RT Journal Article
SR Electronic
T1 PPARγ Deacetylation Confers the Anti-Atherogenic Effect and Improves Endothelial Function in Diabetes Treatment
JF Diabetes
JO Diabetes
FD American Diabetes Association
SP db200217
DO 10.2337/db20-0217
A1 Liu, Longhua
A1 Fan, Lihong
A1 Chan, Michelle
A1 Kraakman, Michael J.
A1 Yang, Jing
A1 Fan, Yong
A1 Aaron, Nicole
A1 Wan, Qianfen
A1 Carrillo-Sepulveda, Maria Alicia
A1 Tall, Alan R
A1 Tabas, Ira
A1 Accili, Domenico
A1 Qiang, Li
YR 2020
UL http://diabetes.diabetesjournals.org/content/early/2020/05/11/db20-0217.abstract
AB 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 (Ldlr–/–) background. 2KR:Ldlr–/– mice showed reduced atherosclerotic lesions compared to Ldlr–/– mice, particularly in aortic arches. With rosiglitazone treatment, 2KR:Ldlr–/– 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.