ArticleAtherosclerosis2014
CETP inhibitors downregulate hepatic LDL receptor and PCSK9 expression in vitro and in vivo through a SREBP2 dependent mechanism.
Article in Atherosclerosis, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 58 citations in OpenAlex.
- Anacetrapib lowers LDL by increasing ApoB clearance in mildly hypercholesterolemic subjects.The Journal of clinical investigation · 2015 · on this mapTrial
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- Lipid Metabolism in Pregnancy Women with Hypothyroidism and Potential Influence on Pregnancy Outcome.Journal of lipids · 2024Review
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- Novel insights into the pathological development of dyslipidemia in patients with hypothyroidism.Bosnian journal of basic medical sciences · 2022Review
- Update on dyslipidemia in hypothyroidism: the mechanism of dyslipidemia in hypothyroidism.Endocrine connections · 2022Review
- Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: A Mendelian randomization study.PLoS genetics · 2021Article
- A small-molecule inhibitor of PCSK9 transcription ameliorates atherosclerosis through the modulation of FoxO1/3 and HNF1α.EBioMedicine · 2020Article
- Sauchinone controls hepatic cholesterol homeostasis by the negative regulation of PCSK9 transcriptional network.Scientific reports · 2018Article
- Liraglutide downregulates hepatic LDL receptor and PCSK9 expression in HepG2 cells and db/db mice through a HNF-1a dependent mechanism.Cardiovascular diabetology · 2018Article
- New insights into ANGPLT3 in controlling lipoprotein metabolism and risk of cardiovascular diseases.Lipids in health and disease · 2018Review
- Lunasin functionally enhances LDL uptake via inhibiting PCSK9 and enhancing LDLR expressionOncotarget · 2017Article
- Baccaurea angulata fruit juice reduces atherosclerotic lesions in diet-induced Hypercholesterolemic rabbits.Lipids in health and disease · 2017Article
- Regulation of lipid metabolism by obeticholic acid in hyperlipidemic hamsters.Journal of lipid research · 2017Article
- Identification of Hepatic Lysophosphatidylcholine Acyltransferase 3 as a Novel Target Gene Regulated by Peroxisome Proliferator-activated Receptor δ.The Journal of biological chemistry · 2017Article
- Modulation of cholesterol transport by maternal hypercholesterolemia in human full-term placenta.PloS one · 2017Article
- Serum sdLDL-C and Cellular SREBP2-dependent Cholesterol Levels; is there a Challenge on Targeting PCSK9?Journal of medical biochemistry · 2016Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
backgroundCETP inhibitors block the transfer of cholesteryl ester from HDL-C to VLDL-C and LDL-C, thereby raising HDL-C and lowering LDL-C. In this study, we explored the effect of CETP inhibitors on hepatic LDL receptor (LDLR) and PCSK9 expression and further elucidated the underlying regulatory mechanism.
resultsWe first examined the effect of anacetrapib (ANA) and dalcetrapib (DAL) on LDLR and PCSK9 expression in hepatic cells in vitro. ANA exhibited a dose-dependent inhibition on both LDLR and PCSK9 expression in CETP-positive HepG2 cells and human primary hepatocytes as well as CETP-negative mouse primary hepatocytes (MPH). Moreover, the induction of LDLR protein expression by rosuvastatin in MPH was blunted by cotreatment with ANA. In both HepG2 and MPH ANA treatment reduced the amount of mature form of SREBP2 (SREBP2-M). In vivo, oral administration of ANA to dyslipidemic C57BL/6J mice at a daily dose of 50 mg/kg for 1 week elevated serum total cholesterol by approximately 24.5% (p < 0.05%) and VLDL-C by 70% (p < 0.05%) with concomitant reductions of serum PCSK9 and liver LDLR/SREBP2-M protein. Finally, we examined the in vitro effect of two other strong CETP inhibitors evacetrapib and torcetrapib on LDLR/PCSK9 expression and observed a similar inhibitory effect as ANA in a concentration range of 1-10 μM.
conclusionOur study revealed an unexpected off-target effect of CETP inhibitors that reduce the mature form of SREBP2, leading to attenuated transcription of hepatic LDLR and PCSK9. This negative regulation of SREBP pathway by ANA manifested in mice where CETP activity was absent and affected serum cholesterol metabolism.
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