Stable reduction of STARD4 alters cholesterol regulation and lipid homeostasis.

TitleStable reduction of STARD4 alters cholesterol regulation and lipid homeostasis.
Publication TypeJournal Article
Year of Publication2020
AuthorsIaea DB, Spahr ZR, Singh RK, Chan RB, Zhou B, Bareja R, Elemento O, Di Paolo G, Zhang X, Maxfield FR
JournalBiochim Biophys Acta Mol Cell Biol Lipids
Date Published2020 04
KeywordsBiological Transport, Cell Line, Tumor, Cell Membrane, Cholesterol, Endocytosis, Humans, Lipid Metabolism, Lipidomics, Membrane Transport Proteins, RNA Interference, RNA, Small Interfering

STARD4, a member of the evolutionarily conserved START gene family, is a soluble sterol transport protein implicated in cholesterol sensing and maintenance of cellular homeostasis. STARD4 is widely expressed and has been shown to transfer sterol between liposomes as well as organelles in cells. However, STARD4 knockout mice lack an obvious phenotype, so the overall role of STARD4 is unclear. To model long term depletion of STARD4 in cells, we use short hairpin RNA technology to stably decrease STARD4 expression in human U2OS osteosarcoma cells (STARD4-KD). We show that STARD4-KD cells display increased total cholesterol, slower cholesterol trafficking between the plasma membrane and the endocytic recycling compartment, and increased plasma membrane fluidity. These effects can all be rescued by transient expression of a short hairpin RNA-resistant STARD4 construct. Some of the cholesterol increase was due to excess storage in late endosomes or lysosomes. To understand the effects of reduced STARD4, we carried out transcriptional and lipidomic profiling of control and STARD4-KD cells. Reduction of STARD4 activates compensatory mechanisms that alter membrane composition and lipid homeostasis. Based on these observations, we propose that STARD4 functions as a critical sterol transport protein involved in sterol sensing and maintaining lipid homeostasis.

Alternate JournalBiochim Biophys Acta Mol Cell Biol Lipids
PubMed ID31917335
PubMed Central IDPMC6996790
Grant ListF31 DK104631 / DK / NIDDK NIH HHS / United States
R01 CA194547 / CA / NCI NIH HHS / United States
R01 GM123462 / GM / NIGMS NIH HHS / United States
R01 NS056049 / NS / NINDS NIH HHS / United States