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PPARγ Deacetylation Confers the Antiatherogenic Effect and Improves Endothelial Function in Diabetes Treatment

Longhua Liu1,2, Lihong Fan1,2,3, Michelle Chan4

  • 1Naomi Berrie Diabetes Center, Columbia University, New York, NY.

Diabetes
|May 16, 2020
PubMed

Insights

Modifying PPARγ acetylation, specifically deacetylation at K268 and K293, offers a promising strategy to combat cardiovascular disease in diabetes. This approach retains insulin sensitization while mitigating TZD side effects like bone loss and fluid retention.

Area of Science:

  • Endocrinology
  • Cardiovascular Research
  • Metabolic Disease

Background:

  • Cardiovascular disease (CVD) is a major cause of mortality in diabetic patients, with current treatments like tight glycemic control showing limited efficacy in reducing CVD risk.
  • Thiazolidinediones (TZDs), PPARγ agonists, improve insulin sensitivity and possess antiatherogenic properties but are associated with significant side effects.
  • PPARγ deacetylation at K268 and K293 uncouples TZD's adverse effects from its insulin-sensitizing and antiatherogenic benefits.

Purpose of the Study:

  • To investigate whether PPARγ deacetylation can confer antiatherogenic properties while retaining insulin sensitization and avoiding TZD-related detriments.
  • To evaluate the therapeutic potential of manipulating PPARγ acetylation in the context of diabetes and atherosclerosis.

Main Methods:

  • Generation of mice with deacetylation-mimetic PPARγ mutations (K268R/K293R, termed 2KR) on an LDL-receptor knockout (Ldlr) background (2KR:Ldlr mice).
  • Assessment of atherosclerotic lesion size in the aorta, particularly the aortic arch, in 2KR:Ldlr mice compared to Ldlr controls.
  • Evaluation of the effects of rosiglitazone treatment on atherosclerosis, bone loss, and fluid retention in 2KR:Ldlr mice.
  • Analysis of endothelial function, including vasorelaxation and expression of proatherogenic factors (iNOS, IL-6, NOX2).

Main Results:

  • 2KR:Ldlr mice exhibited significantly smaller atherosclerotic lesion areas compared to Ldlr mice.
  • Rosiglitazone treatment in 2KR:Ldlr mice showed a residual antiatherogenic response and protected against bone loss and fluid retention.
  • The antiatherosclerotic effect was linked to endothelial protection, evidenced by improved endothelium-dependent vasorelaxation and reduced expression of proatherogenic factors.

Conclusions:

  • PPARγ deacetylation at K268 and K293 confers significant antiatherogenic properties.
  • This modification retains insulin-sensitizing effects of TZDs while circumventing adverse effects like bone loss and fluid retention.
  • Targeting PPARγ acetylation represents a promising therapeutic strategy for managing cardiovascular risk in diabetes.

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