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.
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http://dx.doi.org/10.1016/j.jlr.2024.100699 | DOI Listing |
Hortic Res
December 2024
Hubei Engineering Research Center for Protection and Utilization of Special Biological Resources in the Hanjiang River Basin, College of Life Sciences, Jianghan University, Sanjiaohu Road, Wuhan Economic and Technological Development Zone, Hubei 430056, China.
Genome Biol
December 2024
National Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan, 430070, China.
Background: Plants respond to environmental stimuli by altering gene transcription that is highly related with chromatin status, including histone modification, chromatin accessibility, and three-dimensional chromatin interaction. Vernalization is essential for the transition to reproductive growth for winter wheat. How wheat reshapes its chromatin features, especially chromatin interaction during vernalization, remains unknown.
View Article and Find Full Text PDFJ Lipid Res
November 2024
School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India; Department of Human Medicine, Carl von Ossietzky University, Oldenburg, Germany. Electronic address:
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.
View Article and Find Full Text PDFNat Commun
November 2024
National Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan, 430070, China.
Dissecting the genetic basis of seed traits in wheat is impeded by limited genetic polymorphisms and significant variations caused by environmental conditions and seed position in a spikelet. Seed performance is largely determined by endosperm development controlled by spatiotemporal variation in gene activities, which is greatly affected by chromatin status. Here, we map genome-wide dynamic distributions of H3K27me3, H3K4me3 and H3K9ac modifications and profile gene transcription across wheat endosperm development.
View Article and Find Full Text PDFEpigenomes
October 2024
Department of Medicine Huddinge, Division of Biosciences and Nutrition, Karolinska Institute, NEO Building, SE-141-83 Huddinge, Sweden.
(1) Background: Quiescent cells are those that have stopped dividing and show strongly reduced levels of gene expression during dormancy. In response to appropriate signals, the cells can wake up and start growing again. Many histone modifications are regulated in quiescence, but their exact functions remain to be determined.
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