Piceatannol reduces resistance to statins in hypercholesterolemia by reducing PCSK9 expression through p300 acetyltransferase inhibition. (November 2020)

• Record Type: Journal Article
• Authors: Kim, Hyo-Jin; Lee, Jangho; Chung, Min-Yu; Hong, Seungpyo; Park, Jae Ho; Lee, Seung-Hyun; Park, Sahng Wook; Choi, Hyo-Kyoung; Hwang, Jin-Taek
• Is Part Of: Pharmacological research. Volume 161(2020)
• Publication Date: 2020-11
• Subjects: CBP CREB-binding protein -- CD control diet -- ChIP chromatin immunoprecipitation -- DLPS delipidated serum -- Fasn fatty acid synthase -- GAPDH glyceraldehyde 3-phosphate dehydrogenase -- PCAF p300/CBP-associated factor -- PT piceatannol -- HAT histone acetyltransferase -- HATi histone acetyltransferase inhibitor -- HDAC histone deacetylase -- HDL-C HDL cholesterol -- HMGCR 3-hydroxy-3-methylglutaryl-CoA reductase -- HNF1α hepatocyte nuclear factor 1 alpha -- LDL-C LDL cholesterol -- LDLR low density lipoprotein receptor -- H&E hematoxylin and eosin -- NAFLD non-alcoholic fatty liver disease -- NE nuclear extract -- PPARγ peroxisome proliferator-activated receptor-gamma -- PCSK9 proprotein convertase subtilisin/Kexin type 9 -- qRT-PCR quantitative real-time RT-PCR -- SREBP2 sterol regulatory element-binding protein 2 -- TG triglyceride -- WD Western diet -- WST-1 water-soluble tetrazolium salt; Histone acetyltransferase -- PCSK9 -- Hypercholesterolemia -- Statins -- Piceatannol; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2020.105205
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Highlights: Piceatannol suppresses the statin (rosuvastatin and simvastatin)-induced PCSK9 increase and stabilizes LDLR. P300 histone acetyltransferase is implicated in the PCSK9 increase caused by the statin side effect. Piceatannol has a potent as a p300 histone acetylatransferase inhibitor. Piceatannol abrogates p300 recruitment to the PCSK9 promoter region (-337 ∼ -278 bp). Co-treatment of simvastatin and piceatannol reduces plasma LDL-cholesterol level compared to simvastatin treatment in vivo. Abstract: The purpose of this study was to investigate the role of piceatannol (PT) in statin (rosuvastatin and simvastatin) resistance and tolerance and its association with PCSK9 expression via its p300 inhibitory (p300i) activity. An in vitro study was performed using HepG2 cells that were exposed to statins (rosuvastatin or simvastatin) with or without PT in delipidated serum (DLPS) medium. In the statin exposed conditions, PCSK9 expression was reduced following PT treatment when compared to HepG2 cells w/o PT treatment. Furthermore, no significant difference was observed in the expression of the transcription factors SREBP2 and HNF1α, which regulate PCSK9 expression. This resulted in low density lipoprotein receptor (LDLR) stabilization and reduced cellular cholesterol levels. This indicates that PT epigenetically controls statin-induced PCSK9 expression. Interestingly, PT attenuated p300 histone acetyltransferase (HAT) activity. Moreover, simulation of PT-p300 binding suggested that PT inhibits p300 as PT could be docked in the p300 HAT domain. Furthermore, inhibition of p300 HAT activity using C-646, a selective p300 inhibitor, or through an siRNA system effectively reduced PCSK9 induction upon statin exposure in HepG2 cells. The chromatin immunoprecipitation (ChIP) assays revealed that PT blocked the recruitment of p300 to the PCSK9 promoter region. In summary, PT attenuated statin-induced PCSK9 expression by inhibiting p300 HAT activity. Finally, co-administration of simvastatin and PT for 10 weeks further reduced plasma low-density lipoprotein-cholesterol (LDL-C) levels and stabilized the hepatic LDLR protein level compared with those resulting from single treatment of simvastatin in a high-fat diet-induced hypercholesterolemia mouse model. Our findings indicate that PT is a new nutraceutical candidate to reduce the statin resistance and tolerance that occurs in patients with hypercholesterolemia.