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PPARγ Deacetylation Confers the Anti-Atherogenic Effect and Improves Endothelial Function in Diabetes Treatment.

Citation
Liu, L., et al. “Pparγ Deacetylation Confers The Anti-Atherogenic Effect And Improves Endothelial Function In Diabetes Treatment.”. Diabetes.
Center Columbia University
Featured
Author Longhua Liu, Lihong Fan, Michelle Chan, Michael J Kraakman, Jing Yang, Yong Fan, Nicole Aaron, Qianfen Wan, Maria Alicia Carrillo-Sepulveda, Alan R Tall, Ira Tabas, Domenico Accili, Li Qiang
Abstract

Cardiovascular disease (CVD) is the leading cause of death in diabetic patients; however, tight glycemic control fails to lower the risk. The thiazolidinediones (TZDs), a class of PPARγ agonists, are potent insulin sensitizers with anti-atherogenic properties, but their clinical utilization is limited by the side effects. PPARγ deacetylation on two lysine residues (K268 and K293) induces brown remodeling of white adipose tissue and uncouples TZD's adverse effects from insulin sensitization. Here we show that PPARγ deacetylation confers anti-atherogenic properties and retains the insulin-sensitizing effects of TZD while circumventing its detriments. We generated mice homozygous for deacetylation-mimetic PPARγ mutations K268R/K293R (2KR) mice on an LDL-receptor knockout ( ) background. mice showed reduced atherosclerotic lesions compared to mice, particularly in aortic arches. With rosiglitazone treatment, mice demonstrated a residual anti-atherogenic response and significant protection against bone loss and fluid retention. The anti-atherosclerotic effect of 2KR was attributed to the protection of endothelium, indicated by the improved endothelium-dependent vasorelaxation and repressed expression of pro-atherogenic factors including inducible NO synthase (iNOS), IL-6, and NADPH oxidase 2 (Nox2). Therefore, manipulating PPARγ acetylation is a promising therapeutic strategy to control CVD risk in diabetes treatment.

Year of Publication
2020
Journal
Diabetes
Date Published
05/2020
ISSN Number
1939-327X
DOI
10.2337/db20-0217
Alternate Journal
Diabetes
PMID
32409492
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