New epigenome players in the regulation of PCSK9-H3K4me3 and H3K9ac alterations by statin in hypercholesterolemia
Statins are the most effective drugs used worldwide to lower the serum LDL-C by inhibiting the rate-limiting step, HMG-CoA reductase, in cholesterol biosynthesis. Despite its prevalent use, statins are known to increase proprotein convertase subtilisin/kexin type 9 (PCSK9) expression, hindering its...
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Elsevier
2025-01-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227524002049 |
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| author | Sushmitha Duddu Yash T. Katakia Rituparna Chakrabarti Pooja Sharma Praphulla Chandra Shukla |
| author_facet | Sushmitha Duddu Yash T. Katakia Rituparna Chakrabarti Pooja Sharma Praphulla Chandra Shukla |
| author_sort | Sushmitha Duddu |
| collection | DOAJ |
| description | Statins are the most effective drugs used worldwide to lower the serum LDL-C by inhibiting the rate-limiting step, HMG-CoA reductase, in cholesterol biosynthesis. Despite its prevalent use, statins are known to increase proprotein convertase subtilisin/kexin type 9 (PCSK9) expression, hindering its efficiency. However, the underlying mechanisms remain elusive. In this study, we have unraveled the pleiotropic effects of statins on hypercholesterolemia via epigenetic regulation of PCSK9. We observed that atorvastatin (ATS) increases the fold enrichment of H3K4me3 at the promoter of PCSK9 by elevating the expression of the SET1/COMPASS family of proteins like SET1b and MLL1 in HepG2. In addition, ATS also acetylates H3K9 by increasing the expression of acetyltransferases like CBP and PCAF. Similarly, in mice fed a high-fat diet, ATS showed increased levels of H3K4me3 and H3K9ac in the liver. Furthermore, a pharmacological intervention that inhibits the H3K4me3 and H3K9ac enrichment resulted in the reversal of statin-induced upregulation of PCSK9. Combining statin and OICR-9429 or resveratrol improved the overall uptake of LDL by hepatocytes. Together, these findings suggest that statin induces the colocalization of H3K4me3 and H3K9ac to transcribe PCSK9 actively and that inhibiting these marks reduces PCSK9 expression and ultimately increases hepatocyte LDL uptake. Our study unveils a previously unknown epigenetic mechanism of PCSK9 regulation that may open new avenues to increase statin efficacy in patients and provide a potential therapeutic solution. |
| format | Article |
| id | doaj-art-c2335232606148ae9f4c6dcbc36452e6 |
| institution | Kabale University |
| issn | 0022-2275 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj-art-c2335232606148ae9f4c6dcbc36452e62025-01-30T05:12:35ZengElsevierJournal of Lipid Research0022-22752025-01-01661100699New epigenome players in the regulation of PCSK9-H3K4me3 and H3K9ac alterations by statin in hypercholesterolemiaSushmitha Duddu0Yash T. Katakia1Rituparna Chakrabarti2Pooja Sharma3Praphulla Chandra Shukla4School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, IndiaDepartment of Biological Sciences, Birla Institute of Technology and Science (BITS), Pilani, IndiaSchool of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, IndiaSchool of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, IndiaSchool of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India; Department of Human Medicine, Carl von Ossietzky University, Oldenburg, Germany; For correspondence: Praphulla Chandra ShuklaStatins are the most effective drugs used worldwide to lower the serum LDL-C by inhibiting the rate-limiting step, HMG-CoA reductase, in cholesterol biosynthesis. Despite its prevalent use, statins are known to increase proprotein convertase subtilisin/kexin type 9 (PCSK9) expression, hindering its efficiency. However, the underlying mechanisms remain elusive. In this study, we have unraveled the pleiotropic effects of statins on hypercholesterolemia via epigenetic regulation of PCSK9. We observed that atorvastatin (ATS) increases the fold enrichment of H3K4me3 at the promoter of PCSK9 by elevating the expression of the SET1/COMPASS family of proteins like SET1b and MLL1 in HepG2. In addition, ATS also acetylates H3K9 by increasing the expression of acetyltransferases like CBP and PCAF. Similarly, in mice fed a high-fat diet, ATS showed increased levels of H3K4me3 and H3K9ac in the liver. Furthermore, a pharmacological intervention that inhibits the H3K4me3 and H3K9ac enrichment resulted in the reversal of statin-induced upregulation of PCSK9. Combining statin and OICR-9429 or resveratrol improved the overall uptake of LDL by hepatocytes. Together, these findings suggest that statin induces the colocalization of H3K4me3 and H3K9ac to transcribe PCSK9 actively and that inhibiting these marks reduces PCSK9 expression and ultimately increases hepatocyte LDL uptake. Our study unveils a previously unknown epigenetic mechanism of PCSK9 regulation that may open new avenues to increase statin efficacy in patients and provide a potential therapeutic solution.http://www.sciencedirect.com/science/article/pii/S0022227524002049atorvastatincholesterol metabolismepigeneticshistone modificationhypercholesterolemia |
| spellingShingle | Sushmitha Duddu Yash T. Katakia Rituparna Chakrabarti Pooja Sharma Praphulla Chandra Shukla New epigenome players in the regulation of PCSK9-H3K4me3 and H3K9ac alterations by statin in hypercholesterolemia Journal of Lipid Research atorvastatin cholesterol metabolism epigenetics histone modification hypercholesterolemia |
| title | New epigenome players in the regulation of PCSK9-H3K4me3 and H3K9ac alterations by statin in hypercholesterolemia |
| title_full | New epigenome players in the regulation of PCSK9-H3K4me3 and H3K9ac alterations by statin in hypercholesterolemia |
| title_fullStr | New epigenome players in the regulation of PCSK9-H3K4me3 and H3K9ac alterations by statin in hypercholesterolemia |
| title_full_unstemmed | New epigenome players in the regulation of PCSK9-H3K4me3 and H3K9ac alterations by statin in hypercholesterolemia |
| title_short | New epigenome players in the regulation of PCSK9-H3K4me3 and H3K9ac alterations by statin in hypercholesterolemia |
| title_sort | new epigenome players in the regulation of pcsk9 h3k4me3 and h3k9ac alterations by statin in hypercholesterolemia |
| topic | atorvastatin cholesterol metabolism epigenetics histone modification hypercholesterolemia |
| url | http://www.sciencedirect.com/science/article/pii/S0022227524002049 |
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