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Article

N-SREBP2 Provides a Mechanism for Dynamic Control of Cellular Cholesterol Homeostasis

by
Tozen Ozkan-Nikitaras
1,†,
Dominika J. Grzesik
1,2,3,†,
Lisa E. L. Romano
1,‡,
J. P. Chapple
1,
Peter J. King
1 and
Carol C. Shoulders
1,*
1
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
2
Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30 Göteborg, Sweden
3
Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, 405 30 Göteborg, Sweden
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Current address: Department of Molecular Genetics and Microbiology, Center for NeuroGenetics, University of Florida, 2033 Mowry Road, Gainesville, FL 32610, USA.
Cells 2024, 13(15), 1255; https://doi.org/10.3390/cells13151255
Submission received: 14 June 2024 / Revised: 5 July 2024 / Accepted: 22 July 2024 / Published: 25 July 2024
(This article belongs to the Special Issue Cellular Homeostasis and Quality Control)

Abstract

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–proteasome 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.
Keywords: cholesterol; nucleus; control; ER cholesterol; nucleus; control; ER

Share and Cite

MDPI and ACS Style

Ozkan-Nikitaras, T.; Grzesik, D.J.; Romano, L.E.L.; Chapple, J.P.; King, P.J.; Shoulders, C.C. N-SREBP2 Provides a Mechanism for Dynamic Control of Cellular Cholesterol Homeostasis. Cells 2024, 13, 1255. https://doi.org/10.3390/cells13151255

AMA Style

Ozkan-Nikitaras T, Grzesik DJ, Romano LEL, Chapple JP, King PJ, Shoulders CC. N-SREBP2 Provides a Mechanism for Dynamic Control of Cellular Cholesterol Homeostasis. Cells. 2024; 13(15):1255. https://doi.org/10.3390/cells13151255

Chicago/Turabian Style

Ozkan-Nikitaras, Tozen, Dominika J. Grzesik, Lisa E. L. Romano, J. P. Chapple, Peter J. King, and Carol C. Shoulders. 2024. "N-SREBP2 Provides a Mechanism for Dynamic Control of Cellular Cholesterol Homeostasis" Cells 13, no. 15: 1255. https://doi.org/10.3390/cells13151255

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