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Metabolomic analysis of a selective ABCA1 inducer in obesogenic challenge provides a rationale for therapeutic development

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journal contribution
posted on 22.11.2022, 22:47 authored by Cutler T Lewandowski, Md Wasim KhanMd Wasim Khan, Manel Ben AissaManel Ben Aissa, Oleksii Dubrovskyi, Martha Ackerman-Berrier, Mary LaduMary Ladu, Brian LaydenBrian Layden, Gregory RJ Thatcher
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.

Funding

Center for Clinical and Translational Science Award U54 | Funder: National Institutes of Health (National Center for Advancing Translational Sciences) | Grant ID: UL1TR002003

The Function and Regulation of the Novel Pregnancy-Specific Hexokinase HKDC1 | Funder: National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases) | Grant ID: R01DK104927

Training Program in the Biology and Translational Research on Alzheimer's Disease and Related Dementias | Funder: National Institutes of Health (National Institute on Aging) | Grant ID: T32AG057468

Role of Nutrient Sensing Receptors for the Gut Microbiota in Metabolism | Funder: United States Department of Veterans Affairs | Grant ID: I01BX003382

History

Citation

Lewandowski, C. T., Khan, M. W., BenAissa, M., Dubrovskyi, O., Ackerman-Berrier, M., LaDu, M. J., Layden, B. T.Thatcher, G. R. J. (2021). Metabolomic analysis of a selective ABCA1 inducer in obesogenic challenge provides a rationale for therapeutic development. EBioMedicine, 66, 103287-. https://doi.org/10.1016/j.ebiom.2021.103287

Publisher

Elsevier BV

Language

en

issn

2352-3964