SREBP1 regulates Lgals3 activation in response to cholesterol loading
Aberrant smooth muscle cell (SMC) plasticity is etiological to vascular diseases. Cholesterol induces SMC phenotypic transition featuring high LGALS3 (galectin-3) expression. This proatherogenic process is poorly understood for its molecular underpinnings, in particular, the mechanistic role of ster...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-06-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S216225312200141X |
| _version_ | 1818254026401120256 |
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| author | Jing Li Hongtao Shen Gary K. Owens Lian-Wang Guo |
| author_facet | Jing Li Hongtao Shen Gary K. Owens Lian-Wang Guo |
| author_sort | Jing Li |
| collection | DOAJ |
| description | Aberrant smooth muscle cell (SMC) plasticity is etiological to vascular diseases. Cholesterol induces SMC phenotypic transition featuring high LGALS3 (galectin-3) expression. This proatherogenic process is poorly understood for its molecular underpinnings, in particular, the mechanistic role of sterol regulatory-element binding protein-1 (SREBP1), a master regulator of lipid metabolism. Herein we show that cholesterol loading stimulated SREBP1 expression in mouse, rat, and human SMCs. SREBP1 positively regulated LGALS3 expression (and vice versa), whereas Krüppel-like factor-15 (KLF15) acted as a negative regulator. Both bound to the Lgals3 promoter, yet at discrete sites, as revealed by chromatin immunoprecipitation-qPCR and electrophoretic mobility shift assays. SREBP1 and LGALS3 each abated KLF15 protein, and blocking the bromo/extraterminal domain-containing proteins (BETs) family of acetyl-histone readers abolished cholesterol-stimulated SREBP1/LGALS3 protein production. Furthermore, silencing bromodomain protein 2 (BRD2; but not other BETs) reduced SREBP1; endogenous BRD2 co-immunoprecipitated with SREBP1’s transcription-active domain, its own promoter DNA, and that of Lgals3. Thus, results identify a previously uncharacterized cholesterol-responsive dyad—SREBP1 and LGALS3, constituting a feedforward circuit that can be blocked by BETs inhibition. This study provides new insights into SMC phenotypic transition and potential interventional targets. |
| first_indexed | 2024-12-12T16:49:25Z |
| format | Article |
| id | doaj.art-ad2bf11430fb4b0a9324e4e0e564b23a |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-12T16:49:25Z |
| publishDate | 2022-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-ad2bf11430fb4b0a9324e4e0e564b23a2022-12-22T00:18:25ZengElsevierMolecular Therapy: Nucleic Acids2162-25312022-06-0128892909SREBP1 regulates Lgals3 activation in response to cholesterol loadingJing Li0Hongtao Shen1Gary K. Owens2Lian-Wang Guo3Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22908, USADepartment of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22908, USADepartment of Molecular Physiology and Biophysics, University of Virginia, Charlottesville, VA 22908, USA; Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USADepartment of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA; Corresponding author Lian-Wang Guo, PhD, Department of Surgery, School of Medicine, University of Virginia, 409 Lane Road, Charlottesville, VA 22908, USA.Aberrant smooth muscle cell (SMC) plasticity is etiological to vascular diseases. Cholesterol induces SMC phenotypic transition featuring high LGALS3 (galectin-3) expression. This proatherogenic process is poorly understood for its molecular underpinnings, in particular, the mechanistic role of sterol regulatory-element binding protein-1 (SREBP1), a master regulator of lipid metabolism. Herein we show that cholesterol loading stimulated SREBP1 expression in mouse, rat, and human SMCs. SREBP1 positively regulated LGALS3 expression (and vice versa), whereas Krüppel-like factor-15 (KLF15) acted as a negative regulator. Both bound to the Lgals3 promoter, yet at discrete sites, as revealed by chromatin immunoprecipitation-qPCR and electrophoretic mobility shift assays. SREBP1 and LGALS3 each abated KLF15 protein, and blocking the bromo/extraterminal domain-containing proteins (BETs) family of acetyl-histone readers abolished cholesterol-stimulated SREBP1/LGALS3 protein production. Furthermore, silencing bromodomain protein 2 (BRD2; but not other BETs) reduced SREBP1; endogenous BRD2 co-immunoprecipitated with SREBP1’s transcription-active domain, its own promoter DNA, and that of Lgals3. Thus, results identify a previously uncharacterized cholesterol-responsive dyad—SREBP1 and LGALS3, constituting a feedforward circuit that can be blocked by BETs inhibition. This study provides new insights into SMC phenotypic transition and potential interventional targets.http://www.sciencedirect.com/science/article/pii/S216225312200141Xvascular smooth muscle cellcholesterol loadingphenotypic transitionSREBP1LGALS3feedforward circuit |
| spellingShingle | Jing Li Hongtao Shen Gary K. Owens Lian-Wang Guo SREBP1 regulates Lgals3 activation in response to cholesterol loading Molecular Therapy: Nucleic Acids vascular smooth muscle cell cholesterol loading phenotypic transition SREBP1 LGALS3 feedforward circuit |
| title | SREBP1 regulates Lgals3 activation in response to cholesterol loading |
| title_full | SREBP1 regulates Lgals3 activation in response to cholesterol loading |
| title_fullStr | SREBP1 regulates Lgals3 activation in response to cholesterol loading |
| title_full_unstemmed | SREBP1 regulates Lgals3 activation in response to cholesterol loading |
| title_short | SREBP1 regulates Lgals3 activation in response to cholesterol loading |
| title_sort | srebp1 regulates lgals3 activation in response to cholesterol loading |
| topic | vascular smooth muscle cell cholesterol loading phenotypic transition SREBP1 LGALS3 feedforward circuit |
| url | http://www.sciencedirect.com/science/article/pii/S216225312200141X |
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