Abstract
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.
Highlights
CHOLESTEROL IN MEMBRANESCellular bilayer membranes are mostly composed of phospholipids arranged with their hydrophilic head groups facing the aqueous medium and their fatty acyl tails forming a hydrophobic membrane core
Steroid hormones are made from cholesterol, primarily derived from lipoproteins that enter cells via receptor-mediated endocytosis
These conserved StAR-related lipid transfer (START) domains of both MLN64 and steroidogenic acute regulatory protein (StAR) can bind cholesterol, but whereas StAR acts as a cholesterol transporter in mitochondria [144], MLN64 participates in cholesterol transport from endosomes to cytoplasmic acceptor(s) [131]
Summary
Cellular bilayer membranes are mostly composed of phospholipids arranged with their hydrophilic head groups facing the aqueous medium and their fatty acyl tails forming a hydrophobic membrane core. The polar lipids bind the cholesterol in the plasma membrane; cholesterol intercalated between the phospholipid molecules of the lipid membrane maintains membrane fluidity. Cholesterol in excess of the complexing capacity of the membrane lipids is the “active” cholesterol, which can move to intracellular membranes, restoring plasma membrane cholesterol to its resting level [11]. This cholesterol is sometimes referred to as “free” cholesterol; it is not “free” in the sense that it is in solution but only in the sense that it is accessible and moveable. The pool of “active” or “free” cholesterol can be distinguished kinetically, but not chemically, from the cholesterol tightly bound to the membrane [11]. As mitochondria have the capacity to synthesize the entire PE pool required for cell growth [15], the flux of PS into the mitochondria and its subsequent decarboxylation and export as PE can account for the biosynthesis of the majority of glycrophospholipids present in all cell membranes
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