Steroid hormones are made from
cholesterol, primarily derived from
lipoproteins that enter cells via receptor-mediated endocytosis. In endo-lysosomes,
cholesterol is released from
cholesterol esters by
lysosomal acid lipase (LAL; disordered in
Wolman disease) and exported via Niemann-Pick type C (NPC)
proteins (disordered in NPC disease). These diseases are characterized by accumulated
cholesterol and
cholesterol esters in most cell types. Mechanisms for trans-cytoplasmic
cholesterol transport, membrane insertion, and retrieval from membranes are less clear.
Cholesterol esters and "free"
cholesterol are enzymatically interconverted in lipid droplets.
Cholesterol transport to the
cholesterol-poor outer mitochondrial membrane (OMM) appears to involve
cholesterol transport proteins.
Cytochrome P450scc (
CYP11A1) then initiates steroidogenesis by converting
cholesterol to
pregnenolone on the inner mitochondrial membrane (IMM). Acute steroidogenic responses are regulated by
cholesterol delivery from OMM to IMM, triggered by the
steroidogenic acute regulatory protein (StAR). Chronic steroidogenic capacity is determined by
CYP11A1 gene transcription. StAR mutations cause congenital lipoid adrenal
hyperplasia, with absent steroidogenesis, potentially lethal
salt loss, and 46,XY sex reversal. StAR mutations initially destroy most, but not all steroidogenesis; low levels of StAR-independent steroidogenesis are lost later due to cellular damage, explaining the clinical findings. Rare P450scc mutations cause a similar syndrome. This review addresses these early steps in
steroid biosynthesis.