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) make up the main cellular mechanism by which intracellular cholesterol is regulated and play important roles in inflammation and disease pathogenesis. N, N-dimethyl-3β-hydroxy-cholenamide (DMHCA), a selective LXR agonist, specifically activates the cholesterol efflux arm of the LXR pathway without stimulating triglyceride synthesis. In this study, we use a multisystem approach to understand the effects and molecular mechanisms of DMHCA treatment in type 2 diabetic (db/db) mice and human circulating angiogenic cells (CACs), which are hematopoietic progenitor cells with vascular reparative capacity. We found that DMHCA is sufficient to correct retinal and BM dysfunction in diabetes, thereby restoring retinal structure, function, and cholesterol homeostasis; rejuvenating membrane fluidity in CACs; hampering systemic inflammation; and correcting BM pathology. Using single-cell RNA sequencing on lineage-sca1+c-Kit+ (LSK) hematopoietic stem cells (HSCs) from untreated and DMHCA-treated diabetic mice, we provide potentially novel insights into hematopoiesis and reveal DMHCA's mechanism of action in correcting diabetic HSCs by reducing myeloidosis and increasing CACs and erythrocyte progenitors. Taken together, these findings demonstrate the beneficial effects of DMHCA treatment on diabetes-induced retinal and BM pathology.
Highlights
The landmark ACCORD Eye study demonstrated that, in individuals with type 2 diabetes (T2D) and dyslipidemia, tight glycemic control supplemented with fenofibrate/statin combination significantly reduced the progression of diabetic retinopathy (DR) compared with intensive glycemia treatment alone [1]
To test whether selective Liver X receptors (LXRs) agonism, using systemic DMHCA treatment (Figure 1A), is sufficient to reduce the levels of cholesterol in the retina, T2D db/db mice were treated with oral DMHCA for 6 months after the onset of diabetes
Given the selective nature of DMHCA’s mechanism of LXR agonism, which promotes cholesterol efflux and hampers systemic inflammation with less induction of hypertriglyceridemia compared with earlier agents, we chose DMHCA for our studies
Summary
The landmark ACCORD Eye study demonstrated that, in individuals with type 2 diabetes (T2D) and dyslipidemia, tight glycemic control supplemented with fenofibrate/statin combination significantly reduced the progression of diabetic retinopathy (DR) compared with intensive glycemia treatment alone [1]. Subgroup analysis of the dyslipidemia cohort revealed that elevated LDL-cholesterol was the only individual lipid measurement that was significantly associated with worse DR progression. These data establish diabetic dyslipidemia, and hypercholesterolemia as risk factors for DR and support the notion that therapies targeting lipid metabolism are clinically efficacious in T2D. The first line treatment for hypercholesterolemia, predominantly target cholesterol biosynthesis and thereby decrease circulating LDL, as well as peripheral cholesterol biosynthesis [3].
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