| First Author | Liu L | Year | 2020 |
| Journal | Diabetes | Volume | 69 |
| Issue | 8 | Pages | 1793-1803 |
| PubMed ID | 32409492 | Mgi Jnum | J:296907 |
| Mgi Id | MGI:6460225 | Doi | 10.2337/db20-0217 |
| Citation | Liu L, et al. (2020) PPARgamma Deacetylation Confers the Antiatherogenic Effect and Improves Endothelial Function in Diabetes Treatment. Diabetes 69(8):1793-1803 |
| abstractText | Cardiovascular disease (CVD) is the leading cause of death in patients with diabetes, and tight glycemic control fails to reduce the risk of developing CVD. Thiazolidinediones (TZDs), a class of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, are potent insulin sensitizers with antiatherogenic properties, but their clinical use is limited by side effects. PPARgamma deacetylation on two lysine residues (K268 and K293) induces brown remodeling of white adipose tissue and uncouples the adverse effects of TZDs from insulin sensitization. Here we show that PPARgamma deacetylation confers antiatherogenic properties and retains the insulin-sensitizing effects of TZD while circumventing its detriments. We generated mice homozygous with mice with deacetylation-mimetic PPARgamma mutations K268R/K293R (2KR) on an LDL-receptor knockout (Ldlr (-/-) ) background. 2KR:Ldlr (-/-) mice showed smaller atherosclerotic lesion areas than Ldlr (-/-) mice, particularly in aortic arches. With rosiglitazone treatment, 2KR:Ldlr (-/-) mice demonstrated a residual antiatherogenic response and substantial protection against bone loss and fluid retention. The antiatherosclerotic effect of 2KR was attributed to the protection of endothelium, indicated by improved endothelium-dependent vasorelaxation and repressed expression of proatherogenic factors including inducible nitric oxide synthase, interleukin-6, and NADPH oxidase 2. Therefore, manipulating PPARgamma acetylation is a promising therapeutic strategy to control risk of CVD in diabetes treatment. |
