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Pharmacologic Inhibition of Site 1 Protease Activity Inhibits Sterol Regulatory Element-Binding Protein Processing and Reduces Lipogenic Enzyme Gene Expression and Lipid Synthesis in Cultured Cells and Experimental Animals

Hawkins, Julie L. and Robbins, Michael D. and Warren, Laurie C. and Xia, Donghui and Petras, Stephen F. and Valentine, James J. and Varghese, Alison H. and Wang, Ing-Kae and Subashi, Timothy A. and Shelly, Lorraine D. and Hay, Bruce A. and Landschulz, Katherine T. and Geoghegan, Kieran F. and Harwood, H. James, Jr. (2008) Pharmacologic Inhibition of Site 1 Protease Activity Inhibits Sterol Regulatory Element-Binding Protein Processing and Reduces Lipogenic Enzyme Gene Expression and Lipid Synthesis in Cultured Cells and Experimental Animals. Journal of Pharmacology and Experimental Therapeutics, 326 (3). pp. 801-808. ISSN 0022-3565. doi:10.1124/jpet.108.139626. https://resolver.caltech.edu/CaltechAUTHORS:20200505-144706115

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Abstract

Sterol regulatory element-binding proteins (SREBPs) are major transcriptional regulators of cholesterol, fatty acid, and glucose metabolism. Genetic disruption of SREBP activity reduces plasma and liver levels of cholesterol and triglycerides and insulin-stimulated lipogenesis, suggesting that SREBP is a viable target for pharmacological intervention. The proprotein convertase SREBP site 1 protease (S1P) is an important posttranscriptional regulator of SREBP activation. This report demonstrates that 10 μM PF-429242 (Bioorg Med Chem Lett 17:4411–4414, 2007), a recently described reversible, competitive aminopyrrolidineamide inhibitor of S1P, inhibits endogenous SREBP processing in Chinese hamster ovary cells. The same compound also down-regulates the signal from an SRE-luciferase reporter gene in human embryonic kidney 293 cells and the expression of endogenous SREBP target genes in cultured HepG2 cells. In HepG2 cells, PF-429242 inhibited cholesterol synthesis, with an IC₅₀ of 0.5 μM. In mice treated with PF-429242 for 24 h, the expression of hepatic SREBP target genes was suppressed, and the hepatic rates of cholesterol and fatty acid synthesis were reduced. Taken together, these data establish that small-molecule S1P inhibitors are capable of reducing cholesterol and fatty acid synthesis in vivo and, therefore, represent a potential new class of therapeutic agents for dyslipidemia and for a variety of cardiometabolic risk factors associated with diabetes, obesity, and the metabolic syndrome.


Item Type:Article
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URLURL TypeDescription
https://doi.org/10.1124/jpet.108.139626DOIArticle
Additional Information:© 2008 by The American Society for Pharmacology and Experimental Therapeutics. Received April 2, 2008; accepted June 23, 2008.
Issue or Number:3
DOI:10.1124/jpet.108.139626
Record Number:CaltechAUTHORS:20200505-144706115
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200505-144706115
Official Citation:Pharmacologic Inhibition of Site 1 Protease Activity Inhibits Sterol Regulatory Element-Binding Protein Processing and Reduces Lipogenic Enzyme Gene Expression and Lipid Synthesis in Cultured Cells and Experimental Animals. Julie L. Hawkins, Michael D. Robbins, Laurie C. Warren, Donghui Xia, Stephen F. Petras, James J. Valentine, Alison H. Varghese, Ing-Kae Wang, Timothy A. Subashi, Lorraine D. Shelly, Bruce A. Hay, Katherine T. Landschulz, Kieran F. Geoghegan and H. James Harwood. Journal of Pharmacology and Experimental Therapeutics September 1, 2008, 326 (3) 801-808; DOI: https://doi.org/10.1124/jpet.108.139626
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:103006
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:05 May 2020 21:52
Last Modified:16 Nov 2021 18:17

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