protein folding capacity of the ER and degradation of misfolded proteins. The ER is also intimately connected with lipid metabolism, including de novo ceramide synthesis, phospholipid and cholesterol synthesis, and lipid droplet formation. Following their activation, the UPR transducers also regulate lipogenic pathways in the liver. With persistent ER stress, cellular adaptation fails, resulting in hepatocyte apoptosis, a pathological marker of liver disease. In addition to the ER–nucleus signaling activated by the UPR, the ER can interact with other organelles via membrane contact sites. Modulating intracellular communication between ER and endosomes, lipid droplets, and mitochondria to restore ER homeostasis could have therapeutic efficacy in ameliorating liver disease. Recent studies have also demonstrated that cells can convey ER stress by the release of extracellular vesicles. This review discusses lipotoxic ER stress and the central role of the ER in communicating ER stress to other intracellular organelles in MASLD pathogenesis. Metabolic dysfunction–associated steatotic liver disease, or MASLD, earlier known as nonalcoholic fatty liver disease, is the most common chronic liver disease worldwide with an overall prevalence of 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. The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis.Lancet Gastroenterol Hepatol. 2022; 7: 851-861Abstract Full Text Full Text PDF PubMed Scopus (440) Google Scholar In the background of consistently rising obesity, MASLD affects up to 48% of the US population and is the foremost cause of liver-related mortality and morbidity.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. The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis.Lancet Gastroenterol Hepatol. 2022; 7: 851-861Abstract Full Text Full Text PDF PubMed Scopus (440) Google Scholar MASLD encompasses a clinico-pathological spectrum that includes metabolic dysfunction–associated fatty liver, a benign, nonprogressive macrovesicular accumulation of intracellular lipids and metabolic dysfunction–associated steatohepatitis (MASH), a more severe and progressive condition with evidence of cell injury, inflammation, hepatocyte degeneration, apoptosis, and fibrosis. MASH has the potential to progress to cirrhosis, an antecedent to end-stage liver disease and hepatocellular carcinoma.2Parthasarathy G. Revelo X. Malhi H. Pathogenesis of nonalcoholic steatohepatitis: an overview.Hepatol Commun. 2020; 4: 478-492Crossref PubMed Scopus (222) Google Scholar The primary insult in MASLD is hepatic lipotoxicity that occurs when the hepatocyte's capacity to handle and export free fatty acids (FA) is exceeded either due to an excessive free FA influx or de novo lipogenesis. Several molecular mechanisms orchestrate lipotoxicity, including endoplasmic reticulum (ER) and oxidative stress, autophagy, inflammation, and lipoapoptosis.3Rada P. Gonzalez-Rodriguez A. Garcia-Monzon C. Valverde A.M. Understanding lipotoxicity in NAFLD pathogenesis: is CD36 a key driver?.Cell Death Dis. 2020; 11: 802Crossref PubMed Scopus (201) Google Scholar The ER is an intracellular organelle whose role in protein synthesis, folding, modification, and trafficking has been well studied. It plays a vital role in synthesizing glycoproteins, cholesterol, and phospholipids, while also maintaining calcium homeostasis.4Malhotra J.D. Kaufman R.J. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword?.Antioxid Redox Signal. 2007; 9: 2277-2293Crossref PubMed Scopus (1285) Google Scholar,5Xu C. Bailly-Maitre B. Reed J.C. Endoplasmic reticulum stress: cell life and death decisions.J Clin Invest. 2005; 115: 2656-2664Crossref PubMed Scopus (1969) Google Scholar When ER homeostasis is perturbed, ER stress occurs, which has been implicated in various conditions including inflammation, diabetes mellitus, atherosclerosis, metabolic disorders, and cancers.6Hotamisligil G.S. Endoplasmic reticulum stress and atherosclerosis.Nat Med. 2010; 16: 396-399Crossref PubMed Scopus (240) Google Scholar, 7Hotamisligil G.S. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease.Cell. 2010; 140: 900-917Abstract Full Text Full Text PDF PubMed Scopus (2196) Google Scholar, 8Hummasti S. Hotamisligil G.S. Endoplasmic reticulum stress and inflammation in obesity and diabetes.Circ Res. 2010; 107: 579-591Crossref PubMed Scopus (343) Google Scholar Cellular stress also impacts other membranous organelles, including mitochondria, endosomes, and lysosomes, which have functional contacts with the ER, and in turn exert direct or indirect effects on the outcome of ER stress signaling.9Xiong X. Kuang H. Ansari S. Liu T. Gong J. Wang S. Zhao X.-Y. Ji Y. Li C. Guo L. Zhou L. Chen Z. Leon-Mimila P. Chung M.T. Kurabayashi K. Opp J. Campos-Pérez F. Villamil-Ramirez H. Canizales-Quinteros S. Lyons R. Lumeng C.N. Zhou B. Qi L. Huertas-Vazquez A. Lusis A.J. Xu X.Z.S. Li S. Yu Y. Li J.Z. Lin J.D. Landscape of intercellular crosstalk in healthy and NASH liver revealed by single-cell secretome gene analysis.Mol Cell. 2019; 75: 644-660.e5Abstract Full Text Full Text PDF PubMed Scopus (396) Google Scholar In this article, the authors offer succinct insights into the cellular processes that underlie ER stress, with a particular emphasis on its role in the evolution of MASLD/MASH. In addition, the global landscape of organelle crosstalk and its mediators that show promise as therapeutic targets has been reviewed. The ER is an interconnected network largely made up of three main structures: the nuclear envelope, the peripheral ER consisting of smooth tubules and rough sheets, and the cortical ER that abuts the plasma membrane. The nuclear envelope is composed of two lipid bilayers, the inner and outer nuclear membrane, which has numerous pores to facilitate transport of RNAs and proteins. The outer membrane of the nuclear envelope is continuous with the ER membrane and connected to the sheets and cisternae of the peripheral ER through their shared lumen. Sheets are flat structures that have a stacked appearance due to the parallel arrangement of the layers with consistent luminal spacing. The curved regions in the membrane edges connect them to one another.10Terasaki M. Shemesh T. Kasthuri N. Klemm R.W. Schalek R. Hayworth K.J. Hand A.R. Yankova M. Huber G. Lichtman J.W. Rapoport T.A. Kozlov M.M. Stacked endoplasmic reticulum sheets are connected by helicoidal membrane motifs.Cell. 2013; 154: 285-296Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar Rough ER sheets possess ribosomes on the cytosolic surface, thus allowing them to partake in protein synthesis and folding. Smooth ER tubules are dynamic structures that are constantly remodeling and characterized by scant ribosome attachment and binding. Cortical ER, abutting the plasma membrane, is a combination of sheets and tubules, and plays a role in calcium signaling.11Schwarz D.S. Blower M.D. The endoplasmic reticulum: structure, function and response to cellular signaling.Cell Mol Life Sci. 2016; 73: 79-94Crossref PubMed Scopus (841) Google Scholar The distinctions in the subcellular architecture of the ER and the differences in the ratio of sheets to tubules across cell types facilitate diverse cellular functions.12Staehelin L.A. The plant ER: a dynamic organelle composed of a large number of discrete functional domains.Plant J. 1997; 11: 1151-1165Crossref PubMed Scopus (343) Google Scholar For instance, cells with high secretory demand such as B cells (antibody synthesis and secretion) and pancreatic acinar cells (insulin synthesis and secretion) have large amounts of stacked sheets in the rough ER, whereas cells involved in lipid synthesis such as hepatocytes and Leydig cells have more tubules in their smooth ER. This difference in the ratio of sheets to tubules has been identified because of different ER shaping proteins, most prominent being the reticulon family of proteins. In vivo studies have demonstrated that a change in ER structure with respect to tubule formation can alter changes in normal lipid metabolism leading to an increase in lipid droplets (LDs) and triglyceride content, and an up-regulation of enzymes involved in de novo lipogenesis. Primary hepatocytes from obese mice models have shown that enriching ER sheets and increasing the ER sheet to tubule ratio via ER-shaping membrane proteins such as the 63-kDa cytoskeleton-linking membrane protein (Climp-63) can decrease lipogenesis and glucose production.13Parlakgul G. Arruda A.P. Pang S. Cagampan E. Min N. Guney E. Lee G.Y. Inouye K. Hess H.F. Xu C.S. Hotamisligil G.S. Regulation of liver subcellular architecture controls metabolic homeostasis.Nature. 2022; 603: 736-742Crossref PubMed Scopus (35) Google Scholar Thus, the spatial organization of the ER provides functional flexibility and metabolic diversity to the cell. Structural complexity and flexibility of subcellular components aid in meeting the complex metabolic demands and maximizing the metabolic efficiency of multicellular organisms. Numerous studies have extensively characterized the subcellular architecture in relation to metabolic homeostasis, revealing that the structural organization of cellular components is a critical factor influencing their respective functions.13Parlakgul G. Arruda A.P. Pang S. Cagampan E. Min N. Guney E. Lee G.Y. Inouye K. Hess H.F. Xu C.S. Hotamisligil G.S. Regulation of liver subcellular architecture controls metabolic homeostasis.Nature. 2022; 603: 736-742Crossref PubMed Scopus (35) Google Scholar A primary biosynthetic role of the ER is to ensure cotranslational folding of nascent polypeptides, whether they are secreted proteins, proteins intended for the plasma membrane and other membranous organelles, or luminal proteins within the ER, Golgi, and lysosomes. Translation of these proteins begins in the cytosol, where the ribosome–mRNA complex is formed. A topogenic signal sequence in the nascent polypeptide is identified by the signal recognition particle, or SRP.14Walter P. Blobel G. Translocation of proteins across the endoplasmic reticulum. II. Signal recognition protein (SRP) mediates the selective binding to microsomal membranes of in-vitro-assembled polysomes synthesizing secretory protein.J Cell Biol. 1981; 91: 551-556Crossref PubMed Scopus (282) Google Scholar,15Walter P. Ibrahimi I. Blobel G. Translocation of proteins across the endoplasmic reticulum. I. Signal recognition protein (SRP) binds to in-vitro-assembled polysomes synthesizing secretory protein.J Cell Biol. 1981; 91: 545-550Crossref PubMed Scopus (433) Google Scholar The ribosome–mRNA complex encounters the nascent polypeptide–SRP complex, and the four-component complex, composed of the ribosome, mRNA, nascent polypeptide, and SRP complex, is recruited to the ER membrane where it docks on the SRP receptor.16Meyer D.I. Krause E. Dobberstein B. Secretory protein translocation across membranes-the role of the 'docking protein.Nature. 1982; 297: 647-650Crossref PubMed Scopus (365) Google Scholar Translation continues on the ER membrane. Depending on whether the protein is directed to be an integral membrane protein or secreted, translocation will pause embedding the nascent polypeptide in the ER membrane, or will be transported completely into the ER lumen, respectively. In the event of misfolded proteins or aggregates, proteins either remain in the ER lumen or enter ER-associated degradation. Thus, ER quality control mechanisms prevent the secretion of anomalous proteins.17Ruggiano A. Foresti O. Carvalho P. Quality control: ER-associated degradation: protein quality control and beyond.J Cell Biol. 2014; 204: 869-879Crossref PubMed Scopus (440) Google Scholar Apart from protein synthesis, the second biosynthetic process integral to the ER membrane is lipid biogenesis, reviewed elsewhere in detail.18Jacquemyn J. Cascalho A. Goodchild R.E. The ins and outs of endoplasmic reticulum-controlled lipid biosynthesis.EMBO Rep. 2017; 18: 1905-1921Crossref PubMed Scopus (142) Google Scholar In hepatocytes, the smooth ER is abundant and is a site for the synthesis of almost all lipid classes. Most lipid synthesis enzymes are transmembrane proteins located in both the smooth and rough ER membranes, with some pathways focused in subdomains of the ER membrane, such as ER–organelle membrane contact sites.18Jacquemyn J. Cascalho A. Goodchild R.E. The ins and outs of endoplasmic reticulum-controlled lipid biosynthesis.EMBO Rep. 2017; 18: 1905-1921Crossref PubMed Scopus (142) Google Scholar Phospholipids are synthesized in the cytosol-facing lipid bilayer of the ER membrane. Ceramides formed in the ER are exported to the Golgi where they are further enzymatically modified to generate glycosphingolipids and sphingomyelin in the lumen-facing Golgi lipid bilayer.19Promlek T. Ishiwata-Kimata Y. Shido M. Sakuramoto M. Kohno K. Kimata Y. Membrane aberrancy and unfolded proteins activate the endoplasmic reticulum stress sensor Ire1 in different ways.Mol Biol Cell. 2011; 22: 3520-3532Crossref PubMed Scopus (195) Google Scholar In addition to phospholipid and sphingolipid synthesis, cholesterol synthesis, triglyceride synthesis, and LD and lipoprotein formation occur in the ER membrane.20Olzmann J.A. Carvalho P. Dynamics and functions of lipid droplets.Nat Rev Mol Cell Biol. 2019; 20: 137-155Crossref PubMed Scopus (1185) Google Scholar The nuclear envelope is a double membrane structure, and the outer nuclear membrane is continuous with the ER. Due to this continuity, the nuclear envelope and the ER share many proteins. Like the ER, the nuclear envelope is also a site for lipid metabolism. Mutations in protein of the nuclear envelope proteins may be pathogenic, resulting in multisystem disease, including lipodystrophies and susceptibility to MASLD and MASH. These genetic links demonstrate that lipid metabolism at the nuclear envelope. and through their connections to chromatin, can affect lipid metabolism gene programs.21Östlund C. Hernandez-Ono A. Shin J.Y. The nuclear envelope in lipid metabolism and pathogenesis of NAFLD.Biology (Basel). 2020; 9: 338PubMed Google Scholar Lastly, the ER plays a crucial rule in calcium homeostasis by employing proteins that aid in pumping Ca2+ from the cytosol into the lumen against the electrochemical gradient, storing Ca2+ by way of sequestering using luminal binding proteins and releasing Ca2+ back into the cytosol via channels along the electrochemical gradient. Calcium homeostasis is maintained by the smooth ER Ca2+ ATPase (SERCA) transporters, which pump Ca2+ into the ER lumen, and inositol 1,4,5-triphosphate (IP3) receptor activation–mediated release of stored Ca2+ from the ER lumen into the cytosol.11Schwarz D.S. Blower M.D. The endoplasmic reticulum: structure, function and response to cellular signaling.Cell Mol Life Sci. 2016; 73: 79-94Crossref PubMed Scopus (841) Google Scholar The aforementioned processes underscore that the ER is integral to both cellular and organismal lipid homeostasis. In homeostatic conditions, several checks and balances are in place to prevent an accumulation of misfolded proteins in the ER.22Ajoolabady A. Kaplowitz N. Lebeaupin C. Kroemer G. Kaufman R.J. Malhi H. Ren J. Endoplasmic reticulum stress in liver diseases.Hepatology. 2023; 77: 619-639Crossref PubMed Scopus (51) Google Scholar When cells accumulate unfolded and/or misfolded proteins in the ER, they undergo ER stress. In response to this, to maintain homeostasis, several compensatory mechanisms occur including translation inhibition, increase in chaperones and folding enzymes and degradation of the unfolded/misfolded proteins. Failure to recover from ER stress triggers cell death. In mammals, these signaling pathways are mediated by the three proximal UPR sensors: inositol requiring enzyme 1α (IRE1α), protein kinase-like ER kinase (PERK), and activating transcription factor 6α (ATF6α). The UPR sensors are inactive basally, and in this configuration, their luminal domains are bound to the chaperone 78-kDa glucose-regulated protein (GRP78)/binding immunoglobulin protein (BiP) (Figure 1). Misfolded proteins can trigger activation of the UPR sensors by binding to GRP78/BiP or direct interactions with the UPR sensors. There are three described models of stress sensing by IRE1α. In the direct association model, it is postulated that the misfolded proteins trigger conformational changes, which result in stabilization of IRE1α homodimers by binding to the peptide binding pocket created in the luminal domain of dimers, activating its kinase and endoribonuclease activities.19Promlek T. Ishiwata-Kimata Y. Shido M. Sakuramoto M. Kohno K. Kimata Y. 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PERK, like IREα, is a transmembrane protein, whose N-terminal domain is bound by BiP. PERK dimerization and autotransphosphorylation leads to the phosphorylation of the eukaryotic translation initiation factor 2-α (eIF2α).27Harding H.P. Zhang Y. Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase.Nature. 1999; 397: 271-274Crossref PubMed Scopus (2650) Google Scholar eIF2α phosphorylation results in the global attenuation of protein translation with selective translation of activation transcription factor 4 mRNA (ATF4). ATF4 can thereafter up-regulate the expression of C/EBP homologous protein (CHOP), a proapoptotic transcription factor. In a negative feedback loop, CHOP induces the expression of GADD34, which along with protein phosphatase 1 (PP1) dephosphorylates eIF2α, thus allowing for translation to proceed.28Malhi H. Kaufman R.J. Endoplasmic reticulum stress in liver disease.J Hepatol. 2011; 54: 795-809Abstract Full Text Full Text PDF PubMed Scopus (918) Google Scholar The third UPR sensor, ATF6α, translocates from ER to the Golgi apparatus, where it is cleaved sequentially by site-1 protease and site-2 protease to generate an N-terminal fragment (ATF6f) from the cytosolic domain that functions as a transcription factor.29Ye J. Rawson R.B. Komuro R. Chen X. Dave U.P. Prywes R. Brown M.S. Goldstein J.L. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs.Mol Cell. 2000; 6: 1355-1364Abstract Full Text Full Text PDF PubMed Scopus (1454) Google Scholar Overall, these pathways work in concert to restore proteostasis. If restoration of proteostasis fails, sustained activation of the UPR results in apoptosis. ER stress–induced apoptosis has been implicated to occur via the transcription factor CHOP, the mitogen activated protein kinase c-Jun N-terminal kinase (JNK), the death receptor 5, Bcl-2 family proteins, calcium, redox homeostasis, and caspase activation.30Brancolini C. Iuliano L. Proteotoxic stress and cell death in cancer cells.Cancers (Basel). 2020; 12: 2385Crossref PubMed Scopus (32) Google Scholar Lipotoxicity is defined as a dysregulation of the lipid environment and/or intracellular composition that leads to accumulation or transient generation of toxic lipids, resulting in cell injury or death, described in many cell types including hepatocytes and pancreatic β-cells.31Malhi H. Gores G.J. Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease.Semin Liver Dis. 2008; 28: 360-369Crossref PubMed Scopus (447) Google Scholar Lipotoxicity can be induced by several toxic lipid species such as saturated fatty acids (SFA) like palmitate, sphingolipids (C16:0 ceramide), the phospholipid lysophosphatidylcholine (LPC), and free cholesterol. By contrast, monosaturated free FAs, such as oleate and palmitoleate, protect from SFA-induced toxicity. Although excess palmitate can be incorporated into triglycerides and phospholipids, it can also serve as a substrate for ceramide synthesis and LPC formation. Ceramide C16 accumulation induced ER stress by causing a disturbance in the Ca2+ homeostasis, leading to cell death through PERK/ATF4 and ATF6α arms of the UPR, leading to induction of CHOP expression.32Aflaki E. Doddapattar P. Radovic B. Povoden S. Kolb D. Vujic N. Wegscheider M. Koefeler H. Hornemann T. Graier W.F. Malli R. Madeo F. Kratky D. 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Thus, inhibition of PLA2 has shown to decrease intracellular LPC and palmitate-induced apoptosis.44Kakisaka K. Cazanave S.C. Fingas C.D. Guicciardi M.E. Bronk S.F. Werneburg N.W. Mott J.L. Gores G.J. Mechanisms of lysophosphatidylcholine-induced hepatocyte lipoapoptosis.Am J Physiol Gastrointest Liver Physiol. 2012; 302: G77-84Crossref PubMed Scopus (166) Google Scholar PLA2 activation also depletes membrane PC resulting in loss of hepatocyte membrane integrity, lipotoxic extracellular vesicle (EV) release, inflammation, and apoptosis.42Song M.J. Malhi H. The unfolded protein response and hepatic lipid metabolism in non alcoholic fatty liver disease.Pharmacol Ther. 2019; 203107401Crossref PubMed Scopus (79) Google Scholar Additionally, LPC induces ER stress via eIF2α phosphorylation, increased CHOP expression, and JNK activation leading to the induction of the BH3-only protein PUMA (p53 upregulated modulator of apoptosis). Increased PUMA results in Bax and caspa
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