Abnormal elevation of lipid synthesis underlies many human diseases, including fatty liver disease and certain cancers. Normal control of lipid synthesis is orchestrated by Scap, a cholesterol-binding membrane protein that regulates activation of SREBPs, transcription factors that upregulate genes for the synthesis of cholesterol, fatty acids, and triglycerides. To reduce lipid synthesis, we sought to develop a specific inhibitor of Scap. Using an unconventional screening strategy based on the striking similarities between Scap and a cholesterol-binding bacterial toxin, we identified a small molecule, called UT-59, that binds to Scap’s cholesterol-binding site, thereby blocking SREBP activation and halting lipid synthesis. UT-59 and other compounds identified using this approach are promising leads to develop therapies for fatty liver and certain cancers.
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