Taurine alleviates dysfunction of cholesterol metabolism under hyperuricemia by inhibiting A2AR-SREBP-2/CREB/HMGCR axis.

Abstract

Dysfunctional cholesterol metabolism is highly prevalent in patients with hyperuricemia. Both uric acid and cholesterol are independent risk factors for atherosclerosis, contributing to an increased incidence of cardiovascular disease in hyperuricemia. Investigating the pathological mechanisms underlying cholesterol metabolism dysfunction in hyperuricemia is essential. This study identified adenosine and inosine, two major purine metabolites, as key regulators of cholesterol biosynthesis. These metabolites up-regulate 3-hydroxy-3-methylglutaryl-CoA (HMGCR). Further mechanistic studies revealed that adenosine/inosine up-regulated the expression of HMGCR by activating adenosine A2A receptor (A2AR) via the sterol-regulatory element binding protein 2 (SREBP-2)/CREB axis in hyperuricemia. Additionally, we found that taurine deficiency contributes to cholesterol metabolism dysfunction in hyperuricemia. Taurine administration in hyperuricemia mice significantly reduced cholesterol elevation by inhibiting A2AR. This study provides a promising strategy for treating comorbid hypercholesterolemia and hyperuricemia.