The intracellular cholesterol pool in steroidogenic cells plays a role in basal steroidogenesis

Abstract

The framework of steroidogenesis across steroidogenic cells is constructed around cholesterol — the precursor substrate molecule for all steroid hormones — including its cellular uptake, storage in intracellular lipid droplets, mobilization upon steroidogenic stimulation, and finally, its transport to the mitochondria, where steroidogenesis begins. Thus, cholesterol and the mitochondria are highly interconnected in steroidogenic cells. Moreover, accruing evidence suggests that autophagy and mitochondrial dynamics are important cellular events in the regulation of trophic hormone-induced cholesterol homeostasis and steroidogenesis. However, a potential role of cholesterol in itself in the regulation of steroidogenic factors and events remain largely unexplored. We tested the hypothesis that cholesterol plays a role in the regulation of cell-intrinsic factors and events involving steroidogenesis. Here, we show that depleting the intracellular cholesterol pool in steroidogenic cells induces autophagy, affects mitochondrial dynamics, and upregulates steroidogenic factors and basal steroidogenesis in three different steroidogenic cell types producing different steroid hormones. Notably, the cholesterol insufficiency-induced changes in different steroidogenic cell types occur independent of pertinent hormone stimulation and work in a dynamic and temporal manner with or without hormonal stimulation. Such effects of cholesterol deprivation on autophagy and mitochondrial dynamics were not observed in the non-steroidogenic cells, indicating that cholesterol insufficiency-induced changes in steroidogenic cells are specific to steroidogenesis. Thus, our data suggests a role of cholesterol in steroidogenesis beyond being a mere substrate for steroid hormones. The implications of our findings are broad and offer new insights into trophic hormone-dependent and hormone-independent steroidogenesis during development, as well as in health and disease.