Topic
Sterol
About: Sterol is a research topic. Over the lifetime, 8117 publications have been published within this topic receiving 309926 citations. The topic is also known as: sterols & sterol lipids.
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TL;DR: Studies of the feedback regulation of cholesterol synthesis in animals have led to the identification of a unique family of membrane-bound transcription factors, sterol regulatory element binding proteins (SREBPs), in the presence of cholesterol.
Abstract: Studies of the feedback regulation of cholesterol synthesis in animals have led to the identification of a unique family of membrane-bound transcription factors, sterol regulatory element binding proteins (SREBPs) ([Brown and Goldstein, 1997][1]). In the presence of cholesterol, SREBPs are
173 citations
TL;DR: Synthetic oxysterol‐mimetic drugs that activate LXR receptors within the CNS may provide novel therapeutics for management of AD and other neurological afflictions characterized by deranged tissue cholesterol homeostasis.
Abstract: Aberrant cholesterol metabolism has been implicated in Alzheimer disease (AD) and other neurological disorders. Oxysterols and other cholesterol oxidation products are effective ligands of liver X activated receptor (LXR) nuclear receptors, major regulators of genes subserving cholesterol homeostasis. LXR receptors act as molecular sensors of cellular cholesterol concentrations and effectors of tissue cholesterol reduction. Following their interaction with oxysterols, activation of LXRs induces the expression of ATP-binding cassette, sub-family A member 1, a pivotal modulator of cholesterol efflux. The relative solubility of oxysterols facilitates lipid flux among brain compartments and egress across the blood-brain barrier. Oxysterol-mediated LXR activation induces local apoE biosynthesis (predominantly in astrocytes) further enhancing cholesterol re-distribution and removal. Activated LXRs invoke additional neuroprotective mechanisms, including induction of genes governing bile acid synthesis (sterol elimination pathway), apolipoprotein elaboration, and amyloid precursor protein processing. The latter translates into attenuated beta-amyloid production that may ameliorate amyloidogenic neurotoxicity in AD brain. Stress-induced up-regulation of the heme-degrading enzyme, heme oxygenase-1 in AD-affected astroglia may impact central lipid homeostasis by promoting the oxidation of cholesterol to a host of oxysterol intermediates. Synthetic oxysterol-mimetic drugs that activate LXR receptors within the CNS may provide novel therapeutics for management of AD and other neurological afflictions characterized by deranged tissue cholesterol homeostasis.
172 citations
TL;DR: These findings provide the first in vivo demonstration of a role for Abcg4 in sterol efflux in the brain and show that Abcgl and AbcG4 have overlapping functions in astrocytes, promoting efflux of cholesterol, desmosterol, and possibly other sterol biosynthetic intermediates to HDL.
Abstract: Transporters in the ABCG family appear to be involved in the cellular excretion of cholesterol and other sterols in a cell- and tissue-specific fashion. Overexpression of ATP-binding cassette transporters G1 (Abcg1) and G4 (Abcg4) can promote cellular cholesterol efflux to high-density lipoprotein (HDL), but the in vivo functions of Abcg4 are poorly understood. We used mice with knockouts of Abcg1 or Abcg4 singly or together to further elucidate the function of these transporters. Abcg1 and Abcg4 are highly expressed in the brain and are found in both astrocytes and neurons. Whereas Abcg1(-/-) or Abcg4(-/-) mice showed essentially normal levels of brain sterols, in Abcg1(-/-)/Abcg4(-/-) mice, levels of several sterol intermediates in the cholesterol biosynthetic pathway, namely desmosterol, lathosterol, and lanosterol, as well as 27-OH cholesterol, were increased 2- to 3-fold. Overexpression of Abcg1 or Abcg4 promoted efflux of desmosterol and cholesterol from cells to HDL, and combined deficiency of these transporters led to defective efflux and accumulation of these sterols in primary astrocytes. Consistent with defective efflux and sterol accumulation, cholesterol biosynthesis was reduced in Abcg1(-/-)/Abcg4(-/-) astrocytes. The accumulation of desmosterol, a known liver-X receptor (LXR) activator, was associated with increased expression of LXR target genes, including ATP-binding cassette transporter A1, and increased apolipoprotein E secretion in Abcg1(-/-)/Abcg4(-/-) astrocytes. Our findings provide the first in vivo demonstration of a role for Abcg4 in sterol efflux in the brain and show that Abcg1 and Abcg4 have overlapping functions in astrocytes, promoting efflux of cholesterol, desmosterol, and possibly other sterol biosynthetic intermediates to HDL.
171 citations
TL;DR: Results imply that ER stress-induced SREBP-2 activation occurs through the conventional pathway that normally regulates SRE BP in accordance with intracellular sterol concentration.
171 citations
TL;DR: It is clear from the studies reviewed here that small changes in the structure of sphingolipids alter their partitioning between lateral domains substantially, and one of the roles of cholesterol is apparently to modulate the fluidity of the sphingoipid domains and also to help segregate the domains for functional purposes.
171 citations