Abstract
Vitamin D3 metabolites inhibit the expression of lipogenic genes by impairing sterol regulatory element-binding protein (SREBP), a master transcription factor of lipogenesis, independent of their canonical activity through a vitamin D receptor (VDR). Herein, we designed and synthesized a series of vitamin D derivatives to search for a drug-like small molecule that suppresses the SREBP-induced lipogenesis without affecting the VDR-controlled calcium homeostasis in vivo. Evaluation of the derivatives in cultured cells and mice led to the discovery of VDR-silent SREBP inhibitors and to the development of KK-052 (50), the first vitamin D-based SREBP inhibitor that has been demonstrated to mitigate hepatic lipid accumulation without calcemic action in mice. KK-052 maintained the ability of 25-hydroxyvitamin D3 to induce the degradation of SREBP but lacked in the VDR-mediated activity. KK-052 serves as a valuable compound for interrogating SREBP/SCAP in vivo and may represent an unprecedented translational opportunity of synthetic vitamin D analogues.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Body Weight / drug effects
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CHO Cells
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Cricetinae
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Cricetulus
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Cycloaddition Reaction
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Disease Models, Animal
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Drug Design*
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Drug Evaluation, Preclinical
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Fatty Liver / drug therapy
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Humans
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Lipogenesis / drug effects
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Obese
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Receptors, Calcitriol / antagonists & inhibitors
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Receptors, Calcitriol / metabolism
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Sterol Regulatory Element Binding Proteins / antagonists & inhibitors
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Sterol Regulatory Element Binding Proteins / genetics
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Sterol Regulatory Element Binding Proteins / metabolism*
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Vitamin D / analogs & derivatives*
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Vitamin D / metabolism
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Vitamin D / pharmacology
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Vitamin D / therapeutic use
Substances
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Receptors, Calcitriol
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SREBP cleavage-activating protein
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Sterol Regulatory Element Binding Proteins
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Vitamin D