Cellular cholesterol homeostasis

Effect of endocytosed cholesterol on cellular cholesterol homeostasis The chylomicron remnant-, IDL-, and LDL-derived cholesterol affects cellular cholesterol content in several ways (see Figure 18.20). First, HMG CoA reductase is inhibited by ttfi cholesterol, as a result of which, de novo cholesterol synthesis decreases. Second, synthesis of new LDL receptor protein is reduced by decreasing the expression of the LDL receptor gene, thus limiting further entry of LDL cholestrol into cells. [Note ... 

Bieberich E, Freischutz B, Suzuki M, Yu RK. Differential effects of glycolipid biosynthesis inhibitors on ceramide-induced cell death in neuroblastoma cells. J. Neurochem. 1999 72 1040-1049. Makino A, Ishii K, Murate M, Hayakawa T, et al. D-threo-1-Phenyl-2-decanoylamino-3-morpholino-l-propanol alters cellular cholesterol homeostasis by modulating the endosome lipid domains. Biochemistry 2006 45 4530-4541. 

Schmitz G, Becker A, Aslanidis C (1996) ACAT/CEH and ACEH/LAL two key enzymes in hepatic cellular cholesterol homeostasis and their involvement in genetic disorders. Z Gastroenterol 34(Suppl 3) 68-72... 

HDL is antiatherogenic and removes cholesterol from peripheral cells and tissues for eventual transport to hepatocytes and excretion in the bile directly or after conversion into bile acids. The efflux of cholesterol from peripheral cells is mediated by the ATP-binding cassette (ABC) transporter protein (discussed later). The flux of cholesterol transport from extrahepatic tissues (e.g., blood vessel wall) toward liver for excretion is known as the reverse cholesterol transport pathway. In contrast, the forward cholesterol pathway involves the transport of cholesterol from liver to the peripheral cells and tissues via the VLDL IDL LDL pathway. It should be noted, however, that the liver plays a major role in the removal of these lipoproteins. Thus, the system of reverse cholesterol transport consisting of LCAT, CETP, apo D, and their carrier lipoproteins is critical for maintaining cellular cholesterol homeostasis. The role of CETP is exemplified in clinical studies involving patients with polymorphic... 

LDL, the expression and activity of HMG-CoA reductase, the rate-controlling enzyme in cholesterol biosynthesis, is suppressed, whereas the activity of acyhcholesterol acyl transferase (ACAT), which converts cholesterol into the esterlfled storage form, is Increased. Conversely, when the cellular cholesterol level begins to fall as cells use more cholesterol, expression of the LDL receptor and HMG-CoA reductase increases and the activity of ACAT decreases. Such coordinate regulation is an efficient way for cells to maintain cellular cholesterol homeostasis. 

Cholesterol efflux is one mechanism that maintains cellular cholesterol homeostasis. An important regulator of cellular cholesterol efflux is the ATP-binding cassette receptor Al (ABCA-1). ABCA-1 is critical for the formation of plasma high-density lipoproteins (HDL) that are inversely related to cardiovascular disease risk (Schaefer et al., 1994). Two groups investigated the role of... 

In Tangier disease, a rare disorder with complete lack of HDL in the plasma associated with splenomegaly, enlarged tonsils, and lipid storage in the cells of the reticuloendothehal system but no elevated risk for atherosclerosis, the disturbances of cellular cholesterol homeostasis were studied in detail. In patients with Tangier disease there is a normal rate of Apo A-I synthesis, a normal primary structure of Apo A-I, normal conversion from pro-Apo A-I to mature Apo A-I, and normal association of Tangier Apo A-I with normal HDL, while HDL are completely absent and there is a decreased Apo A-I concentration (< 2% of normal). In these patients accelerated catabolism of HDL has been postulated. Our own experiments showed that Tangier patients may suffer from a disorder of intracellular transport of HDL or its precursors (Fig. 4). 

S. Yokoyama. 2000. Release of cellular cholesterol Molecular mechanism for cholesterol homeostasis in cells and in the body Biochim. Biophys. Acta 1529 231-244. (PubMed)... 

Other lines of evidence also support the notion that deregulated cholesterol homeostasis may contribute to the AD pathogenesis. AD patients have been reported to develop intracellular A/1 accumulation in the late endo-somes and lysosomes. Similar pathological features, including swollen late endosomes and A/ accumulation, have also been reported in Niemann-Pick type C disease patients [52,53], Npcl deficient mice as well as in mouse models of AD [54,55]. The Npcl gene product is essential for the mobihzation of cellular cholesterol. Excess cholesterol can be transported into endoplasmic reticulum and esterified by acyl co enzyme A cholesterol acyltransferase (ACAT) and stored in lipid droplets. Inhibition of ACAT activity has been reported to reduce A/3 levels in vitro and plaque pathology in animal models of AD [56,57]. 

ATP-binding cassette transporter ABCAl (member 1 of human transporter subfamily ABCA) ABCAl is a human protein and gene. This transporter is a major regulator of cellular cholesterol and phospholipids homeostasis. ABCAl functions as a cholesterol efflux pump in the cellular lipid removal pathway. 

Several sources of cellular cholesterol contribute to RCT. Part of the process of RCT reflects peripheral (extra-hepatic) cholesterol synthesis. Despite the down-regulation of cholesterol synthesis mediated by the LDL receptor via the delivery of LDL, a considerable amount of sterol is made in peripheral tissues. The importance of this source of cholesterol to homeostasis may be as great as that of dietary cholesterol in many individuals. After hydrolysis of LDL-CE by cellular cholesterol esterases, this cholesterol is made available for recycling to the cell surface and can be recovered there by apo A1 for incorporation into HDLs. Cholesterol is also available from VLDLs, LDLs, and chylomicrons directly internalized by peripheral cells. Cholesterol from HDLs bypasses the lysosomal pathway and becomes part of recycling endosomes that return to the cell surface. Some of the cholesterol recovered on HDLs originates from blood cells. Finally, some cholesterol is transferred directly to other lipoproteins from chylomicrons, VLDLs, and LDLs, without entering the cell. 

The LDL receptor is a key component in the feedback-regulated maintenance of cholesterol homeostasis [1]. In fact, as an active interface between extracellular and intracellular cholesterol pools, it is itself subject to regulation at the cellular level (Fig. 2). LDL-derived cholesterol (generated by hydrolysis of LDL-bome cholesteryl esters) and its intracellularly generated oxidized derivatives mediate a complex series of feedback control mechanisms that protect the cell from over-accumulation of cholesterol. First, (oxy)sterols suppress the activities of key enzymes that determine the rate of cellular cholesterol biosynthesis. Second, the cholesterol activates the cytoplasmic enzyme acyl-CoA cholesterol acyltransferase, which allows the cells to store excess cholesterol in re-esterified form. Third, the synthesis of new LDL receptors is suppressed, preventing further cellular entry of LDL and thus cholesterol overloading. The coordinated regulation of LDL receptors and cholesterol synthetic enzymes relies on the sterol-modulated proteolysis of a membrane-bound transcription factor, SREBP, as described in Chapter 14. 

More general information about the potential role of apoE in cellular lipoprotein uptake has come from studies with cultured cells (e.g., fibroblasts). Such cells manifest surface receptors for LDL that bind apoB, the protein component of LDL. This is followed by receptor-mediated endocytosis, fusion of the endo-cytic vesicles with lysosomes, and LDL degradation within the lysosomes (see Goldstein and Brown, 1979 Brown et al., 1981, for reviews and references). Cholesteryl esters taken into cells in this manner are hydrolyzed by a lysosomal acid lipase. The liberated cholesterol then leaves the lysosome and is used in the cell for membrane synthesis and as a regulator of intracellular cholesterol homeostasis. 

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