PMID- 27707816 OWN - NLM STAT- MEDLINE DCOM- 20170818 LR - 20211103 IS - 1539-7262 (Electronic) IS - 0022-2275 (Print) IS - 0022-2275 (Linking) VI - 57 IP - 12 DP - 2016 Dec TI - Dose-dependent effects of siRNA-mediated inhibition of SCAP on PCSK9, LDLR, and plasma lipids in mouse and rhesus monkey. PG - 2150-2162 LID - S0022-2275(20)34541-7 [pii] LID - 10.1194/jlr.M071498 [doi] AB - SREBP cleavage-activating protein (SCAP) is a key protein in the regulation of lipid metabolism and a potential target for treatment of dyslipidemia. SCAP is required for activation of the transcription factors SREBP-1 and -2. SREBPs regulate the expression of genes involved in fatty acid and cholesterol biosynthesis, and LDL-C clearance through the regulation of LDL receptor (LDLR) and PCSK9 expression. To further test the potential of SCAP as a novel target for treatment of dyslipidemia, we used siRNAs to inhibit hepatic SCAP expression and assess the effect on PCSK9, LDLR, and lipids in mice and rhesus monkeys. In mice, robust liver Scap mRNA knockdown (KD) was achieved, accompanied by dose-dependent reduction in SREBP-regulated gene expression, de novo lipogenesis, and plasma PCSK9 and lipids. In rhesus monkeys, over 90% SCAP mRNA KD was achieved resulting in approximately 75, 50, and 50% reduction of plasma PCSK9, TG, and LDL-C, respectively. Inhibition of SCAP function was demonstrated by reduced expression of SREBP-regulated genes and de novo lipogenesis. In conclusion, siRNA-mediated inhibition of SCAP resulted in a significant reduction in circulating PCSK9 and LDL-C in rodent and primate models supporting SCAP as a novel target for the treatment of dyslipidemia. CI - Copyright (c) 2016 by the American Society for Biochemistry and Molecular Biology, Inc. FAU - Jensen, Kristian K AU - Jensen KK AD - Cardiometabolic Disease Merck & Co. Inc., Kenilworth, NJ. Electronic address: kristian_jensen@merck.com. FAU - Tadin-Strapps, Marija AU - Tadin-Strapps M AD - Genetics and Pharmacogenomics, Merck & Co. Inc., Boston, MA. FAU - Wang, Sheng-Ping AU - Wang SP AD - Cardiometabolic Disease Merck & Co. Inc., Kenilworth, NJ. FAU - Hubert, James AU - Hubert J AD - Cardiometabolic Disease Merck & Co. Inc., Kenilworth, NJ. FAU - Kan, Yanqing AU - Kan Y AD - Cardiometabolic Disease Merck & Co. Inc., Kenilworth, NJ. FAU - Ma, Yong AU - Ma Y AD - Sirna Therapeutics Merck & Co. Inc., San Francisco, CA. FAU - McLaren, David G AU - McLaren DG AD - Pharmacology, Merck & Co. Inc., Kenilworth, NJ. FAU - Previs, Stephen F AU - Previs SF AD - Cardiometabolic Disease Merck & Co. Inc., Kenilworth, NJ. FAU - Herath, Kithsiri B AU - Herath KB AD - Cardiometabolic Disease Merck & Co. Inc., Kenilworth, NJ. FAU - Mahsut, Ablatt AU - Mahsut A AD - Cardiometabolic Disease Merck & Co. Inc., Kenilworth, NJ. FAU - Liaw, Andy AU - Liaw A AD - Biostatistics, Merck & Co. Inc., Rahway, NJ. FAU - Wang, Shubing AU - Wang S AD - Biostatistics, Merck & Co. Inc., Rahway, NJ. FAU - Stout, Steven J AU - Stout SJ AD - Cardiometabolic Disease Merck & Co. Inc., Kenilworth, NJ. FAU - Keohan, CarolAnn AU - Keohan C AD - Pharmacology, Merck & Co. Inc., Kenilworth, NJ. FAU - Forrest, Gail AU - Forrest G AD - Pharmacology, Merck & Co. Inc., Kenilworth, NJ. FAU - Coelho, David AU - Coelho D AD - Sirna Therapeutics Merck & Co. Inc., San Francisco, CA. FAU - Yendluri, Satya AU - Yendluri S AD - Sirna Therapeutics Merck & Co. Inc., San Francisco, CA. FAU - Williams, Stephanie AU - Williams S AD - RNA Therapeutics, Merck & Co. Inc., West Point, PA. FAU - Koser, Martin AU - Koser M AD - RNA Therapeutics, Merck & Co. Inc., West Point, PA. FAU - Bartz, Steven AU - Bartz S AD - Business Development and Licensing, Merck & Co. Inc., San Francisco, CA. FAU - Akinsanya, Karen O AU - Akinsanya KO AD - Cardiometabolic Disease Merck & Co. Inc., Kenilworth, NJ. FAU - Pinto, Shirly AU - Pinto S AD - Cardiometabolic Disease Merck & Co. Inc., Kenilworth, NJ. LA - eng PT - Journal Article DEP - 20161005 PL - United States TA - J Lipid Res JT - Journal of lipid research JID - 0376606 RN - 0 (Hypolipidemic Agents) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Lipids) RN - 0 (Membrane Proteins) RN - 0 (RNA, Messenger) RN - 0 (RNA, Small Interfering) RN - 0 (Receptors, LDL) RN - 0 (SREBP cleavage-activating protein) RN - 0 (Sterol Regulatory Element Binding Proteins) RN - AGG2FN16EV (Simvastatin) RN - EC 3.4.21.- (Pcsk9 protein, mouse) RN - EC 3.4.21.- (Proprotein Convertase 9) SB - IM MH - Animals MH - Female MH - Gene Expression MH - Gene Knockdown Techniques MH - Humans MH - Hypolipidemic Agents/pharmacology MH - Intracellular Signaling Peptides and Proteins/*genetics/metabolism MH - Lipids/*blood MH - Lipogenesis MH - Liver/enzymology MH - Macaca mulatta MH - Male MH - Membrane Proteins/*genetics/metabolism MH - Mice, Inbred C57BL MH - Proprotein Convertase 9/*genetics/metabolism MH - RNA Interference MH - RNA, Messenger/genetics/metabolism MH - RNA, Small Interfering/*genetics MH - Receptors, LDL/*genetics/metabolism MH - Signal Transduction MH - Simvastatin/pharmacology MH - Sterol Regulatory Element Binding Proteins/genetics/metabolism PMC - PMC5321219 OTO - NOTNLM OT - SREBP cleavage-activating protein OT - animal models OT - cardiometabolic disease OT - cholesterol OT - drug therapy OT - dyslipidemia OT - lipid and lipoprotein metabolism OT - lipids/liver OT - low density lipoprotein OT - metabolic disease OT - proprotein convertase subtilisin kexin type 9 OT - small interfering ribonucleic acid EDAT- 2016/10/22 06:00 MHDA- 2017/08/19 06:00 PMCR- 2016/11/28 CRDT- 2016/10/07 06:00 PHST- 2016/08/12 00:00 [received] PHST- 2016/10/01 00:00 [revised] PHST- 2016/10/22 06:00 [pubmed] PHST- 2017/08/19 06:00 [medline] PHST- 2016/10/07 06:00 [entrez] PHST- 2016/11/28 00:00 [pmc-release] AID - S0022-2275(20)34541-7 [pii] AID - m071498 [pii] AID - 10.1194/jlr.M071498 [doi] PST - ppublish SO - J Lipid Res. 2016 Dec;57(12):2150-2162. doi: 10.1194/jlr.M071498. Epub 2016 Oct 5.