PPARy deacetylation confers the anti-atherogenic effect and improves endothelial function in diabetes treatment
figureposted on 14.05.2020, 12:36 by Ada Admin, 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
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 PPARg agonists, are potent insulin sensitizers with anti-atherogenic properties, but their clinical utilization is limited by the side effects. PPARg 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 PPARg deacetylation confers anti-atherogenic properties and retains the insulin-sensitizing effects of TZD while circumventing its detriments. We generated mice homozygous for deacetylation-mimetic PPARg 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 PPARg acetylation is a promising therapeutic strategy to control CVD risk in diabetes treatment.