{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T00:02:51Z","timestamp":1794009771690,"version":"4.8.0"},"reference-count":101,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T00:00:00Z","timestamp":1721865600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["FS\/12\/25\/29569"],"award-info":[{"award-number":["FS\/12\/25\/29569"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["PG\/16\/7\/31977"],"award-info":[{"award-number":["PG\/16\/7\/31977"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cholesterol is required to maintain the functional integrity of cellular membrane systems and signalling pathways, but its supply must be closely and dynamically regulated because excess cholesterol is toxic. Sterol regulatory element-binding protein 2 (SREBP2) and the ER-resident protein HMG-CoA reductase (HMGCR) are key regulators of cholesterol biosynthesis. Here, we assessed the mechanistic aspects of their regulation in hepatic cells. Unexpectedly, we found that the transcriptionally active fragment of SREBP2 (N-SREBP2) was produced constitutively. Moreover, in the absence of an exogenous cholesterol supply, nuclear N-SREBP2 became resistant to proteasome-mediated degradation. This resistance was paired with increased occupancy at the HMGCR promoter and HMGCR expression. Inhibiting nuclear N-SREBP2 degradation did not increase HMGCR RNA levels; this increase required cholesterol depletion. Our findings, combined with previous physiological and biophysical investigations, suggest a new model of SREBP2-mediated regulation of cholesterol biosynthesis in the organ that handles large and rapid fluctuations in the dietary supply of this key lipid. Specifically, in the nucleus, cholesterol and the ubiquitin\u2013proteasome system provide a short-loop system that modulates the rate of cholesterol biosynthesis via regulation of nuclear N-SREBP2 turnover and HMGCR expression. Our findings have important implications for maintaining cellular cholesterol homeostasis and lowering blood cholesterol via the SREBP2-HMGCR axis.<\/jats:p>","DOI":"10.3390\/cells13151255","type":"journal-article","created":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T14:31:07Z","timestamp":1721917867000},"page":"1255","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["N-SREBP2 Provides a Mechanism for Dynamic Control of Cellular Cholesterol Homeostasis"],"prefix":"10.3390","volume":"13","author":[{"given":"Tozen","family":"Ozkan-Nikitaras","sequence":"first","affiliation":[{"name":"Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4722-4995","authenticated-orcid":false,"given":"Dominika J.","family":"Grzesik","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK"},{"name":"Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30 G\u00f6teborg, Sweden"},{"name":"Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, 405 30 G\u00f6teborg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3531-5013","authenticated-orcid":false,"given":"Lisa E. L.","family":"Romano","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1876-1505","authenticated-orcid":false,"given":"J. P.","family":"Chapple","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"King","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol C.","family":"Shoulders","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1016\/j.immuni.2016.04.011","article-title":"A Cholesterol-Based Allostery Model of T Cell Receptor Phosphorylation","volume":"44","author":"Swamy","year":"2016","journal-title":"Immunity"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-3-030-14265-0_1","article-title":"Cholesterol-Recognition Motifs in Membrane Proteins","volume":"1135","author":"Fantini","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1016\/j.cell.2018.12.042","article-title":"Molecular Discrimination between Two Conformations of Sphingomyelin in Plasma Membranes","volume":"176","author":"Endapally","year":"2019","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1111\/tra.12762","article-title":"Active Cholesterol 20 Years on","volume":"21","author":"Lange","year":"2020","journal-title":"Traffic"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1091\/mbc.e05-02-0100","article-title":"Cholesterol Is Required for Efficient Endoplasmic Reticulum-to-Golgi Transport of Secretory Membrane Proteins","volume":"17","author":"Ridsdale","year":"2006","journal-title":"Mol. Biol. Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2412","DOI":"10.1016\/j.cell.2021.03.035","article-title":"ER-to-Golgi Protein Delivery through an Interwoven, Tubular Network Extending from ER","volume":"184","author":"Weigel","year":"2021","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s12944-019-0965-z","article-title":"Role of Cholesterol and Sphingolipids in Brain Development and Neurological Diseases","volume":"18","author":"Hussain","year":"2019","journal-title":"Lipids Health Dis."},{"key":"ref_8","first-page":"889","article-title":"Steroidogenesis-Adrenal Cell Signal Transduction","volume":"4","author":"Battista","year":"2014","journal-title":"Compr. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Kiriyama, Y., and Nochi, H. (2019). The Biosynthesis, Signaling, and Neurological Functions of Bile Acids. Biomolecules, 9.","DOI":"10.3390\/biom9060232"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Kacher, R., Mounier, C., Caboche, J., and Betuing, S. (2022). Altered Cholesterol Homeostasis in Huntington\u2019s Disease. Front. Aging Neurosci., 14.","DOI":"10.3389\/fnagi.2022.797220"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1042\/CS20220752","article-title":"Regulation of Cholesterol Homeostasis in Osteoporosis Mechanisms and Therapeutics","volume":"137","author":"Bao","year":"2023","journal-title":"Clin. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/j.cmet.2012.04.004","article-title":"Increased Hepatic Synthesis and Dysregulation of Cholesterol Metabolism Is Associated with the Severity of Nonalcoholic Fatty Liver Disease","volume":"15","author":"Min","year":"2012","journal-title":"Cell Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1993","DOI":"10.1001\/jama.2009.1619","article-title":"Major Lipids, Apolipoproteins, and Risk of Vascular Disease","volume":"302","author":"Sarwar","year":"2009","journal-title":"JAMA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1016\/j.jacl.2019.09.007","article-title":"Coronary Artery Disease in a Child with Homozygous Familial Hypercholesterolemia: Regression after Liver Transplantation","volume":"13","author":"Cephus","year":"2019","journal-title":"J. Clin. Lipidol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1146\/annurev-genom-091212-153412","article-title":"Disorders of Cholesterol Metabolism and Their Unanticipated Convergent Mechanisms of Disease","volume":"15","author":"Platt","year":"2014","journal-title":"Annu. Rev. Genom. Hum. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1016\/S0022-2275(20)33881-5","article-title":"Validation of Deuterium Incorporation against Sterol Balance for Measurement of Human Cholesterol Biosynthesis","volume":"39","author":"Jones","year":"1998","journal-title":"J. Lipid Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e1700689","DOI":"10.1002\/mnfr.201700689","article-title":"Cholesterol Absorption and Synthesis in Vegetarians and Omnivores","volume":"62","author":"Meyer","year":"2018","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1161\/ATVBAHA.111.240754","article-title":"Liver-Specific Deletion of 3-Hydroxy-3-Methylglutaryl Coenzyme a Reductase Causes Hepatic Steatosis and Death","volume":"32","author":"Nagashima","year":"2012","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1194\/jlr.M057406","article-title":"Plasma Cholesterol-Lowering and Transient Liver Dysfunction in Mice Lacking Squalene Synthase in the Liver","volume":"56","author":"Nagashima","year":"2015","journal-title":"J. Lipid Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1016\/S0092-8674(00)81304-5","article-title":"Sterol-Regulated Release of SREBP-2 from Cell Membranes Requires Two Sequential Cleavages, One within a Transmembrane Segment","volume":"85","author":"Sakai","year":"1996","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/S0092-8674(00)00037-4","article-title":"Regulated Step in Cholesterol Feedback Localized to Budding of SCAP from ER Membranes","volume":"102","author":"Nohturfft","year":"2000","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"12753","DOI":"10.1073\/pnas.162488899","article-title":"Insig-2, a Second Endoplasmic Reticulum Protein That Binds SCAP and Blocks Export of Sterol Regulatory Element-Binding Proteins","volume":"99","author":"Yabe","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/S0092-8674(02)00872-3","article-title":"Crucial Step in Cholesterol Homeostasis: Sterols Promote Binding of SCAP to INSIG-1, a Membrane Protein That Facilitates Retention of SREBPs in ER","volume":"110","author":"Yang","year":"2002","journal-title":"Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"52479","DOI":"10.1074\/jbc.M310053200","article-title":"Insig-Dependent Ubiquitination and Degradation of Mammalian 3-Hydroxy-3-Methylglutaryl-CoA Reductase Stimulated by Sterols and Geranylgeraniol","volume":"278","author":"Sever","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1073\/pnas.1620506114","article-title":"Loss of Astrocyte Cholesterol Synthesis Disrupts Neuronal Function and Alters Whole-Body Metabolism","volume":"114","author":"Ferris","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","unstructured":"Feingold, K.R., and Grunfeld, C. (2024, June 15). Introduction to Lipids and Lipoproteins, Endotext, Available online: http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/26247089."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"251","DOI":"10.7555\/JBR.34.20190124","article-title":"LDL, LDL Receptors, and PCSK9 as Modulators of the Risk for Type 2 Diabetes: A Focus on White Adipose Tissue","volume":"34","author":"Faraj","year":"2020","journal-title":"J. Biomed. Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Yeo, X.Y., Tan, L.Y., Chae, W.R., Lee, D.Y., Lee, Y.A., Wuestefeld, T., and Jung, S. (2023). Liver\u2019s Influence on the Brain through the Action of Bile Acids. Front. Neurosci., 17.","DOI":"10.3389\/fnins.2023.1123967"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1172\/JCI2961","article-title":"Activation of Cholesterol Synthesis in Preference to Fatty Acid Synthesis in Liver and Adipose Tissue of Transgenic Mice Overproducing Sterol Regulatory Element-Binding Protein-2","volume":"101","author":"Horton","year":"1998","journal-title":"J. Clin. Investig."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1194\/jlr.M100417-JLR200","article-title":"Transcriptional Activities of Nuclear SREBP-1a, -1c, and -2 to Different Target Promoters of Lipogenic and Cholesterogenic Genes","volume":"43","author":"Shimano","year":"2002","journal-title":"J. Lipid Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"12027","DOI":"10.1073\/pnas.1534923100","article-title":"Combined Analysis of Oligonucleotide Microarray Data from Transgenic and Knockout Mice Identifies Direct SREBP Target Genes","volume":"100","author":"Horton","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Zhao, Q., Lin, X., and Wang, G. (2022). Targeting SREBP-1-Mediated Lipogenesis as Potential Strategies for Cancer. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.952371"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"29422","DOI":"10.1074\/jbc.270.49.29422","article-title":"Hairpin Orientation of Sterol Regulatory Element-Binding Protein-2 in Cell Membranes as Determined by Protease Protection","volume":"270","author":"Hua","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"12778","DOI":"10.1074\/jbc.272.19.12778","article-title":"Cleavage Site for Sterol-Regulated Protease Localized to a Leu-Ser Bond in the Lumenal Loop of Sterol Regulatory Element-Binding Protein-2","volume":"272","author":"Duncan","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"22805","DOI":"10.1074\/jbc.274.32.22805","article-title":"Secreted Site-1 Protease Cleaves Peptides Corresponding to Luminal Loop of Sterol Regulatory Element-Binding Proteins","volume":"274","author":"Cheng","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5123","DOI":"10.1073\/pnas.97.10.5123","article-title":"Asparagine-Proline Sequence within Membrane-Spanning Segment of SREBP Triggers Intramembrane Cleavage by Site-2 Protease","volume":"97","author":"Ye","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"S15","DOI":"10.1194\/jlr.R800054-JLR200","article-title":"Cholesterol Feedback: From Schoenheimer\u2019s Bottle to Scap\u2019s MELADL","volume":"50","author":"Brown","year":"2009","journal-title":"J. Lipid Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.1073\/pnas.81.6.1674","article-title":"Biogenesis of 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase, an Integral Glycoprotein of the Endoplasmic Reticulum","volume":"81","author":"Brown","year":"1984","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3330","DOI":"10.1091\/mbc.e08-09-0953","article-title":"Dislocation of HMG-CoA Reductase and Insig-1, Two Polytopic Endoplasmic Reticulum Proteins, En Route to Proteasomal Degradation","volume":"20","author":"Leichner","year":"2009","journal-title":"Mol. Biol. Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"19288","DOI":"10.1074\/jbc.M110.134213","article-title":"Sterol-Induced Dislocation of 3-Hydroxy-3-Methylglutaryl Coenzyme a Reductase from Endoplasmic Reticulum Membranes into the Cytosol through a Subcellular Compartment Resembling Lipid Droplets","volume":"285","author":"Hartman","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e25466","DOI":"10.7554\/eLife.25466","article-title":"Continuous Transport of a Small Fraction of Plasma Membrane Cholesterol to Endoplasmic Reticulum Regulates Total Cellular Cholesterol","volume":"6","author":"Infante","year":"2017","journal-title":"eLife"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3689","DOI":"10.1016\/j.cell.2021.05.019","article-title":"Scap Structures Highlight Key Role for Rotation of Intertwined Luminal Loops in Cholesterol Sensing","volume":"184","author":"Kober","year":"2021","journal-title":"Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2\u2212\u0394\u0394CT Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An Open-Source Platform for Biological-Image Analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1111\/j.1365-2818.2006.01706.x","article-title":"A Guided Tour into Subcellular Colocalization Analysis in Light Microscopy","volume":"224","author":"Bolte","year":"2006","journal-title":"J. Microsc."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"18480","DOI":"10.1016\/S0021-9258(19)81383-2","article-title":"Multiple Sterol Regulatory Elements in Promoter for Hamster 3-Hydroxy-3-Methylglutaryl-Coenzyme A Synthase","volume":"263","author":"Smith","year":"1988","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1161\/ATVBAHA.113.302728","article-title":"A Regulator of Secretory Vesicle Size, Kelch-like Protein 12, Facilitates the Secretion of Apolipoprotein B100 and Very-Low-Density Lipoproteins--Brief Report","volume":"34","author":"Butkinaree","year":"2014","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4244","DOI":"10.1074\/jbc.M113.479980","article-title":"The Endoplasmic Reticulum Coat Protein II Transport Machinery Coordinates Cellular Lipid Secretion and Cholesterol Biosynthesis","volume":"289","author":"Fryer","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1093\/hmg\/ddi128","article-title":"Evidence for Effect of Mutant PCSK9 on Apolipoprotein B Secretion as the Cause of Unusually Severe Dominant Hypercholesterolaemia","volume":"14","author":"Sun","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_50","first-page":"729","article-title":"A Novel Role for ABCA1-Generated Large Pre-\u03b2 Migrating Nascent HDL in the Regulation of Hepatic VLDL Triglyceride Secretion","volume":"51","author":"Chung","year":"2010","journal-title":"J. Lipid Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"S27","DOI":"10.1067\/mhj.2002.130300","article-title":"Structural Mechanism for Statin Inhibition of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase","volume":"144","author":"Istvan","year":"2002","journal-title":"Am. Heart J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"6511","DOI":"10.1073\/pnas.0700899104","article-title":"Sterol-Regulated Transport of SREBPs from Endoplasmic Reticulum to Golgi: Oxysterols Block Transport by Binding to Insig","volume":"104","author":"Radhakrishnan","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"26483","DOI":"10.1074\/jbc.M504041200","article-title":"Insig Required for Sterol-Mediated Inhibition of Scap\/SREBP Binding to COPII Proteins in Vitro","volume":"280","author":"Sun","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.1016\/S0021-9258(19)45558-0","article-title":"Studies on the Biological Properties of Polyene Antibiotics. Evidence for the Direct Interaction of Filipin with Cholesterol","volume":"247","author":"Norman","year":"1972","journal-title":"J. Biol. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3333","DOI":"10.1093\/jn\/132.11.3333","article-title":"Dietary Polyunsaturated Fats Regulate Rat Liver Sterol Regulatory Element Binding Proteins-1 and -2 in Three Distinct Stages and by Different Mechanisms","volume":"132","author":"Xu","year":"2002","journal-title":"J. Nutr."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1194\/jlr.M039339","article-title":"Hepatic SREBP-2 and Cholesterol Biosynthesis Are Regulated by FoxO3 and Sirt6","volume":"54","author":"Tao","year":"2013","journal-title":"J. Lipid Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1101\/gad.274167.115","article-title":"The LATS2 Tumor Suppressor Inhibits SREBP and Suppresses Hepatic Cholesterol Accumulation","volume":"30","author":"Aylon","year":"2016","journal-title":"Genes Dev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"5373","DOI":"10.1074\/jbc.M115.696872","article-title":"SREBP2 Activation Induces Hepatic Long-Chain Acyl-CoA Synthetase 1 (ACSL1) Expression in Vivo and in Vitro through a Sterol Regulatory Element (SRE) Motif of the ACSL1 C-Promoter","volume":"291","author":"Singh","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1006\/bbrc.1999.0930","article-title":"Alteration of SREBP Activation in Liver of Trisomy 21 Fetuses","volume":"260","author":"Diomede","year":"1999","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.cca.2014.10.034","article-title":"Negative Feedback Loop of Cholesterol Regulation Is Impaired in the Livers of Patients with Alagille Syndrome","volume":"440","author":"Miyahara","year":"2015","journal-title":"Clin. Chim. Acta"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Qi, Y., Liang, X., Guan, H., Sun, J., and Yao, W. (2021). RhoGDI1-Cdc42 Signaling Is Required for PDGF-BB-Induced Transformation of Vascular Smooth Muscle Cells and Neointima Formation. Biomedicines, 9.","DOI":"10.3390\/biomedicines9091169"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1093\/hmg\/ddz298","article-title":"Mutant Huntingtin Interacts with the Sterol Regulatory Element-Binding Proteins and Impairs Their Nuclear Import","volume":"29","author":"Monyror","year":"2020","journal-title":"Hum. Mol. Genet."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Cremer, T., Cremer, M., H\u00fcbner, B., Silahtaroglu, A., Hendzel, M., Lanct\u00f4t, C., Strickfaden, H., and Cremer, C. (2020). The Interchromatin Compartment Participates in the Structural and Functional Organization of the Cell Nucleus. BioEssays, 42.","DOI":"10.1002\/bies.201900132"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Sadowska, A., Osi\u0144ski, P., Roztocka, A., Kaczmarz-Chojnacka, K., Zapora, E., Sawicka, D., and Car, H. (2024). Statins\u2014From Fungi to Pharmacy. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25010466"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"15628","DOI":"10.1074\/jbc.M800391200","article-title":"Selective Binding of Sterol Regulatory Element-Binding Protein Isoforms and Co-Regulatory Proteins to Promoters for Lipid Metabolic Genes in Liver","volume":"283","author":"Bennett","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/0005-2760(75)90080-6","article-title":"Correlation of Rat Liver Chromatin-Bound Free and Esterified Cholesterol with the Circadian Rhythm of Cholesterol Biosynthesis in the Rat","volume":"409","author":"Erickson","year":"1975","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.semcdb.2021.11.007","article-title":"SUMO-SIM Interactions: From Structure to Biological Functions","volume":"132","author":"Lascorz","year":"2021","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"11890","DOI":"10.1093\/nar\/gkaa828","article-title":"Survey and Summary PML Nuclear Bodies and Chromatin Dynamics: Catch. Me If You Can!","volume":"48","author":"Corpet","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"14109","DOI":"10.1038\/ncomms14109","article-title":"Uncovering the SUMOylation and Ubiquitylation Crosstalk in Human Cells Using Sequential Peptide Immunopurification","volume":"8","author":"Lamoliatte","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"15218","DOI":"10.1074\/jbc.RA119.009147","article-title":"Inhibiting Ubiquitination Causes an Accumulation of SUMOylated Newly Synthesized Nuclear Proteins at PML Bodies","volume":"294","author":"Sha","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2946","DOI":"10.1128\/MCB.25.8.2946-2956.2005","article-title":"Spatial Distribution and Function of Sterol Regulatory Element-Binding Protein 1a and 2 Homo- and Heterodimers by In Vivo Two-Photon Imaging and Spectroscopy Fluorescence Resonance Energy Transfer","volume":"25","author":"Zoumi","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1083\/jcb.201507122","article-title":"PML Isoform II Plays a Critical Role in Nuclear Lipid Droplet Formation","volume":"212","author":"Ohsaki","year":"2016","journal-title":"J. Cell Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2456","DOI":"10.1038\/s41467-018-04957-4","article-title":"Site-Specific Characterization of Endogenous SUMOylation across Species and Organs","volume":"9","author":"Hendriks","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"W325","DOI":"10.1093\/nar\/gku383","article-title":"GPS-SUMO: A Tool for the Prediction of Sumoylation Sites and SUMO-Interaction Motifs","volume":"42","author":"Zhao","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Arzumanian, V.A., Kiseleva, O.I., and Poverennaya, E.V. (2021). The Curious Case of the HepG2 Cell Line: 40 Years of Expertise. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222313135"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.molcel.2011.08.025","article-title":"Systematic and Quantitative Assessment of the Ubiquitin-Modified Proteome","volume":"44","author":"Kim","year":"2011","journal-title":"Mol. Cell"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"eabc3593","DOI":"10.1126\/science.abc3593","article-title":"Ubiquitination Is Essential for Recovery of Cellular Activities after Heat Shock","volume":"372","author":"Maxwell","year":"2021","journal-title":"Science"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"104197","DOI":"10.1016\/j.jprot.2021.104197","article-title":"In-Depth Proteomic Analysis of Proteasome Inhibitors Bortezomib, Carfilzomib and MG132 Reveals That Mortality Factor 4-like 1 (MORF4L1) Protein Ubiquitylation Is Negatively Impacted","volume":"241","author":"Reitsma","year":"2021","journal-title":"J. Proteom."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.sbi.2021.06.011","article-title":"Order through Disorder: The Role of Intrinsically Disordered Regions in Transcription Factor Binding Specificity","volume":"71","author":"Brodsky","year":"2021","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Guharoy, M., Lazar, T., Macossay-Castillo, M., and Tompa, P. (2022). Degron Masking Outlines Degronons, Co-Degrading Functional Modules in the Proteome. Commun. Biol., 5.","DOI":"10.1038\/s42003-022-03391-z"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/S0969-2126(98)00067-7","article-title":"Co-Crystal Structure of Sterol Regulatory Element Binding Protein 1a at 2.3 A Resolution","volume":"6","author":"Bellsolell","year":"1998","journal-title":"Structure"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1194\/jlr.M074997","article-title":"Biophysical Studies of Cholesterol Effects on Chromatin","volume":"58","author":"Silva","year":"2017","journal-title":"J. Lipid Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"8007","DOI":"10.1093\/nar\/gkab587","article-title":"Local States of Chromatin Compaction at Transcription Start Sites Control Transcription Levels","volume":"49","author":"Ishihara","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"13479","DOI":"10.1074\/jbc.M116.728469","article-title":"Contribution of Accelerated Degradation to Feedback Regulation of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase and Cholesterol Metabolism in the Liver","volume":"291","author":"Hwang","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"e40009","DOI":"10.7554\/eLife.40009","article-title":"The Sterol-Responsive RNF145 E3 Ubiquitin Ligase Mediates the Degradation of HMG-CoA Reductase Together with Gp78 and Hrd1","volume":"7","author":"Menzies","year":"2018","journal-title":"eLife"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/1743-7075-7-35","article-title":"Recent Progress in Understanding Protein and Lipid Factors Affecting Hepatic VLDL Assembly and Secretion","volume":"7","author":"Sundaram","year":"2010","journal-title":"Nutr. Metab."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"29480","DOI":"10.1074\/jbc.M110.148254","article-title":"Accessibility of Cholesterol in Endoplasmic Reticulum Membranes and Activation of SREBP-2 Switch Abruptly at a Common Cholesterol Threshold","volume":"285","author":"Sokolov","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"4273","DOI":"10.1038\/s41467-022-32025-5","article-title":"Regulated Degradation of HMG CoA Reductase Requires Conformational Changes in Sterol-Sensing Domain","volume":"13","author":"Chen","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/s41586-020-2928-y","article-title":"Feeding Induces Cholesterol Biosynthesis via the MTORC1\u2013USP20\u2013HMGCR Axis","volume":"588","author":"Lu","year":"2020","journal-title":"Nature"},{"key":"ref_90","unstructured":"Burnett, J.R., Hooper, A.J., and Hegele, R.A. (2021). APOB-Related Familial Hypobetalipoproteinemia. GeneReviews, University of Washington."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"19967","DOI":"10.1074\/jbc.M800398200","article-title":"Microsomal Triglyceride Transfer Protein Enhances Cellular Cholesteryl Esterification by Relieving Product Inhibition","volume":"283","author":"Iqbal","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/j.cell.2018.08.033","article-title":"Aster Proteins Facilitate Nonvesicular Plasma Membrane to ER Cholesterol Transport in Mammalian Cells","volume":"175","author":"Sandhu","year":"2018","journal-title":"Cell"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/s42255-022-00722-6","article-title":"Hepatic Nonvesicular Cholesterol Transport Is Critical for Systemic Lipid Homeostasis","volume":"5","author":"Xiao","year":"2023","journal-title":"Nat. Metab."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"e00255-20","DOI":"10.1128\/MCB.00255-20","article-title":"Aster Proteins Regulate the Accessible Cholesterol Pool in the Plasma Membrane","volume":"40","author":"Ferrari","year":"2020","journal-title":"Mol. Cell. Biol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1016\/S0022-2275(20)34420-5","article-title":"Measurement of Rates of Cholesterol Synthesis Using Tritiated Water","volume":"25","author":"Dietschy","year":"1984","journal-title":"J. Lipid Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"3959","DOI":"10.1210\/en.2005-0345","article-title":"Short-Term Stimulation of Lipogenesis by 3,5-Diiodo-L-Thyronine in Cultured Rat Hepatocytes","volume":"146","author":"Giudetti","year":"2005","journal-title":"Endocrinology"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1016\/S0022-2275(20)32353-1","article-title":"Identification of Peroxisomal Targeting Signals in Cholesterol Biosynthetic Enzymes: AA-CoA Thiolase, HMG-CoA Synthase, MPPD, and FPP Synthase","volume":"41","author":"Olivier","year":"2000","journal-title":"J. Lipid Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2166","DOI":"10.1016\/j.molcel.2024.04.026","article-title":"MTORC1-CTLH E3 Ligase Regulates the Degradation of HMG-CoA Synthase 1 through the Pro\/N-Degron Pathway","volume":"84","author":"Yi","year":"2024","journal-title":"Mol. Cell"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.ygeno.2014.04.006","article-title":"Strategies to Fine-Map Genetic Associations with Lipid Levels by Combining Epigenomic Annotations and Liver-Specific Transcription Profiles","volume":"104","author":"Lo","year":"2014","journal-title":"Genomics"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"759S","DOI":"10.1093\/jn\/136.3.759S","article-title":"Significance of Garlic and Its Constituents in Cancer and Cardiovascular Disease Inhibition of Sterol 4a-Methyl Oxidase Is the Principal Mechanism by Which Garlic Decreases Cholesterol Synthesis 1\u20133","volume":"136","author":"Singh","year":"2006","journal-title":"J. Nutr."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.molmet.2019.12.015","article-title":"Role of ATP-Binding Cassette Transporter A1 in Suppressing Lipid Accumulation by Glucagon-like Peptide-1 Agonist in Hepatocytes","volume":"34","author":"Lyu","year":"2020","journal-title":"Mol. Metab."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/15\/1255\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:23:34Z","timestamp":1760109814000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/15\/1255"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,25]]},"references-count":101,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["cells13151255"],"URL":"https:\/\/doi.org\/10.3390\/cells13151255","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,25]]}}}