Our data, followed by others, clearly support ACAT inhibition as a strategy for the treatment of AD

Our data, followed by others, clearly support ACAT inhibition as a strategy for the treatment of AD. and long-chain fatty acyl coenzyme A as substrates to convert FC into CE. Cholesteryl ester hydrolases (CEH) are responsible for the reverse reaction transforming CE into FC [34, 35]. ACAT and CEH take action in reverse directions to maintain the dynamic equilibrium between FC and CE. ACAT has been the focus of intense research as the enzyme responsible for the generation of CEs in atherosclerotic plaques. CEH function is likely performed by many enzymes, which have not yet been positively recognized in mammalian cells. FC is stored in membrane bilayers, whereas CEs are hydrophobic in nature and require a special environment to remain stable in aqueous cytoplasm. Lipid droplets surrounded by a phospholipid monolayer serve as a microdomain storing neutral lipids [36]. In addition to their storage function, evidence indicates that lipid droplets also carry proteins generally found on the plasma membrane. 1.1 RS-127445 Acyl-coenzyme A: cholesterol acyl-transferase (ACAT) and cholesteryl esters Two ACAT (or and or hypothesize that ACAT1 is involved in the synthesis of intracellular CE and ACAT2 functions by supplying the CE to LDL for lipoprotein assembly [51, 52]. RS-127445 To accomplish this, ACAT1 and ACAT2 would have different topologies in the ER, targeting CEs to cytoplasmic lipid droplets or to lipoprotein assembly in the lumenal side of ER, respectively. Both enzymes are ER-resident protein, spanning the ER five or seven occasions [53, 54]. Identification of the putative active site residues of ACAT1 and ACAT2 led to the conclusion that this amino acid requirement for ACAT activity may be different for the two enzymes [55, 56]. The putative RS-127445 active site of ACAT1 was located to the cytoplasmic side of the ER, whereas the active site of ACAT2 is located at the lumenal side of the ER [53]. The fact that ACAT1 and ACAT2 can functionally match each other [57] indicates that their membrane topologies are not fixed. While ACAT1 is an allosteric enzyme [48], its gene does not contain the sterol regulatory element (SRE) that is widely present within the promoter regions of many cholesterol-regulatory genes. Therefore, cholesterol may not directly regulate ACAT expression [58]. More interestingly, ACAT1 does not contain a sterol-sensing domain name (SSD) [59], which is the cholesterol binding motif found in almost all cholesterol regulating proteins. 1.2 Intracellular lipid droplets In most cell types, cytoplasmic lipid droplets are prevalently occupied by CEs. In adipocytes, however, triacylglycerides represent the main component of lipid droplets [60]. Adipocytes possess a unique morphology that allows for formation of large lipid droplets. These large droplets sometimes occupy almost the entire cell volume by pushing other intracellular compartments to the cell periphery [61]. Detailed studies on lipid RS-127445 droplet biogenesis and function in adipocytes are being conducted to understand how lipid droplets sequester extra CEs and triacylglycerides in metabolic diseases such as obesity, diabetes and atherosclerosis caused by genetic disorders or consumption of cholesterol-rich diet. CEs are generated in the cytoplasmic leaflet of the ER or between the two leaflets, before being pinched off into highly mobile cytoplasmic lipid droplets [62]. Apart from being a fundamental component of lipid homeostasis, lipid droplets RS-127445 also act as crucial organelles during development. Novel conversation of lipid droplets with microtubules is considered a crucial feature in developmentally regulated cellular positioning of [63]. Specific NGF proteins are found in and around the ER membrane domains adjacent to the proposed site of lipid droplets biogenesis. These proteins are part of the PAT family, consisting of perilipin, adipophilin and TIP47 (tail-interacting protein of 47 kDa) [64, 65]. A number of cellular proteins involved in vesicle trafficking, membrane fusion and cytoskeletal reorganization were found associated with the lipid droplets via direct or.