Figure 5.

Cellular model of steroidogenesis and LCAH. Low and high density lipoproteins (LDL and HDL) are captured by receptors on the cell membrane. Initial metabolism of LDL lipids occurs in the lysosome where cholesteryl esters are hydrolyzed by acidic cholesteryl ester hydrolases (acidic CEH). The resulting free cholesterol (Ch) is re-esterified by the cytosolic acyl-CoA:cholesterol acyltransferase (ACAT) and stored in lipid droplets. Cholesterol can also be synthesized de novo in the endoplasmic reticulum. In the resting cell, cholesterol is constantly hydrolyzed/re-esterified by neutral CEH and ACAT. With the help of lipid transporters, free cholesterol can be conveyed at the OMM. Then cholesterol present at the OMM can be transferred to the IMM for conversion to pregnenolone without STARD1. This low capacity system may explain the basal level of hormone production (10–13%) for homeostasis. Following an acute event (stress, dehydration, puberty, etc.), tropic hormones stimulate steroidogenic cells and activate PKA, which in turn leads to three actions: The activation of the hormone-sensitive lipase (HSL) which releases cholesterol from lipid droplets, the de novo synthesis of STARD1, and the formation of a multiprotein complex (MPC) somehow involved in the transfer of cholesterol to the IMM (Liu et al., 2006; Bose et al., 2008a). Then STARD1 may act as a high capacity system by catalyzing the delivery of cholesterol to the OMM and the MPC complex for its transfer to P450scc in response to the acute demand for steroid hormones. In the case of LCAH, the STARD1 high capacity system is impaired cannot support the substantial throughput of cholesterol, and the latter accumulates in the cytosol; lipid droplets become engorged with cholesterol. As lipid droplets accumulate, the cell becomes less functional and LCAH is onset.