The Nuclear Envelope in Lipid Metabolism and Pathogenesis of NAFLD
Abstract
Simple Summary
Abstract
1. Introduction
2. Nuclear Envelope and Lipid Metabolism
2.1. Nuclear Lipid Droplets
2.2. Nuclear Lamins and Membrane Proteins Implicated in Lipid Metabolism
2.2.1. Lamin B receptor (LBR)
2.2.2. Lipins and CTDNEP1/NEP1R1
2.2.3. Choline-Phosphate Cytidylyltransferase A (PCYT1A)
2.2.4. A-Type Lamins
2.2.5. LAP2
2.2.6. Lamin B1
3. The TorsinA/LAP1 Complex in Lipid Metabolism and NASH Development
3.1. The Discovery of LAP1 and TorsinA Interaction and Its Implications in Human Diseases
3.2. The TorsinA/LAP1 Complex in LD Biogenesis and Hepatic Lipid Secretion
3.3. NASH Development in Chow-Fed Mice with Depletion of LAP1 or TorsinA
4. Possible Cellular Mechanisms Connecting Defective Nuclear Envelope Proteins to NAFLD/NASH Pathogenesis
4.1. VLDL Assembly and Secretion
4.2. LD Homeostasis and Fatty Acid (FA) Mobilization/Oxidation
4.3. Phospholipid Metabolism: Balance between Lipid Storage and Membrane Lipid Synthesis
4.4. Lipid Metabolites and Lipid-Mediated Cell Signaling
4.5. Nuclear Receptors and Transcription Factors
4.6. Epigenetic Regulation
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Friedman, S.L.; Neuschwander-Tetri, B.A.; Rinella, M.; Sanyal, A.J. Mechanisms of NAFL development and therapeutic strategies. Nat. Med. 2018, 24, 908–922. [Google Scholar] [CrossRef] [PubMed]
- Anstee, Q.M.; Targher, G.; Day, C.P. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat. Rev. Gastroenterol. 2013, 10, 330. [Google Scholar] [CrossRef] [PubMed]
- Younossi, Z.M.; Blissett, D.; Blissett, R.; Henry, L.; Stepanova, M.; Younossi, Y.; Racila, A.; Hunt, S.; Beckerman, R. The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology 2016, 64, 1577–1586. [Google Scholar] [CrossRef]
- Younossi, Z.M.; Loomba, R.; Rinella, M.E.; Bugianesi, E.; Marchesini, G.; Neuschwander-Tetri, B.A.; Serfaty, L.; Negro, F.; Caldwell, S.H.; Ratziu, V. Current and future therapeutic regimens for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology 2018, 68, 361–371. [Google Scholar] [CrossRef] [PubMed]
- Kim, K.H.; Lee, M.-S. Pathogenesis of nonalcoholic steatohepatitis and hormone-based therapeutic approaches. Front. Endocrinol. 2018, 9, 485. [Google Scholar] [CrossRef] [PubMed]
- Barbara, M.; Scott, A.; Alkhouri, N. New insights into genetic predisposition and novel therapeutic targets for nonalcoholic fatty liver disease. Hepatobiliary Surg. Nutr. 2018, 7, 372–381. [Google Scholar] [CrossRef]
- Yu, J.; Marsh, S.; Hu, J.; Feng, W.; Wu, C. The pathogenesis of nonalcoholic fatty liver disease: Interplay between diet, gut microbiota, and genetic background. Gastroenterol. Res. Pract. 2016, 2016, 1–13. [Google Scholar] [CrossRef]
- Wang, X.; Zheng, Z.; Caviglia, J.M.; Corey, K.E.; Herfel, T.M.; Cai, B.; Masia, R.; Chung, R.T.; Lefkowitch, J.H.; Schwabe, R.F.; et al. Hepatocyte TAZ/WWTR1 Promotes Inflammation and Fibrosis in Nonalcoholic Steatohepatitis. Cell Metab. 2016, 24, 848–862. [Google Scholar] [CrossRef]
- Sun, X.; Seidman, J.S.; Zhao, P.; Troutman, T.D.; Spann, N.J.; Que, X.; Zhou, F.; Liao, Z.; Pasillas, M.; Yang, X. Neutralization of Oxidized Phospholipids Ameliorates Non-alcoholic Steatohepatitis. Cell Metab. 2020, 31, 189–206. [Google Scholar] [CrossRef]
- Connolly, J.J.; Ooka, K.; Lim, J.K. Future pharmacotherapy for non-alcoholic steatohepatitis (NASH): Review of phase 2 and 3 trials. J. Clin. Transl. Hepatol. 2018, 6, 264–275. [Google Scholar] [CrossRef]
- Dauer, W.T.; Worman, H.J. The nuclear envelope as a signaling node in development and disease. Dev. Cell 2009, 17, 626–638. [Google Scholar] [CrossRef] [PubMed]
- Worman, H.J.; Schirmer, E.C. Nuclear membrane diversity: Underlying tissue-specific pathologies in disease? Curr. Opin. Cell Biol. 2015, 34, 101–112. [Google Scholar] [CrossRef] [PubMed]
- Östlund, C.; Chang, W.; Gundersen, G.G.; Worman, H.J. Pathogenic mutations in genes encoding nuclear envelope proteins and defective nucleocytoplasmic connections. Exp. Biol. Med. 2019, 244, 1333–1344. [Google Scholar] [CrossRef] [PubMed]
- Hoelz, A.; Debler, E.W.; Blobel, G. The structure of the nuclear pore complex. Annu. Rev. Biochem. 2011, 80, 613–643. [Google Scholar] [CrossRef]
- Worman, H.J. Nuclear lamins and laminopathies. J. Pathol. 2012, 226, 316–325. [Google Scholar] [CrossRef]
- Siniossoglou, S. Lipins, lipids and nuclear envelope structure. Traffic 2009, 10, 1181–1187. [Google Scholar] [CrossRef]
- Jacquemyn, J.; Cascalho, A.; Goodchild, R.E. The ins and outs of endoplasmic reticulum-controlled lipid biosynthesis. EMBO Rep. 2017, 18, 1905–1921. [Google Scholar] [CrossRef]
- Sołtysik, K.; Ohsaki, Y.; Fujimoto, T. Duo in a Mystical Realm—Nuclear Lipid Droplets and the Inner Nuclear Membrane. Contact 2019, 2. [Google Scholar] [CrossRef]
- Sołtysik, K.; Ohsaki, Y.; Tatematsu, T.; Cheng, J.; Fujimoto, T. Nuclear lipid droplets derive from a lipoprotein precursor and regulate phosphatidylcholine synthesis. Nat. Commun. 2019, 10, 1–12. [Google Scholar] [CrossRef]
- Bahmanyar, S.; Schlieker, C. Lipid and protein dynamics that shape nuclear envelope identity. Mol. Biol. Cell 2020, 31, 1315–1323. [Google Scholar] [CrossRef]
- Lagrutta, L.C.; Montero-Villegas, S.; Layerenza, J.P.; Sisti, M.S.; García de Bravo, M.M.; Ves-Losada, A. Reversible nuclear-lipid-droplet morphology induced by oleic acid: A link to cellular-lipid metabolism. PLoS ONE 2017, 12, e0170608. [Google Scholar] [CrossRef]
- Layerenza, J.P.; González, P.; De Bravo, M.G.; Polo, M.P.; Sisti, M.S.; Ves-Losada, A. Nuclear lipid droplets: A novel nuclear domain. BBA-Mol. Cell Biol. Lipids 2013, 1831, 327–340. [Google Scholar] [CrossRef] [PubMed]
- Farese, R.V., Jr.; Walther, T.C. Lipid droplets go nuclear. J. Cell Biol. 2016, 212, 7–8. [Google Scholar] [CrossRef] [PubMed]
- Shin, J.Y.; Hernandez-Ono, A.; Fedotova, T.; Ostlund, C.; Lee, M.J.; Gibeley, S.B.; Liang, C.C.; Dauer, W.T.; Ginsberg, H.N.; Worman, H.J. Nuclear envelope-localized torsinA-LAP1 complex regulates hepatic VLDL secretion and steatosis. J. Clin. Investig. 2019, 130, 4885–4900. [Google Scholar] [CrossRef] [PubMed]
- Ohsaki, Y.; Kawai, T.; Yoshikawa, Y.; Cheng, J.; Jokitalo, E.; Fujimoto, T. PML isoform II plays a critical role in nuclear lipid droplet formation. J. Cell Biol. 2016, 212, 29–38. [Google Scholar] [CrossRef] [PubMed]
- Romanauska, A.; Köhler, A. The inner nuclear membrane is a metabolically active territory that generates nuclear lipid droplets. Cell 2018, 174, 700–715.e18. [Google Scholar] [CrossRef]
- Worman, H.J.; Yuan, J.; Blobel, G.; Georgatos, S.D. A lamin B receptor in the nuclear envelope. Proc. Natl. Acad. Sci. USA 1988, 85, 8531–8534. [Google Scholar] [CrossRef]
- Holmer, L.; Pezhman, A.; Worman, H.J. The human lamin B receptor/sterol reductase multigene family. Genomics 1998, 54, 469–476. [Google Scholar] [CrossRef]
- Worman, H.J.; Evans, C.D.; Blobel, G. The lamin B receptor of the nuclear envelope inner membrane: A polytopic protein with eight potential transmembrane domains. J. Cell Biol. 1990, 111, 1535–1542. [Google Scholar] [CrossRef]
- Hoffmann, K.; Dreger, C.K.; Olins, A.L.; Olins, D.E.; Shultz, L.D.; Lucke, B.; Karl, H.; Kaps, R.; Müller, D.; Vayá, A. Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger–Huet anomaly). Nat. Genet. 2002, 31, 410–414. [Google Scholar] [CrossRef]
- Waterham, H.R.; Koster, J.; Mooyer, P.; Van Noort, G.; Kelley, R.I.; Wilcox, W.R.; Wanders, J.R.; Hennekam, C.R.; Oosterwijk, C.J. Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3β-hydroxysterol Δ14-reductase deficiency due to mutations in the lamin B receptor gene. Am. J. Hum. Genet. 2003, 72, 1013–1017. [Google Scholar] [CrossRef] [PubMed]
- Clayton, P.; Fischer, B.; Mann, A.; Mansour, S.; Rossier, E.; Veen, M.; Lang, C.; Baasanjav, S.; Kieslich, M.; Brossuleit, K. Mutations causing Greenberg dysplasia but not Pelger anomaly uncouple enzymatic from structural functions of a nuclear membrane protein. Nucleus 2010, 1, 354–366. [Google Scholar] [CrossRef] [PubMed]
- Tsai, P.-L.; Zhao, C.; Turner, E.; Schlieker, C. The Lamin B receptor is essential for cholesterol synthesis and perturbed by disease-causing mutations. eLife 2016, 5, e16011. [Google Scholar] [CrossRef] [PubMed]
- Reue, K.; Dwyer, J.R. Lipin proteins and metabolic homeostasis. J. Lipid Res. 2009, 50, S109–S114. [Google Scholar] [CrossRef]
- Siniossoglou, S. Phospholipid metabolism and nuclear function: Roles of the lipin family of phosphatidic acid phosphatases. BBA-Mol. Cell Biol. Lipids 2013, 1831, 575–581. [Google Scholar] [CrossRef]
- Kim, Y.; Gentry, M.S.; Harris, T.E.; Wiley, S.E.; Lawrence, J.C.; Dixon, J.E. A conserved phosphatase cascade that regulates nuclear membrane biogenesis. Proc. Natl. Acad. Sci. USA 2007, 104, 6596–6601. [Google Scholar] [CrossRef]
- Han, S.; Bahmanyar, S.; Zhang, P.; Grishin, N.; Oegema, K.; Crooke, R.; Graham, M.; Reue, K.; Dixon, J.E.; Goodman, J.M. Nuclear envelope phosphatase 1-regulatory subunit 1 (formerly TMEM188) is the metazoan Spo7p ortholog and functions in the lipin activation pathway. J. Biol. Chem. 2012, 287, 3123–3137. [Google Scholar] [CrossRef]
- Jacquemyn, J.; Foroozandeh, J.; Vints, K.; Swerts, J.; Verstreken, P.; Gounko, N.V.; Gallego, S.F.; Goodchild, R. The Torsin/NEP1R1-CTDNEP1/Lipin axis regulates nuclear envelope lipid metabolism for nuclear pore complex insertion. bioRxiv 2020. [Google Scholar] [CrossRef]
- Peterson, T.R.; Sengupta, S.S.; Harris, T.E.; Carmack, A.E.; Kang, S.A.; Balderas, E.; Guertin, D.A.; Madden, K.L.; Carpenter, A.E.; Finck, B.N. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 2011, 146, 408–420. [Google Scholar] [CrossRef]
- Kim, J.; Guan, K.L. mTOR as a central hub of nutrient signalling and cell growth. Nat. Cell Biol. 2019, 21, 63–71. [Google Scholar] [CrossRef]
- Aitchison, A.J.; Arsenault, D.J.; Ridgway, N.D. Nuclear-localized CTP: Phosphocholine cytidylyltransferase α regulates phosphatidylcholine synthesis required for lipid droplet biogenesis. Mol. Biol. Cell 2015, 26, 2927–2938. [Google Scholar] [CrossRef] [PubMed]
- Cao, H.; Hegele, R.A. Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum. Mol. Genet. 2000, 9, 109–112. [Google Scholar] [CrossRef] [PubMed]
- Speckman, R.A.; Garg, A.; Du, F.; Bennett, L.; Veile, R.; Arioglu, E.; Taylor, S.I.; Lovett, M.; Bowcock, A.M. Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the globular C-terminal domain of lamin A/C. Am. J. Hum. Genet. 2000, 66, 1192–1198. [Google Scholar] [CrossRef] [PubMed]
- Hegele, R.A. Familial partial lipodystrophy: A monogenic form of the insulin resistance syndrome. Mol. Genet. Metab. 2000, 71, 539–544. [Google Scholar] [CrossRef]
- Lüdtke, A.; Genschel, J.; Brabant, G.; Bauditz, J.; Taupitz, M.; Koch, M.; Wermke, W.; Worman, H.J.; Schmidt, H.H.-J. Hepatic steatosis in Dunnigan-type familial partial lipodystrophy. Am. J. Gastroenterol. 2005, 100, 2218–2224. [Google Scholar] [CrossRef] [PubMed]
- Guenantin, A.; Briand, N.; Bidault, G.; Afonso, P.; Bereziat, V.; Vatier, C.; Lascols, O.; Caron-Debarle, M.; Capeau, J.; Vigouroux, C. Nuclear envelope-related lipodystrophies. Semin. Cell Dev. Biol. 2014, 29, 148–157. [Google Scholar] [CrossRef]
- Kwan, R.; Brady, G.F.; Brzozowski, M.; Weerasinghe, S.V.; Martin, H.; Park, M.J.; Brunt, M.J.; Menon, R.K.; Tong, X.; Yin, L.; et al. Hepatocyte-Specific Deletion of Mouse Lamin A/C Leads to Male-Selective Steatohepatitis. Cell. Mol. Gastroenterol. Hepatol. 2017, 4, 365–383. [Google Scholar] [CrossRef]
- Brady, G.F.; Kwan, R.; Ulintz, P.J.; Nguyen, P.; Bassirian, S.; Basrur, V.; Nesvizhskii, A.I.; Loomba, R.; Omary, M.B. Nuclear lamina genetic variants, including a truncated LAP2, in twins and siblings with nonalcoholic fatty liver disease. Hepatology 2017, 67, 1710–1725. [Google Scholar] [CrossRef]
- Padiath, Q.S.; Saigoh, K.; Schiffmann, R.; Asahara, H.; Yamada, T.; Koeppen, A.; Hogan, K.; Ptacek, L.J.; Fu, Y.H. Lamin B1 duplications cause autosomal dominant leukodystrophy. Nat. Genet. 2006, 38, 1114–1123. [Google Scholar] [CrossRef]
- Nmezi, B.; Giorgio, E.; Raininko, R.; Lehman, A.; Spielmann, M.; Koenig, M.K.; Adejumo, R.; Knight, M.; Gavrilova, R.; Alturkustani, M.; et al. Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy. Neurol. Genet. 2019, 5, e305. [Google Scholar] [CrossRef]
- Padiath, Q.S. Autosomal Dominant Leukodystrophy: A Disease of the Nuclear Lamina. Front. Cell Dev. Biol. 2019, 7, 41. [Google Scholar] [CrossRef] [PubMed]
- Rolyan, H.; Tyurina, Y.Y.; Hernandez, M.; Amoscato, A.A.; Sparvero, L.J.; Nmezi, B.C.; Lu, Y.; Estecio, M.R.; Lin, K.; Chen, J.; et al. Defects of Lipid Synthesis Are Linked to the Age-Dependent Demyelination Caused by Lamin B1 Overexpression. J. Neurosci. 2015, 35, 12002–12017. [Google Scholar] [CrossRef] [PubMed]
- Senior, A.; Gerace, L. Integral membrane proteins specific to the inner nuclear membrane and associated with the nuclear lamina. J. Cell Biol. 1988, 107, 2029–2036. [Google Scholar] [CrossRef]
- Foisner, R.; Gerace, L. Integral membrane proteins of the nuclear envelope interact with lamins and chromosomes, and binding is modulated by mitotic phosphorylation. Cell 1993, 73, 1267–1279. [Google Scholar] [CrossRef]
- Shin, J.-Y.; Méndez-López, I.; Hong, M.; Wang, Y.; Tanji, K.; Wu, W.; Shugol, L.; Krauss, R.S.; Dauer, W.T.; Worman, H.J. Lamina-associated polypeptide 1 is dispensable for embryonic myogenesis but required for postnatal skeletal muscle growth. Hum. Mol. Genet. 2017, 26, 65–78. [Google Scholar] [CrossRef] [PubMed]
- Santos, M.; Domingues, S.C.; Costa, P.; Muller, T.; Galozzi, S.; Marcus, K.; e Silva, E.F.d.C.; e Silva, O.A.d.C.; Rebelo, S. Identification of a novel human LAP1 isoform that is regulated by protein phosphorylation. PLoS ONE 2014, 9, e113732. [Google Scholar] [CrossRef]
- Shin, J.Y.; Dauer, W.T.; Worman, H.J. Lamina-associated polypeptide 1: Protein interactions and tissue-selective functions. Semin. Cell Dev. Biol. 2014, 29C, 164–168. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Shin, J.Y.; Mendez-Lopez, I.; Wang, Y.; Hays, A.P.; Tanji, K.; Lefkowitch, J.H.; Schulze, P.C.; Worman, H.J.; Dauer, W.T. Lamina-Associated Polypeptide-1 Interacts with the Muscular Dystrophy Protein Emerin and Is Essential for Skeletal Muscle Maintenance. Dev. Cell 2013, 26, 591–603. [Google Scholar] [CrossRef] [PubMed]
- Santos, M.; Rebelo, S.; Van Kleeff, P.J.; Kim, C.E.; Dauer, W.T.; Fardilha, M.; da Cruz e Silva, O.A.; da Cruz e Silva, E.F. The nuclear envelope protein, LAP1B, is a novel protein phosphatase 1 substrate. PLoS ONE 2013, 8, e76788. [Google Scholar] [CrossRef] [PubMed]
- Serrano, J.B.; Da Cruz e Silva, O.A.; Rebelo, S. Lamina associated polypeptide 1 (LAP1) interactome and its functional features. Membranes 2016, 6, 8. [Google Scholar] [CrossRef]
- Pereira, C.D.; Martins, F.; Santos, M.; Müeller, T.; da Cruz e Silva, O.A.; Rebelo, S. Nuclear Accumulation of LAP1: TRF2 Complex during DNA Damage Response Uncovers a Novel Role for LAP1. Cells 2020, 9, 1804. [Google Scholar] [CrossRef] [PubMed]
- Goodchild, R.E.; Dauer, W.T. The AAA+ protein torsinA interacts with a conserved domain present in LAP1 and a novel ER protein. J. Cell Biol. 2005, 168, 855–862. [Google Scholar] [CrossRef] [PubMed]
- Ozelius, L.J.; Hewett, J.W.; Page, C.E.; Bressman, S.B.; Kramer, P.L.; Shalish, C.; De Leon, D.; Brin, M.F.; Raymond, D.; Corey, D.P. The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein. Nat. Genet. 1997, 17, 40–48. [Google Scholar] [CrossRef] [PubMed]
- Rampello, A.J.; Prophet, S.M.; Schlieker, C. The Role of Torsin AAA+ Proteins in Preserving Nuclear Envelope Integrity and Safeguarding Against Disease. Biomolecules 2020, 10, 468. [Google Scholar] [CrossRef] [PubMed]
- Goodchild, R.E.; Dauer, W.T. Mislocalization to the nuclear envelope: An effect of the dystonia-causing torsinA mutation. Proc. Natl. Acad. Sci. USA 2004, 101, 847–852. [Google Scholar] [CrossRef] [PubMed]
- Rose, A.E.; Brown, R.S.; Schlieker, C. Torsins: Not your typical AAA+ ATPases. Crit. Rev. Biochem. Mol. 2015, 50, 532–549. [Google Scholar] [CrossRef] [PubMed]
- Zhao, C.; Brown, R.S.; Chase, A.R.; Eisele, M.R.; Schlieker, C. Regulation of Torsin ATPases by LAP1 and LULL1. Proc. Natl. Acad. Sci. USA 2013, 110, E1545–E1554. [Google Scholar] [CrossRef]
- Sosa, B.A.; Demircioglu, F.E.; Chen, J.Z.; Ingram, J.; Ploegh, H.L.; Schwartz, T.U. How lamina-associated polypeptide 1 (LAP1) activates Torsin. eLife 2014, 3, e03239. [Google Scholar] [CrossRef]
- Demircioglu, F.E.; Sosa, B.A.; Ingram, J.; Ploegh, H.L.; Schwartz, T.U. Structures of TorsinA and its disease-mutant complexed with an activator reveal the molecular basis for primary dystonia. eLife 2016, 5, e17983. [Google Scholar] [CrossRef]
- Kayman-Kurekci, G.; Talim, B.; Korkusuz, P.; Sayar, N.; Sarioglu, T.; Oncel, I.; Sharafi, P.; Gundesli, H.; Balci-Hayta, B.; Purali, N.; et al. Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: A novel gene related to nuclear envelopathies. Neuromuscul. Disord. 2014, 24, 624–633. [Google Scholar] [CrossRef]
- Dorboz, I.; Coutelier, M.; Bertrand, A.T.; Caberg, J.H.; Elmaleh-Berges, M.; Laine, J.; Stevanin, G.; Bonne, G.; Boespflug-Tanguy, O.; Servais, L. Severe dystonia, cerebellar atrophy, and cardiomyopathy likely caused by a missense mutation in TOR1AIP1. Orphanet. J. Rare Dis. 2014, 9, 174. [Google Scholar] [CrossRef]
- Ghaoui, R.; Benavides, T.; Lek, M.; Waddell, L.B.; Kaur, S.; North, K.N.; MacArthur, D.G.; Clarke, N.F.; Cooper, S.T. TOR1AIP1 as a cause of cardiac failure and recessive limb-girdle muscular dystrophy. Neuromuscul. Disord. 2016, 26, 500–503. [Google Scholar] [CrossRef] [PubMed]
- Fichtman, B.; Zagairy, F.; Biran, N.; Barsheshet, Y.; Chervinsky, E.; Neriah, Z.B.; Shaag, A.; Assa, M.; Elpeleg, O.; Harel, A. Combined loss of LAP1B and LAP1C results in an early onset multisystemic nuclear envelopathy. Nat. Commun. 2019, 10, 605. [Google Scholar] [CrossRef] [PubMed]
- Lessel, I.; Chen, M.-J.; Lüttgen, S.; Arndt, F.; Fuchs, S.; Meien, S.; Thiele, H.; Jones, J.R.; Shaw, B.R.; Crossman, D.K. Two novel cases further expand the phenotype of tor1aip1-associated nuclear envelopathies. Hum. Genet. 2020, 139, 483–498. [Google Scholar] [CrossRef]
- Shin, J.Y.; Le Dour, C.; Sera, F.; Iwata, S.; Homma, S.; Joseph, L.C.; Morrow, J.P.; Dauer, W.T.; Worman, H.J. Depletion of lamina-associated polypeptide 1 from cardiomyocytes causes cardiac dysfunction in mice. Nucleus 2014, 5, 260–268. [Google Scholar] [CrossRef] [PubMed]
- Kim, C.E.; Perez, A.; Perkins, G.; Ellisman, M.H.; Dauer, W.T. A molecular mechanism underlying the neural-specific defect in torsinA mutant mice. Proc. Natl. Acad. Sci. USA 2010, 107, 9861–9866. [Google Scholar] [CrossRef]
- Ginsberg, H.N.; Fisher, E.A. The ever-expanding role of degradation in the regulation of apolipoprotein B metabolism. J. Lipid Res. 2009, 50, S162–S166. [Google Scholar] [CrossRef]
- Teng, B.; Burant, C.F.; Davidson, N.O. Molecular cloning of an apolipoprotein B messenger RNA editing protein. Science 1993, 260, 1816–1819. [Google Scholar] [CrossRef]
- Kozlitina, J.; Smagris, E.; Stender, S.; Nordestgaard, B.G.; Zhou, H.H.; Tybjærg-Hansen, A.; Vogt, T.F.; Hobbs, H.H.; Cohen, J.C. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 2014, 46, 352–356. [Google Scholar] [CrossRef]
- Smagris, E.; Gilyard, S.; BasuRay, S.; Cohen, J.C.; Hobbs, H.H. Inactivation of Tm6sf2, a gene defective in fatty liver disease, impairs lipidation but not secretion of very low density lipoproteins. J. Biol. Chem. 2016, 291, 10659–10676. [Google Scholar] [CrossRef]
- Di Filippo, M.; Moulin, P.; Roy, P.; Samson-Bouma, M.E.; Collardeau-Frachon, S.; Chebel-Dumont, S.; Peretti, N.; Dumortier, J.; Zoulim, F.; Fontanges, T. Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia. J. Hepatol. 2014, 61, 891–902. [Google Scholar] [CrossRef] [PubMed]
- Hsiao, P.-J.; Lee, M.-Y.; Wang, Y.-T.; Jiang, H.-J.; Lin, P.-C.; Yang, Y.-H.C.; Kuo, K.-K. MTTP-297H polymorphism reduced serum cholesterol but increased risk of non-alcoholic fatty liver disease-a cross-sectional study. BMC Med. Genet. 2015, 16, 93. [Google Scholar] [CrossRef] [PubMed]
- Samuel, V.T.; Shulman, G.I. Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases. Cell Metab. 2018, 27, 22–41. [Google Scholar] [CrossRef]
- Cohen, J.C.; Horton, J.D.; Hobbs, H.H. Human fatty liver disease: Old questions and new insights. Science 2011, 332, 1519–1523. [Google Scholar] [CrossRef] [PubMed]
- Pariyarath, R.; Wang, H.; Aitchison, J.D.; Ginsberg, H.N.; Welch, W.J.; Johnson, A.E.; Fisher, E.A. Co-translational interactions of apoprotein B with the ribosome and translocon during lipoprotein assembly or targeting to the proteasome. J. Biol. Chem. 2001, 276, 541–550. [Google Scholar] [CrossRef]
- Wang, S.; Park, S.; Kodali, V.K.; Han, J.; Yip, T.; Chen, Z.; Davidson, N.O.; Kaufman, R.J. Identification of protein disulfide isomerase 1 as a key isomerase for disulfide bond formation in apolipoprotein B100. Mol. Biol. Cell 2015, 26, 594–604. [Google Scholar] [CrossRef]
- Hussain, M.M.; Bakillah, A.; Jamil, H. Apolipoprotein B binding to microsomal triglyceride transfer protein decreases with increases in length and lipidation: Implications in lipoprotein biosynthesis. Biochemistry 1997, 36, 13060–13067. [Google Scholar] [CrossRef]
- Cuchel, M.; Bloedon, L.T.; Szapary, P.O.; Kolansky, D.M.; Wolfe, M.L.; Sarkis, A.; Millar, J.S.; Ikewaki, K.; Siegelman, E.S.; Gregg, R.E. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N. Engl. J. Med. 2007, 356, 148–156. [Google Scholar] [CrossRef] [PubMed]
- Conlon, D.M.; Thomas, T.; Fedotova, T.; Hernandez-Ono, A.; Di Paolo, G.; Chan, R.B.; Ruggles, K.; Gibeley, S.; Liu, J.; Ginsberg, H.N. Inhibition of apolipoprotein B synthesis stimulates endoplasmic reticulum autophagy that prevents steatosis. J. Clin. Investig. 2016, 126, 3852–3867. [Google Scholar] [CrossRef] [PubMed]
- Greenberg, A.S.; Coleman, R.A.; Kraemer, F.B.; McManaman, J.L.; Obin, M.S.; Puri, V.; Yan, Q.-W.; Miyoshi, H.; Mashek, D.G. The role of lipid droplets in metabolic disease in rodents and humans. J. Clin. Investig. 2011, 121, 2102–2110. [Google Scholar] [CrossRef] [PubMed]
- Krahmer, N.; Farese, R.V., Jr.; Walther, T.C. Balancing the fat: Lipid droplets and human disease. EMBO Mol. Med. 2013, 5, 973–983. [Google Scholar] [CrossRef] [PubMed]
- BasuRay, S.; Wang, Y.; Smagris, E.; Cohen, J.C.; Hobbs, H.H. Accumulation of PNPLA3 on lipid droplets is the basis of associated hepatic steatosis. Proc. Natl. Acad. Sci. USA 2019, 116, 9521–9526. [Google Scholar] [CrossRef]
- Sanyal, A.J.; Campbell–Sargent, C.; Mirshahi, F.; Rizzo, W.B.; Contos, M.J.; Sterling, R.K.; Luketic, V.A.; Shiffman, M.L.; Clore, J.N. Nonalcoholic steatohepatitis: Association of insulin resistance and mitochondrial abnormalities. Gastroenterology 2001, 120, 1183–1192. [Google Scholar] [CrossRef] [PubMed]
- Pessayre, D.; Fromenty, B. NASH: A mitochondrial disease. J. Hepatol. 2005, 42, 928–940. [Google Scholar] [CrossRef] [PubMed]
- Atshaves, B.P.; McIntosh, A.M.; Lyuksyutova, O.I.; Zipfel, W.; Webb, W.W.; Schroeder, F. Liver fatty acid-binding protein gene ablation inhibits branched-chain fatty acid metabolism in cultured primary hepatocytes. J. Biol. Chem. 2004, 279, 30954–30965. [Google Scholar] [CrossRef]
- Hostetler, H.A.; Lupas, D.; Tan, Y.; Dai, J.; Kelzer, M.S.; Martin, G.G.; Woldegiorgis, G.; Kier, A.B.; Schroeder, F. Acyl-CoA binding proteins interact with the acyl-CoA binding domain of mitochondrial carnitine palmitoyl transferase I. Mol. Cell. Biochem. 2011, 355, 135–148. [Google Scholar] [CrossRef] [PubMed]
- Gusarova, V.; Brodsky, J.L.; Fisher, E.A. Apolipoprotein B100 exit from the endoplasmic reticulum (ER) is COPII-dependent, and its lipidation to very low density lipoprotein occurs post-ER. J. Biol. Chem. 2003, 278, 48051–48058. [Google Scholar] [CrossRef] [PubMed]
- Van der Veen, J.N.; Kennelly, J.P.; Wan, S.; Vance, J.E.; Vance, D.E.; Jacobs, R.L. The critical role of phosphatidylcholine and phosphatidylethanolamine metabolism in health and disease. Biochim. Biophys. Acta (BBA) Biomembr. 2017, 1859, 1558–1572. [Google Scholar] [CrossRef]
- Rinella, M.E.; Green, R.M. The methionine-choline deficient dietary model of steatohepatitis does not exhibit insulin resistance. J. Hepatol. 2004, 40, 47–51. [Google Scholar] [CrossRef]
- Jacobs, R.L.; Devlin, C.; Tabas, I.; Vance, D.E. Targeted deletion of hepatic CTP: Phosphocholine cytidylyltransferase α in mice decreases plasma high density and very low density lipoproteins. J. Biol. Chem. 2004, 279, 47402–47410. [Google Scholar] [CrossRef]
- Jacobs, R.L.; Lingrell, S.; Zhao, Y.; Francis, G.A.; Vance, D.E. Hepatic CTP: Phosphocholine cytidylyltransferase-α is a critical predictor of plasma high density lipoprotein and very low density lipoprotein. J. Biol. Chem. 2008, 283, 2147–2155. [Google Scholar] [CrossRef] [PubMed]
- Noga, A.A.; Zhao, Y.; Vance, D.E. An unexpected requirement for phosphatidylethanolaminen-methyltransferase in the secretion of very low density lipoproteins. J. Biol. Chem. 2002, 277, 42358–42365. [Google Scholar] [CrossRef] [PubMed]
- Puri, P.; Baillie, R.A.; Wiest, M.M.; Mirshahi, F.; Choudhury, J.; Cheung, O.; Sargeant, C.; Contos, M.J.; Sanyal, A.J. A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology 2007, 46, 1081–1090. [Google Scholar] [CrossRef] [PubMed]
- Chiappini, F.; Coilly, A.; Kadar, H.; Gual, P.; Tran, A.; Desterke, C.; Samuel, D.; Duclos-Vallée, J.-C.; Touboul, D.; Bertrand-Michel, J. Metabolism dysregulation induces a specific lipid signature of nonalcoholic steatohepatitis in patients. Sci. Rep. 2017, 7, 46658. [Google Scholar] [CrossRef]
- Grillet, M.; Gonzalez, B.D.; Sicart, A.; Pöttler, M.; Cascalho, A.; Billion, K.; Diaz, S.H.; Swerts, J.; Naismith, T.V.; Gounko, N.V. Torsins are essential regulators of cellular lipid metabolism. Dev. Cell 2016, 38, 235–247. [Google Scholar] [CrossRef]
- Cascalho, A.; Foroozandeh, J.; Hennebel, L.; Swerts, J.; Klein, C.; Rous, S.; Dominguez Gonzalez, B.; Pisani, A.; Meringolo, M.; Gallego, S.F. Excess Lipin enzyme activity contributes to TOR1A recessive disease and DYT-TOR1A dystonia. Brain 2020, 143, 1746–1765. [Google Scholar] [CrossRef] [PubMed]
- Monetti, M.; Levin, M.C.; Watt, M.J.; Sajan, M.P.; Marmor, S.; Hubbard, B.K.; Stevens, R.D.; Bain, J.R.; Newgard, C.B.; Farese, R.V., Sr. Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metab. 2007, 6, 69–78. [Google Scholar] [CrossRef]
- Yamaguchi, K.; Yang, L.; McCall, S.; Huang, J.; Yu, X.X.; Pandey, S.K.; Bhanot, S.; Monia, B.P.; Li, Y.X.; Diehl, A.M. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 2007, 45, 1366–1374. [Google Scholar] [CrossRef]
- Listenberger, L.L.; Han, X.; Lewis, S.E.; Cases, S.; Farese, R.V.; Ory, D.S.; Schaffer, J.E. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc. Natl. Acad. Sci. USA 2003, 100, 3077–3082. [Google Scholar] [CrossRef]
- Ioannou, G.N.; Morrow, O.B.; Connole, M.L.; Lee, S.P. Association between dietary nutrient composition and the incidence of cirrhosis or liver cancer in the United States population. Hepatology 2009, 50, 175–184. [Google Scholar] [CrossRef] [PubMed]
- Perry, R.J.; Samuel, V.T.; Petersen, K.F.; Shulman, G.I. The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature 2014, 510, 84–91. [Google Scholar] [CrossRef] [PubMed]
- Luukkonen, P.K.; Zhou, Y.; Sädevirta, S.; Leivonen, M.; Arola, J.; Orešič, M.; Hyötyläinen, T.; Yki-Järvinen, H. Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease. J. Hepatol. 2016, 64, 1167–1175. [Google Scholar] [CrossRef] [PubMed]
- Han, M.S.; Park, S.Y.; Shinzawa, K.; Kim, S.; Chung, K.W.; Lee, J.-H.; Kwon, C.H.; Lee, K.-W.; Lee, J.-H.; Park, C.K. Lysophosphatidylcholine as a death effector in the lipoapoptosis of hepatocytes. J. Lipid Res. 2008, 49, 84–97. [Google Scholar] [CrossRef] [PubMed]
- Samuel, V.T.; Liu, Z.-X.; Qu, X.; Elder, B.D.; Bilz, S.; Befroy, D.; Romanelli, A.J.; Shulman, G.I. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J. Biol. Chem. 2004, 279, 32345–32353. [Google Scholar] [CrossRef] [PubMed]
- Samuel, V.T.; Liu, Z.-X.; Wang, A.; Beddow, S.A.; Geisler, J.G.; Kahn, M.; Zhang, X.-m.; Monia, B.P.; Bhanot, S.; Shulman, G.I. Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease. J. Clin. Investig. 2007, 117, 739–745. [Google Scholar] [CrossRef] [PubMed]
- Muchir, A.; Pavlidis, P.; Decostre, V.; Herron, A.J.; Arimura, T.; Bonne, G.; Worman, H.J. Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy. J. Clin. Investig. 2007, 117, 1282–1293. [Google Scholar] [CrossRef]
- Muchir, A.; Wu, W.; Worman, H.J. Reduced expression of A-type lamins and emerin activates extracellular signal-regulated kinase in cultured cells. Biochim. Biophys. Acta 2009, 1792, 75–81. [Google Scholar] [CrossRef]
- Maraldi, N.M.; Capanni, C.; Cenni, V.; Fini, M.; Lattanzi, G. Laminopathies and lamin-associated signaling pathways. J. Cell Biol. 2011, 112, 979–992. [Google Scholar] [CrossRef]
- Choi, J.C.; Muchir, A.; Wu, W.; Iwata, S.; Homma, S.; Morrow, J.P.; Worman, H.J. Temsirolimus activates autophagy and ameliorates cardiomyopathy caused by lamin A/C gene mutation. Sci. Transl. Med. 2012, 4, 144ra102. [Google Scholar] [CrossRef] [PubMed]
- Singh, S.; Osna, N.A.; Kharbanda, K.K. Treatment options for alcoholic and non-alcoholic fatty liver disease: A review. World J. Gastroenterol. 2017, 23, 6549. [Google Scholar] [CrossRef]
- Mudaliar, S.; Henry, R.R.; Sanyal, A.J.; Morrow, L.; Marschall, H.U.; Kipnes, M.; Adorini, L.; Sciacca, C.I.; Clopton, P.; Castelloe, E. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 2013, 145, 574–582.e1. [Google Scholar] [CrossRef] [PubMed]
- Kong, B.; Luyendyk, J.P.; Tawfik, O.; Guo, G.L. Farnesoid X receptor deficiency induces nonalcoholic steatohepatitis in low-density lipoprotein receptor-knockout mice fed a high-fat diet. J. Pharmacol. Exp. Ther. 2009, 328, 116–122. [Google Scholar] [CrossRef] [PubMed]
- Ratziu, V.; Harrison, S.A.; Francque, S.; Bedossa, P.; Lehert, P.; Serfaty, L.; Romero-Gomez, M.; Boursier, J.; Abdelmalek, M.; Caldwell, S. Elafibranor, an agonist of the peroxisome proliferator—Activated receptor—α and—δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 2016, 150, 1147–1159.e5. [Google Scholar] [CrossRef] [PubMed]
- Tacke, F. Cenicriviroc for the treatment of non-alcoholic steatohepatitis and liver fibrosis. Expert Opin. Investig. Drugs 2018, 27, 301–311. [Google Scholar] [CrossRef]
- Lefebvre, E.; Gottwald, M.; Lasseter, K.; Chang, W.; Willett, M.; Smith, P.; Somasunderam, A.; Utay, N. Pharmacokinetics, safety, and CCR2/CCR5 antagonist activity of cenicriviroc in participants with mild or moderate hepatic impairment. Clin. Transl. Sci. 2016, 9, 139–148. [Google Scholar] [CrossRef]
- Andrés, V.; González, J.M. Role of A-type lamins in signaling, transcription, and chromatin organization. J. Cell Biol. 2009, 187, 945–957. [Google Scholar] [CrossRef]
- Lloyd, D.J.; Trembath, R.C.; Shackleton, S. A novel interaction between lamin A and SREBP1: Implications for partial lipodystrophy and other laminopathies. Hum. Mol. Genet. 2002, 11, 769–777. [Google Scholar] [CrossRef]
- Capanni, C.; Mattioli, E.; Columbaro, M.; Lucarelli, E.; Parnaik, V.K.; Novelli, G.; Wehnert, M.; Cenni, V.; Maraldi, N.M.; Squarzoni, S. Altered pre-lamin A processing is a common mechanism leading to lipodystrophy. Hum. Mol. Genet. 2005, 14, 1489–1502. [Google Scholar] [CrossRef]
- Eslam, M.; Valenti, L.; Romeo, S. Genetics and epigenetics of NAFLD and NASH: Clinical impact. J. Hepatol. 2018, 68, 268–279. [Google Scholar] [CrossRef] [PubMed]
- Nishida, N.; Yada, N.; Hagiwara, S.; Sakurai, T.; Kitano, M.; Kudo, M. Unique features associated with hepatic oxidative DNA damage and DNA methylation in non-alcoholic fatty liver disease. J. Gastroen. Hepatol. 2016, 31, 1646–1653. [Google Scholar] [CrossRef]
- Shen, J.; Wang, S.; Zhang, Y.J.; Kappil, M.; Wu, H.C.; Kibriya, M.G.; Wang, Q.; Jasmine, F.; Ahsan, H.; Lee, P.H. Genome-wide DNA methylation profiles in hepatocellular carcinoma. Hepatology 2012, 55, 1799–1808. [Google Scholar] [CrossRef] [PubMed]
- Lee, J.; Kim, Y.; Friso, S.; Choi, S.-W. Epigenetics in non-alcoholic fatty liver disease. Mol. Asp. Med. 2017, 54, 78–88. [Google Scholar] [CrossRef]
- Kind, J.; Pagie, L.; Ortabozkoyun, H.; Boyle, S.; de Vries, S.S.; Janssen, H.; Amendola, M.; Nolen, L.D.; Bickmore, W.A.; van Steensel, B. Single-cell dynamics of genome-nuclear lamina interactions. Cell 2013, 153, 178–192. [Google Scholar] [CrossRef]
- Kind, J.; van Steensel, B. Genome–nuclear lamina interactions and gene regulation. Curr. Opin. Cell Biol. 2010, 22, 320–325. [Google Scholar] [CrossRef]
- Poleshko, A.; Shah, P.P.; Gupta, M.; Babu, A.; Morley, M.P.; Manderfield, L.J.; Ifkovits, J.L.; Calderon, D.; Aghajanian, H.; Sierra-Pagán, J.E. Genome-nuclear lamina interactions regulate cardiac stem cell lineage restriction. Cell 2017, 171, 573–587. [Google Scholar] [CrossRef]
- Cesarini, E.; Mozzetta, C.; Marullo, F.; Gregoretti, F.; Gargiulo, A.; Columbaro, M.; Cortesi, A.; Antonelli, L.; Di Pelino, S.; Squarzoni, S. Lamin A/C sustains PcG protein architecture, maintaining transcriptional repression at target genes. J. Cell Biol. 2015, 211, 533–551. [Google Scholar] [CrossRef] [PubMed]
- Wilson, K.L.; Foisner, R. Lamin-binding proteins. Cold Spring Harb. Perspect. Biol. 2010, 2, a000554. [Google Scholar] [CrossRef] [PubMed]
References | Reported Year | No. of Affected Individuals | Mutation in TOR1AIP1 | Resultant LAP1 Protein | Phenotypes |
---|---|---|---|---|---|
Kayman-Kurekci et al. [70] | 2014 | 3 | c.186delG/c.186delG | p.E62fs*25 (truncation at 83 aa of LAP1B but intact LAP1C) | muscular dystrophy, joint contracture, cardiomyopathy |
Dorboz et al. [71] | 2014 | 1 | c.1448A > T/c.1448A > T | p.E482A (E to A change in both LAP1 isoforms) | cerebellar atrophy, dystonia, cardiomyopathy, early death |
Ghaoui et al. [72] | 2016 | 2 | c.127delC/c.1181T > C | p.P43fs*15/p.L394P (truncation at 58 aa of LAP1B, L to P change in both LAP1 isoforms) | muscular dystrophy, cardiomyopathy |
Fichtman et al. [73] | 2019 | 7 | c.961C > T/c. 961C > T | p.R321* (truncation at 321 aa of both LAP1 isoforms) | multisytemic abnormalities, early death |
Lessel et al. [74] | 2020 | 2 | c.945_948delCAGT/c.1331G > C | p.Q315fs*9/p.R444P (truncation at 315 aa and R to P changes in both LAP1 isoforms) | congenital hearing loss, developmental delay, brain abnormality |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Östlund, C.; Hernandez-Ono, A.; Shin, J.-Y. The Nuclear Envelope in Lipid Metabolism and Pathogenesis of NAFLD. Biology 2020, 9, 338. https://doi.org/10.3390/biology9100338
Östlund C, Hernandez-Ono A, Shin J-Y. The Nuclear Envelope in Lipid Metabolism and Pathogenesis of NAFLD. Biology. 2020; 9(10):338. https://doi.org/10.3390/biology9100338
Chicago/Turabian StyleÖstlund, Cecilia, Antonio Hernandez-Ono, and Ji-Yeon Shin. 2020. "The Nuclear Envelope in Lipid Metabolism and Pathogenesis of NAFLD" Biology 9, no. 10: 338. https://doi.org/10.3390/biology9100338
APA StyleÖstlund, C., Hernandez-Ono, A., & Shin, J.-Y. (2020). The Nuclear Envelope in Lipid Metabolism and Pathogenesis of NAFLD. Biology, 9(10), 338. https://doi.org/10.3390/biology9100338