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    • br Mechanisms for regulation of intracellular cholesterol ho

    2023-02-01


    Mechanisms for regulation of intracellular cholesterol homeostasis Cells maintain intracellular free cholesterol levels and distribution within stringent tolerances by several mechanisms [55]: (1) uptake of native LDL (the major extracellular carrier of cholesterol) by LDL receptors and modified LDL (e.g. oxLDL) by scavenger receptors; (2) removal of excess intracellular cholesterol by efflux transporters ABCA1 and ABCG1 that function in the lipidation of plasma apolipoprotein acceptors to form high-density lipoprotein particles, HDL or “good cholesterol” and circulation to the liver for excretion in the bile [70]; (3) re-esterification of intracellular free cholesterol by ACAT and storage of the cholesteryl esters in cytoplasmic lipid droplets and (4) sequestration of free cholesterol in the LE/LY subcellular compartment. Due to its hydrophobic nature, very little cholesterol exists in aqueous compartments in cells and is primarily associated with lipid bilayers of membranes, consisting of phospholipids and sphingolipids or associated with sterol binding proteins. The plasma membrane and endocytic-recycling compartment (ERC) are key physiological histamine receptors that harbor most of the free cholesterol in cells [71]. Net expansion of the free cholesterol pools above a threshold level signals transport mechanisms that deliver free cholesterol to the ER for esterification by ACAT [72]. In fact, the steady-state level of free cholesterol in the plasma membrane is set primarily by the capacity of its association with phospholipids [73], [74]. Phospholipid headgroup and acyl chain composition are the primary determinants for the strength of phospholipid-cholesterol interaction in order of sphingomyelin (SM) > phosphatidylserine (PS) > phosphatidylcholine (PC) > phosphatidylethanolamine (PE) [75].
    Mechanisms of transport of cholesterol from LE/LY to ER cholesterol sensors Cholesterol traffics from the LE/LY to the ER by both non-vesicular and vesicular pathways [53], [54], [55]. Following the hydrolysis of cholesteryl esters contained in lipoproteins by the action of lipoprotein lipase in acidic endosomal compartments and release free cholesterol, it binds to the Niemann-Pick type C protein-2 (NPC2) within the aqueous compartment of the LE/LY lumen [76]. The cholesterol is directly transferred from NPC2 to the Niemann-Pick type C protein-1 (NPC1) protein and into the limiting membrane of the LE/LY. Members of the oxysterol-binding protein family, i.e. oxysterol-binding protein-related protein 1L/ORP1L, sense the cholesterol content in the LE/LY limiting membrane. The fate of cholesterol at this point moves from the LE/LY to intracellular compartments, e.g. from NPC1 compartments to the Trans-Golgi apparatus, by vesicular transport mechanisms involving the SNARE protein complex [53] or directly to the endoplasmic reticulum by non-vesicular transport mechanisms, involving the cholesterol sensor ORP1L [54] or ORP5 [77]. ORP1L functions in the reversible assembly of protein complexes including Rab-7 and RILP proteins that modulate LE/LY vesicle trafficking [54], [78]. ORP1L and NPC1 containing late-endosomes mediate cholesterol export to the ER [78]. Studies suggest that in the non-vesicular transport pathway, the oxysterol binding protein-related protein-5 (ORP5) binds to the LE/LY membrane, forming a membrane contact site (MCS) between the LE/LY and ER and mediates desorption of free-cholesterol from the limiting membrane of the LE/LY to the ER membrane. ORP5 can also physically interact with NPC1 to facilitate the transfer of cholesterol to the endoplasmic reticulum membrane [76], [77], [79]. ORP5 is tethered to the ER through its carboxy-terminal domain and binds to the LE/LY membrane by its pleckstrin homology domain (PH) to membrane phospholipids, perhaps phosphoinositide 4 phosphate (PI4P) [80]. ORP5 can bind cholesterol, PI4P and phosphatidylserine (PS) through its oxysterol binding protein related domain (ORD) and recent reports demonstrate that ORP5 can also function in PS/PI4P exchange at ER/plasma membrane MCS [81], [82]. Disassembly of the cholesterol transport protein complex of NPC1, ORP5 and perhaps other proteins may be mediated through the action of the AAA ATPase VPS4/SKD1 upon completion of cholesterol exchange [83].