Lipid droplet screen in human hepatocytes identifies TRRAP as a regulator of cellular triglyceride metabolism.

Deepti Abbey, Donna Conlon, Christopher Rainville, Susannah Elwyn, Katherine Quiroz-Figueroa, Jeffrey Billheimer, David C Schultz, Nicholas J Hand, Sara Cherry, Daniel J Rader

Clinical and translational science 2021 Jul

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Hepatocytes store triglycerides (TGs) in the form of lipid droplets (LDs), which are increased in hepatosteatosis. The regulation of hepatic LDs is poorly understood and new therapies to reduce hepatosteatosis are needed. We performed a siRNA kinase and phosphatase screen in HuH-7 cells using high-content automated imaging of LDs. Changes in accumulated lipids were quantified with developed pipeline that measures intensity, area, and number of LDs. Selected "hits," which reduced lipid accumulation, were further validated with other lipid and expression assays. Among several siRNAs that resulted in significantly reduced LDs, one was targeted to the nuclear adapter protein, transformation/transcription domain-associated protein (TRRAP). Knockdown of TRRAP reduced triglyceride accumulation in HuH-7 hepatocytes, in part by reducing C/EBPα-mediated de novo synthesis of TGs. These findings implicate TRRAP as a novel regulator of hepatic TG metabolism and nominate it as a potential drug target for hepatosteatosis. © 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.

Citation

Deepti Abbey, Donna Conlon, Christopher Rainville, Susannah Elwyn, Katherine Quiroz-Figueroa, Jeffrey Billheimer, David C Schultz, Nicholas J Hand, Sara Cherry, Daniel J Rader. Lipid droplet screen in human hepatocytes identifies TRRAP as a regulator of cellular triglyceride metabolism. Clinical and translational science. 2021 Jul;14(4):1369-1379