Depletion of Hepatic SREBP2 Protects Against Hypercholesterolemia and Atherosclerosis through the ANGPTL3‐LPL Axis
Abstract Lipolysis of triglyceride‐rich lipoproteins by peripheral lipoprotein lipase (LPL) plays an essential role in maintaining systemic cholesterol/lipid homeostasis. Human genetic studies have unequivocally demonstrated that activation of LPL pathway reduces risks for both coronary artery disea...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-05-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202412677 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850122681788137472 |
|---|---|
| author | Yifan Wang Jia You Sarafina Choe Yu Shi Thi Tun Thi Xiaoyun Cao Yang Hu Kai Yan Cheng Hui Li Yang Ji Yan Liu Matthew Ackers‐Johnson Roger S.Y. Foo Yujia Shen Haojie Yu |
| author_facet | Yifan Wang Jia You Sarafina Choe Yu Shi Thi Tun Thi Xiaoyun Cao Yang Hu Kai Yan Cheng Hui Li Yang Ji Yan Liu Matthew Ackers‐Johnson Roger S.Y. Foo Yujia Shen Haojie Yu |
| author_sort | Yifan Wang |
| collection | DOAJ |
| description | Abstract Lipolysis of triglyceride‐rich lipoproteins by peripheral lipoprotein lipase (LPL) plays an essential role in maintaining systemic cholesterol/lipid homeostasis. Human genetic studies have unequivocally demonstrated that activation of LPL pathway reduces risks for both coronary artery disease (CAD) and type 2 diabetes (T2D). Although sterol regulatory element‐binding protein 2 (SREBP2) is well established as the master transcription factor that regulates the hepatic biosynthesis of both cholesterol and fatty acids, whether and how its activity in liver interacts with peripheral LPL pathway remains unknown. Here, it is demonstrated that acute liver‐specific depletion of SREBP2 results in divergent effects on the regulation of peripheral LPL activity in mice, depending on the presence or absence of low‐density lipoprotein receptors (LDLR). SREBP2 deficiency drastically elevates peripheral LPL activity through downregulation of plasma angiopoietin‐related protein 3 (ANGPTL3) levels in LDLR‐deficient mice. Moreover, in addition to SREBP2's transcriptional regulation of ANGPTL3, it is found that SREBP2 promotes proteasome‐based degradation of ANGPTL3 in the presence of LDLR. Remarkably, acute depletion of hepatic SREBP2 protects against hypercholesterolemia and atherosclerosis, in which atherosclerotic lesions are reduced by 45% compared to control littermates. Taken together, these findings outline a liver‐peripheral crosstalk mediated by SREBP2‐ANGPTL3‐LPL axis and suggest that SREBP2 inhibition can be an effective strategy to tackle homozygous familial hypercholesterolemia (HoFH). |
| format | Article |
| id | doaj-art-17d06ca1205f4a5aac920b2b95cee223 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-17d06ca1205f4a5aac920b2b95cee2232025-08-20T02:34:47ZengWileyAdvanced Science2198-38442025-05-011218n/an/a10.1002/advs.202412677Depletion of Hepatic SREBP2 Protects Against Hypercholesterolemia and Atherosclerosis through the ANGPTL3‐LPL AxisYifan Wang0Jia You Sarafina Choe1Yu Shi2Thi Tun Thi3Xiaoyun Cao4Yang Hu5Kai Yan Cheng6Hui Li7Yang Ji8Yan Liu9Matthew Ackers‐Johnson10Roger S.Y. Foo11Yujia Shen12Haojie Yu13Department of Biochemistry Yong Loo Lin School of Medicine National University of Singapore Singapore 117596 SingaporeDepartment of Biochemistry Yong Loo Lin School of Medicine National University of Singapore Singapore 117596 SingaporeDepartment of Biochemistry Yong Loo Lin School of Medicine National University of Singapore Singapore 117596 SingaporeDepartment of Biochemistry Yong Loo Lin School of Medicine National University of Singapore Singapore 117596 SingaporeDepartment of Biochemistry Yong Loo Lin School of Medicine National University of Singapore Singapore 117596 SingaporeCardiovascular Metabolic Disease Translational Research Programme Yong Loo Lin School of Medicine National University of Singapore Singapore 117599 SingaporeDepartment of Biochemistry Yong Loo Lin School of Medicine National University of Singapore Singapore 117596 SingaporeDepartment of Biochemistry Yong Loo Lin School of Medicine National University of Singapore Singapore 117596 SingaporeDepartment of Biochemistry Yong Loo Lin School of Medicine National University of Singapore Singapore 117596 SingaporeDepartment of Biochemistry Yong Loo Lin School of Medicine National University of Singapore Singapore 117596 SingaporeCardiovascular Metabolic Disease Translational Research Programme Yong Loo Lin School of Medicine National University of Singapore Singapore 117599 SingaporeCardiovascular Metabolic Disease Translational Research Programme Yong Loo Lin School of Medicine National University of Singapore Singapore 117599 SingaporeDepartment of Medicine Yong Loo Lin School of Medicine National University of Singapore Singapore 117599 SingaporeDepartment of Biochemistry Yong Loo Lin School of Medicine National University of Singapore Singapore 117596 SingaporeAbstract Lipolysis of triglyceride‐rich lipoproteins by peripheral lipoprotein lipase (LPL) plays an essential role in maintaining systemic cholesterol/lipid homeostasis. Human genetic studies have unequivocally demonstrated that activation of LPL pathway reduces risks for both coronary artery disease (CAD) and type 2 diabetes (T2D). Although sterol regulatory element‐binding protein 2 (SREBP2) is well established as the master transcription factor that regulates the hepatic biosynthesis of both cholesterol and fatty acids, whether and how its activity in liver interacts with peripheral LPL pathway remains unknown. Here, it is demonstrated that acute liver‐specific depletion of SREBP2 results in divergent effects on the regulation of peripheral LPL activity in mice, depending on the presence or absence of low‐density lipoprotein receptors (LDLR). SREBP2 deficiency drastically elevates peripheral LPL activity through downregulation of plasma angiopoietin‐related protein 3 (ANGPTL3) levels in LDLR‐deficient mice. Moreover, in addition to SREBP2's transcriptional regulation of ANGPTL3, it is found that SREBP2 promotes proteasome‐based degradation of ANGPTL3 in the presence of LDLR. Remarkably, acute depletion of hepatic SREBP2 protects against hypercholesterolemia and atherosclerosis, in which atherosclerotic lesions are reduced by 45% compared to control littermates. Taken together, these findings outline a liver‐peripheral crosstalk mediated by SREBP2‐ANGPTL3‐LPL axis and suggest that SREBP2 inhibition can be an effective strategy to tackle homozygous familial hypercholesterolemia (HoFH).https://doi.org/10.1002/advs.202412677ANGPTL3atherosclerosisHoFHLPLSREBP2 |
| spellingShingle | Yifan Wang Jia You Sarafina Choe Yu Shi Thi Tun Thi Xiaoyun Cao Yang Hu Kai Yan Cheng Hui Li Yang Ji Yan Liu Matthew Ackers‐Johnson Roger S.Y. Foo Yujia Shen Haojie Yu Depletion of Hepatic SREBP2 Protects Against Hypercholesterolemia and Atherosclerosis through the ANGPTL3‐LPL Axis Advanced Science ANGPTL3 atherosclerosis HoFH LPL SREBP2 |
| title | Depletion of Hepatic SREBP2 Protects Against Hypercholesterolemia and Atherosclerosis through the ANGPTL3‐LPL Axis |
| title_full | Depletion of Hepatic SREBP2 Protects Against Hypercholesterolemia and Atherosclerosis through the ANGPTL3‐LPL Axis |
| title_fullStr | Depletion of Hepatic SREBP2 Protects Against Hypercholesterolemia and Atherosclerosis through the ANGPTL3‐LPL Axis |
| title_full_unstemmed | Depletion of Hepatic SREBP2 Protects Against Hypercholesterolemia and Atherosclerosis through the ANGPTL3‐LPL Axis |
| title_short | Depletion of Hepatic SREBP2 Protects Against Hypercholesterolemia and Atherosclerosis through the ANGPTL3‐LPL Axis |
| title_sort | depletion of hepatic srebp2 protects against hypercholesterolemia and atherosclerosis through the angptl3 lpl axis |
| topic | ANGPTL3 atherosclerosis HoFH LPL SREBP2 |
| url | https://doi.org/10.1002/advs.202412677 |
| work_keys_str_mv | AT yifanwang depletionofhepaticsrebp2protectsagainsthypercholesterolemiaandatherosclerosisthroughtheangptl3lplaxis AT jiayousarafinachoe depletionofhepaticsrebp2protectsagainsthypercholesterolemiaandatherosclerosisthroughtheangptl3lplaxis AT yushi depletionofhepaticsrebp2protectsagainsthypercholesterolemiaandatherosclerosisthroughtheangptl3lplaxis AT thitunthi depletionofhepaticsrebp2protectsagainsthypercholesterolemiaandatherosclerosisthroughtheangptl3lplaxis AT xiaoyuncao depletionofhepaticsrebp2protectsagainsthypercholesterolemiaandatherosclerosisthroughtheangptl3lplaxis AT yanghu depletionofhepaticsrebp2protectsagainsthypercholesterolemiaandatherosclerosisthroughtheangptl3lplaxis AT kaiyancheng depletionofhepaticsrebp2protectsagainsthypercholesterolemiaandatherosclerosisthroughtheangptl3lplaxis AT huili depletionofhepaticsrebp2protectsagainsthypercholesterolemiaandatherosclerosisthroughtheangptl3lplaxis AT yangji depletionofhepaticsrebp2protectsagainsthypercholesterolemiaandatherosclerosisthroughtheangptl3lplaxis AT yanliu depletionofhepaticsrebp2protectsagainsthypercholesterolemiaandatherosclerosisthroughtheangptl3lplaxis AT matthewackersjohnson depletionofhepaticsrebp2protectsagainsthypercholesterolemiaandatherosclerosisthroughtheangptl3lplaxis AT rogersyfoo depletionofhepaticsrebp2protectsagainsthypercholesterolemiaandatherosclerosisthroughtheangptl3lplaxis AT yujiashen depletionofhepaticsrebp2protectsagainsthypercholesterolemiaandatherosclerosisthroughtheangptl3lplaxis AT haojieyu depletionofhepaticsrebp2protectsagainsthypercholesterolemiaandatherosclerosisthroughtheangptl3lplaxis |