Abstract
Type 2 diabetes mellitus is often treated with insulin-sensitizing drugs called thiazolidinediones (TZD), which improve insulin resistance and glycemic control. Despite their effectiveness in treating diabetes, these drugs provide little protection from eminent cardiovascular disease associated with diabetes. Here we demonstrate how chiglitazar, a configuration-restricted non-TZD peroxisome proliferator-activated receptor (PPAR) pan agonist with moderate transcription activity, preferentially regulates ANGPTL4 and PDK4, which are involved in glucose and lipid metabolism. CDK5-mediated phosphorylation at serine 273 (S273) is a unique regulatory mechanism reserved for PPARγ, and this event is linked to insulin resistance in type 2 diabetes mellitus. Our data demonstrates that chiglitazar modulates gene expression differently from two TZDs, rosiglitazone and pioglitazone, via its configuration-restricted binding and phosphorylation inhibition of PPARγ. Chiglitazar induced significantly greater expression of ANGPTL4 and PDK4 than rosiglitazone and pioglitazone in different cell models. These increased expressions were dependent on the phosphorylation status of PPARγ at S273. Furthermore, ChIP and AlphaScreen assays showed that phosphorylation at S273 inhibited promoter binding and cofactor recruitment by PPARγ. Based on these results, activities from pan agonist chiglitazar can be an effective part of a long-term therapeutic strategy for treating type 2 diabetes in a more balanced action among its targeted organs.
Highlights
Metabolic syndromes, including type 2 diabetes mellitus (T2DM) and its associated complications, have significant worldwide impact
We report that Chi preferentially induced two important peroxisome proliferator-activated receptor (PPAR) target genes, ANGPTL4 and PDK4, which are involved in lipid metabolism and insulin sensitization, relative to Ros and Pio
Considering that serine 273 (S273) phosphorylation by CDK5 is unique to peroxisome proliferator-activated receptor γ (PPARγ), this event is important for dictating binding to the promoter of potential target genes related to glucose and lipid regulation, since PPARγ heterodimerizes with DNA binding domain (DBD) region of RXRα via the β-sheet domain in which S273 resides
Summary
Metabolic syndromes, including type 2 diabetes mellitus (T2DM) and its associated complications (e.g., obesity, cardiovascular symptoms, and dyslipidemia), have significant worldwide impact. Especially the insulin-sensitizing class of drugs called thiazolidinediones (TZD) (i.e., rosiglitazone (Ros) and pioglitazone (Pio)), improve insulin resistance and glycemic control with benefit of improvement in rental complication They offer ambiguous protection from eminent cardiovascular risks associated with the diseases. The TZD class of peroxisome proliferator-activated receptor γ (PPARγ) agonists is one major and important therapeutic that directly targets insulin resistance by protecting pancreatic β-islet cells, dysregulated transcription program on glucolipid modulation, and imparting anti-inflammatory protection. These drugs exhibit a more preventive effect and provide more durable HbA1c control than other diabetes treatments [1, 2]. Development of new type of insulin sensitizers for treating type 2 diabetes and associated complications remains of great interest and potential
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