HDL biogenesis. Mitochondrial cholesterol transport is rate limiting in the (sterol 27-hydroxylase-) dependent generation of oxysterol ligands for LXR (liver X receptor) transcription factors that regulate the expression of genes encoding proteins in the cholesterol efflux pathway, such as ABC transporters (ATP-binding cassette transporters) ABCA1, and ABCG1. These transporters transfer cholesterol and/or phospholipids across the plasma membrane to (apo) lipoprotein acceptors, generating nascent HDLs (high-density lipoproteins), which can safely transport excess cholesterol through the bloodstream to the liver for excretion in bile. Ligand activation of nuclear LXRs (liver X receptors) (LXRα/β) is pivotal in cellular response to elevated sterol content, triggering cholesterol efflux mechanisms: both synthetic and oxysterol LXR agonists potently upregulate ABCA1 and ABCG1 gene expression. Consequently, elimination of excess cholesterol can be achieved, in vivo and in vitro, by cellular cholesterol efflux, orchestrated by ABCA1, ABCG1, ABCG4, and passive diffusion along a concentration gradient, and also “acceptor” (apo) lipoproteins, such as apoA-I, and HDLs (high-density lipoproteins). Notably, LXRs form heterodimers with RXRs (retinoic acid receptors) and bound to the nuclear receptor.
