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Metabolomic analysis of a selective ABCA1 inducer in obesogenic challenge provides a rationale for therapeutic
Cutler T Lewandowski1, Md Wasim Khan2, Manel BenAissa1
1Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL, USA.
Background:
Therapeutic agents with novel mechanisms of action are needed to combat the growing epidemic of type 2 diabetes (T2D) and related metabolic syndromes. Liver X receptor (LXR) agonists possess preclinical efficacy yet produce side effects due to excessive lipogenesis. Anticipating that many beneficial and detrimental effects of LXR agonists are mediated by ABCA1 and SREPB1c expression, respectively, we hypothesized that a phenotypic optimization strategy prioritizing selective ABCA1 induction would identify an efficacious lead compound with an improved side effect profile over existing LXRβ agonists.
Methods:
We synthesized and characterized a novel small molecule for selective induction of ABCA1 vs. SREBP1c in vitro. This compound was evaluated in both wild-type mice and a high-fat diet (HFD) mouse model of obesity-driven diabetes through functional, biochemical, and metabolomic analysis.
Findings:
Six weeks of oral administration of our lead compound attenuated weight gain, glucose intolerance, insulin signaling deficits, and adiposity. Global metabolomics revealed suppression of gluconeogenesis, free fatty acids, and pro-inflammatory metabolites. Target identification linked these beneficial effects to selective LXRβ agonism and PPAR/RXR antagonism.
Interpretation:
Our observations in the HFD model, combined with the absence of lipogenesis and neutropenia in WT mice, support this novel approach to therapeutic development for T2D and related conditions.
Insights
A novel compound selectively targets ABCA1, improving type 2 diabetes (T2D) and metabolic syndrome in mice without causing lipogenesis. This offers a promising therapeutic strategy for T2D.
Area of Science:
- Pharmacology
- Metabolic Diseases
- Drug Discovery
Background:
- Type 2 diabetes (T2D) and metabolic syndromes require novel therapeutics.
- Existing Liver X receptor (LXR) agonists show efficacy but cause side effects like lipogenesis.
- Selective induction of ABCA1 over SREBP1c is hypothesized to yield better therapeutic outcomes.
Purpose of the Study:
- To develop a novel small molecule for selective ABCA1 induction.
- To evaluate the therapeutic potential of this compound in a high-fat diet (HFD) mouse model of T2D.
- To improve the side effect profile compared to existing LXR agonists.
Main Methods:
- Synthesis and in vitro characterization of a novel small molecule targeting ABCA1 vs. SREBP1c.
- In vivo evaluation in wild-type and HFD-induced diabetic mice.
- Functional, biochemical, and metabolomic analyses were performed.
Main Results:
- Oral administration of the lead compound for six weeks attenuated weight gain, glucose intolerance, and insulin resistance in HFD mice.
- Metabolomic analysis revealed suppressed gluconeogenesis, reduced free fatty acids, and decreased pro-inflammatory metabolites.
- Target identification indicated selective LXRβ agonism and PPAR/RXR antagonism.
Conclusions:
- The novel compound demonstrated efficacy in an HFD mouse model of T2D.
- Absence of lipogenesis and neutropenia in wild-type mice suggests an improved safety profile.
- This selective LXRβ agonism approach represents a promising therapeutic strategy for T2D and related metabolic conditions.
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