**Background**
Metabolic disorders, including nonalcoholic steatohepatitis (NASH) and type 2 diabetes, are characterized by insulin resistance and liver injury. The mitochondrial pyruvate carrier (MPC) plays a critical role in regulating the entry of pyruvate into the mitochondria, thereby influencing glucose production and pyruvate oxidation. Targeting the MPC has emerged as a promising strategy to attenuate liver fibrosis and improve systemic insulin sensitivity. Additionally, while thiazolidinediones (TZDs) are known to activate PPARγ, there is a significant research interest in developing “PPARγ-sparing” molecules that provide metabolic benefits without the typical side effects associated with high PPARγ affinity. In this context, we will introduce an orally active TZD-like molecule – Azemiglitazone.
**Definition**
Azemiglitazone (also known as MSDC-0602) is an orally active thiazolidinedione-like molecule that binds to PPARγ with low activating affinity (IC50 of 18.25 μM) and acts as an inhibitor of the mitochondrial pyruvate carrier (MPC).
**In Vitro and In Vivo Studies**
According to the Azemiglitazone description, this compound specifically targets the MPC to modulate metabolic flux. Azemiglitazone in vitro studies demonstrate that at a concentration of 15 μM for 4 hours, the molecule crosslinks specifically to MPC, interacting with MPC2 to inhibit pyruvate oxidation and glucose production in liver mitochondria.
The Azemiglitazone biological activity has been further validated in several animal models. In diet-induced obesity (DIO) C57BL/6 mice, oral administration of 300 ppm Azemiglitazone (resulting in 2-5 μM in blood) for 2-4 weeks improved mitochondrial respiratory rates and insulin sensitivity in the liver, adipose tissue, and striated muscle. This treatment led to reduced plasma insulin concentrations, increased glucose infusion rates, and enhanced glucose uptake in the heart, adipose tissue, and gastrocnemius. Furthermore, in HTF-C diet-fed C57BL6/J mice, Azemiglitazone (331 ppm; 2-5 μM in blood) administered orally for 12 weeks prevented, and for 3 weeks reversed, stellate cell activation and fibrosis, while decreasing plasma ALT and AST levels. Notably, Azemiglitazone In Vivo results showed that weight loss and suppression of stellate cell activation occurred even in LS-Mpc 2-/- C57BL6/J mice, indicating effects both with and without MPC function. In conclusion, Azemiglitazone is a potent MPC inhibitor and PPARγ-sparing TZD-like molecule that holds promise for treating NASH and insulin resistance.
Keywords
Azemiglitazone, 1133819-87-0, MSDC-0602, MSDC0602, MSDC 0602, Mitochondrial Metabolism, PPAR, Peroxisome proliferator-activated receptors, C57BL6/J mice, NASH, MPC, stellate cells, fibrosis, insulin, Inhibitor
References
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