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PPARy deacetylation confers the anti-atherogenic effect and improves endothelial function in diabetes treatment
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posted on 2020-05-14, 12:36 authored by Ada AdminAda 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 QiangCardiovascular 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.