IRE1 endoribonuclease plays a key role in activation of both HIF-1alpha and glucose metabolism in saturated fatty acid-treated human macrophages

In obesity, adipose tissue infiltrating macrophages acquire a unique pro-inflammatory polarization, thereby playing a key role in the development of chronic inflammation and T2D. Increased saturated fatty acids (SFAs) levels have been proposed to drive this specific polarization.
Accordingly, we investigated the immunometabolic reprogramming in SFA-treated human macrophages.
The RNAseq highlighted a pro-inflammatory profile and signatures like UPR, glycolysis, hypoxia. Glycolysis activation, as estimated by glycolytic gene expression, glucose uptake, lactate production and GLUT1 levels, has been dependent on HIF-1alpha stabilization and has fueled the production of IL-1alpha. Concomitantly, SFAs have also induced a strong xbp-1 mRNA splicing via the endoribonuclease IRE1alpha, one ER stress sensor. Interestingly, the knockdown and pharmacological inhibition of IREalpha, unlike the knockdown of XBP1s, have prevented activation of both HIF-1alpha and glycolysis.
These data suggest for the first time that IRE1alpha plays a key role through XBP1s-independent way in glucose metabolism activation in SFAs-treated macrophages.