ikarugamycin and Fatty-Liver

Drugs that mirror the cellular effects of starvation mimics are considered promising therapeutics for common metabolic disorders, such as obesity, liver steatosis, and for ageing. Starvation, or caloric restriction, is known to activate the transcription factor EB (TFEB), a master regulator of lipid metabolism and lysosomal biogenesis and function. Here, we report a nanotechnology-enabled high-throughput screen to identify small-molecule agonists of TFEB and discover three novel compounds that promote autophagolysosomal activity. The three lead compounds include the clinically approved drug, digoxin; the marine-derived natural product, ikarugamycin; and the synthetic compound, alexidine dihydrochloride, which is known to act on a mitochondrial target. Mode of action studies reveal that these compounds activate TFEB via three distinct Ca

Topics: Animals; Autophagosomes; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Biguanides; Caenorhabditis elegans; Calcium; Caloric Restriction; Diet, High-Fat; Digoxin; Enzyme Inhibitors; Fatty Liver; HeLa Cells; High-Throughput Screening Assays; Humans; Lactams; Lipid Metabolism; Liver; Longevity; Lysosomes; Metabolic Syndrome; Mice; Mitochondria; Starvation