Selective LXR agonist, DMHCA, corrects the retina-bone marrow axis in type 2 diabetes

Abstract

In diabetic dyslipidemia, cholesterol accumulates in the plasma membrane, decreasing fluidity and thereby suppressing the ability of cells to transduce ligand-activated signaling pathways. Liver X receptors (LXRs) are the main cellular mechanism by which intracellular cholesterol is regulated and play important roles in inflammation and disease pathogenesis. N,N-dimethyl-3{beta}-hydroxy-cholenamide (DMHCA), a selective LXR agonist, specifically activates the cholesterol efflux arm of the LXR pathway without stimulating triglyceride synthesis. Thus, DMHCA possesses superior clinical potential as a cholesterol lowering agent than current LXR pan-agonist. In this study, we use a multi-systems approach to understand the effects and molecular mechanisms of DMHCA treatment in type 2 diabetic db/db mice and human -derived circulating angiogenic cells (CACs), which are vascular reparative cells. We find that DMHCA is sufficient to correct the retina-bone marrow (BM) axis in diabetes, thereby restoring retinal structure, function, and cholesterol homeostasis, rejuvenating membrane fluidity in circulating vascular reparative cells, hampering systemic inflammation, and correcting BM dysfunction. Using single-cell RNA-seq on lineage-sca1+cKit+ (LSK) hematopoietic stem cells (HSCs) from untreated and DMHCA-treated diabetic mice, we provide novel insights into hematopoiesis and reveal DMHCAs mechanism of action in correcting diabetic HSCs by reducing myeloidosis and increasing CACs and erythrocyte progenitors. Taken together, these findings demonstrate the broad and pleiotropic effects of DMHCA treatment, which has exciting potential to correct the retina-BM axis in diabetic subjects.