Cholesteryl ester-rich lipid droplets accumulate in steroidogenic tissues under physiological conditions and constitute an important source of cholesterol as the precursor for the synthesis of all steroid hormones. The mechanisms specifically involved in cholesteryl ester-rich lipid droplet formation have not been directly studied and are assumed by most to occur in a fashion analogous to triacylglycerol-rich lipid droplets. Seipin is an ER protein that forms oligomeric complexes at ER-lipid droplet contact sites, and seipin deficiency results in severe alterations in lipid droplet maturation and morphology as seen in Berardinelli-Seip congenital lipodystrophy type 2. While seipin is critical for triacylglycerol-rich lipid droplet formation, no studies have directly addressed whether seipin is important for cholesteryl ester-rich lipid droplet biogenesis. To address this issue, mice with deficient expression of seipin specifically in adrenal, testis and ovary, steroidogenic tissues that accumulate cholesteryl ester-rich lipid droplets under normal physiological conditions were generated. We found that the steroidogenic-specific seipin deficient mice displayed a marked reduction in lipid droplet and cholesterol/cholesteryl ester accumulation in the adrenals, demonstrating the pivotal role of seipin in cholesteryl ester-rich lipid droplet accumulation/formation. Moreover, the reduction in cholesteryl ester-rich lipid droplets was associated with significant defects in adrenal and gonadal steroid hormone production that could not be completely reversed by addition of exogenous lipoprotein cholesterol. We conclude that seipin has a heretofore unappreciated role in intracellular cholesterol trafficking.
View details for DOI 10.1016/j.jlr.2022.100309
View details for PubMedID 36332685