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evolution
along with acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), ACAT1 and ACAT2 are founding members of the membrane-bound O-acyltransferase (MBOAT) enzyme family. MBOATs are multispan membrane enzymes that use long-chain or medium-chain fatty acyl-CoA as the first substrate, and catalyze the transfer of the fatty acyl group to the 3beta-hydroxyl moiety of a certain hydrophobic substance as the second substrate. An MBOAT contains two active sites: a histidine within a long hydrophobic peptide region, and an asparagine located within a long hydrophilic peptide region
evolution
along with acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), ACAT1 and ACAT2 are founding members of the membrane-bound O-acyltransferase (MBOAT) enzyme family. MBOATs are multispan membrane enzymes that use long-chain or medium-chain fatty acyl-CoA as the first substrate, and catalyze the transfer of the fatty acyl group to the 3beta-hydroxyl moiety of a certain hydrophobic substance as the second substrate. An MBOAT contains two active sites: a histidine within a long hydrophobic peptide region, and an asparagine located within a long hydrophilic peptide region
malfunction
mice lacking ACAT1 or ACAT2 do not have a decreased PREG ester contents in adrenals, nor do they have altered levels of the three major secreted adrenal steroids in serum
malfunction
mice lacking ACAT1 or ACAT2 do not have a decreased pregnenolone ester contents in adrenals, nor do they have altered levels of the three major secreted adrenal steroids in serum
malfunction
ACAT1 deficiency significantly increases free cholesterol levels in hepatic stellate cells, augmenting Toll-like receptor 4, TLR4, protein and downregulating expression of transforming growth factor-beta (TGFbeta) pseudoreceptor Bambi (bone morphogenetic protein and activin membrane-bound inhibitor), leading to sensitization of hepatic stellate cells to TGFbeta activation. Exacerbation of liver fibrosis by ACAT1 deficiency is dependent on free cholesterol accumulation-induced enhancement of TLR4 signaling, effects of ACAT1 deficiency on induced liver fibrosis, overview. ACAT1 deficiency does not affect hepatocellular damage
malfunction
ACAT1 deficiency significantly increases free cholesterol levels in hepatic stellate cells, augmenting Toll-like receptor 4, TLR4, protein and downregulating expression of transforming growth factor-beta (TGFbeta) pseudoreceptor Bambi (bone morphogenetic protein and activin membrane-bound inhibitor), leading to sensitization of hepatic stellate cells to TGFbeta activation. Exacerbation of liver fibrosis by ACAT1 deficiency is dependent on free cholesterol accumulation-induced enhancement of TLR4 signaling. ACAT1 deficiency does not affect hepatic ACAT2 expression, effects of ACAT1 deficiency on induced liver fibrosis, overview
malfunction
aortic atherosclerosis development is significantly lower in all mice with global or tissue-restricted SOAT2 gene deletions. Nevertheless, liver-specific and complete SOAT2-/-LDLr-/- knockout mice have less aortic cholesterol esters accumulation and smaller aortic lesions than intestine-specific SOAT2SI-/SI-LDLr-/- mice
malfunction
blocking ACAT enzyme activity with ACAT inhibitors, or with genetic ablation of ACAT1, significantly increases macrophage apoptosis
malfunction
blocking ACAT enzyme activity with ACAT inhibitors, or with genetic ablation of ACAT1, significantly increases macrophage apoptosis
malfunction
genetic deficiency, antisense oligonucleotide, or small molecule inhibitors of enzyme SOAT2 can effectively reduce atherosclerotic cardiovascular disease progression, and even promote regression of established cardiovascular disease, also causing compensatory upregulation of ABCA1 in the liver of mice. SOAT2 inhibition can also stabilize highly advanced plaques when given in the late phases of atherosclerosis progression. The ability of SOAT2 inhibitors to protect against atherosclerosis can be in part attributed to decreased intestinal cholesterol absorption, reduced hepatic very low density lipoprotein, and blunted retention of low density lipoprotein in the artery wall. Either chronic or acute inhibition of SOAT2 promotes a non-biliary pathway of reverse cholesterol transport called transintestinal cholesterol excretion. Intestine or liver specific deletion of SOAT2 is not sufficient to enhance LXR-stimulated fecal neutral sterol loss, and SOAT2 only modestly alters XR-driven reorganization of cholesterol-sensitive gene expression in the liver and small intestine
malfunction
mice lacking sterol O-acyltransferase 2 have less hepatic cholesterol entrapment and improved liver function. mRNA expression levels for several markers of inflammation are all significantly lower in mutants lacking sterol O-acyltransferase 2
malfunction
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ACAT1 deficiency significantly increases free cholesterol levels in hepatic stellate cells, augmenting Toll-like receptor 4, TLR4, protein and downregulating expression of transforming growth factor-beta (TGFbeta) pseudoreceptor Bambi (bone morphogenetic protein and activin membrane-bound inhibitor), leading to sensitization of hepatic stellate cells to TGFbeta activation. Exacerbation of liver fibrosis by ACAT1 deficiency is dependent on free cholesterol accumulation-induced enhancement of TLR4 signaling, effects of ACAT1 deficiency on induced liver fibrosis, overview. ACAT1 deficiency does not affect hepatocellular damage
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metabolism
the enzyme converts cholesterol to cholesteryl esters and plays key roles in the regulation of cellular cholesterol homeostasis. It metabolizes diverse substrates including both sterols and certain steroids, and it contains two different binding sites for steroidal molecules
metabolism
the enzyme converts cholesterol to cholesteryl esters and plays key roles in the regulation of cellular cholesterol homeostasis. It metabolizes diverse substrates including both sterols and certain steroids, and it contains two different binding sites for steroidal molecules
metabolism
the enzyme plays a major role in the cholesterol ester cycle, and has a potential role as a regulator of reverse cholesterol transport (RCT) called transintestinal cholesterol excretion. Combination of SOAT2 inhibition with LXR agonist treatment results in a marked negative cholesterol balance. SOAT2's key role in promoting intestinal cholesterol absorption and suppressing the non-biliary TICE pathway are both likely contributing mechanisms underlying SOAT2's ability to oppose LXR-stimulated fecal cholesterol disposal
physiological function
a key event for the transformation of macrophages in foam cells is the activation of ACAT1 leading to an increased uptake of modified low-density lipoprotein, accumulation of cholesteryl esters, and decreased cholesterol efflux to high-density lipoprotein
physiological function
a major function of ACATs is to protect against the unnecessary built up of free cholesterol within the cell membranes. ACAT1 may be involved in negatively regulating steroidogenesis in human adrenal cells. Both ACAT1 and ACAT2 can control the oxysterol levels by directly esterifying them, in a cell-type specific manner. ACAT can also control oxysterol levels by altering the cholesterol pool from which oxysterols are derived
physiological function
a major function of ACATs is to protect against the unnecessary built up of free cholesterol within the cell membranes. Both ACAT1 and ACAT2 can control the oxysterol levels by directly esterifying them, in a cell-type specific manner. ACAT can also control oxysterol levels by altering the cholesterol pool from which oxysterols are derived
physiological function
a major function of ACATs is to protect against the unnecessary built up of free cholesterol within the cell membranes. In intestines, ACAT2 provides cholesteryl esters for lipoprotein assemblies. Both ACAT1 and ACAT2 can control the oxysterol levels by directly esterifying them, in a cell-type specific manner. ACAT can also control oxysterol levels by altering the cholesterol pool from which oxysterols are derived
physiological function
a major function of ACATs is to protect against the unnecessary built up of free cholesterol within the cell membranes. In intestines, ACAT2 provides cholesteryl esters for lipoprotein assemblies. Both ACAT1 and ACAT2 can control the oxysterol levels by directly esterifying them, in a cell-type specific manner. ACAT can also control oxysterol levels by altering the cholesterol pool from which oxysterols are derived
physiological function
acyl-CoA:cholesterol acyltransferase 1 mediates liver fibrosis by regulating free cholesterol accumulation in hepatic stellate cells, role of ACAT1 in the pathogenesis of liver fibrosis, overview
physiological function
acyl-CoA:cholesterol acyltransferase 1 mediates liver fibrosis by regulating free cholesterol accumulation in hepatic stellate cells, role of ACAT1 in the pathogenesis of liver fibrosis, overview
physiological function
cholesterol esters, especially cholesterol oleate, generated by hepatic and intestinal sterol O-acyltransferase 2 (SOAT2) play a critical role in cholesterol homeostasis. SOAT2-derived cholesterol esters from both the intestine and liver significantly contribute to the development of atherosclerosis, although the cholesterol esters from the hepatic enzyme appear to promote more atherosclerosis development. Intestinal SOAT2, but not liver SOAT2, is a critical determinant of cholesterol absorption and of biliary cholesterol levels
physiological function
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isozyme ACAT2 is responsible for absorption of dietary cholesterol from the intestine and lipoprotein production by the liver, the steryl esters catalyzed by ACAT2 can incorporate into both intracellular lipid droplets and extracellular lipoproteins
physiological function
sterol O-acyltransferase 2-driven cholesterol esterification can alter both the packaging and retention of atherogenic apoB-containing lipoproteins and opposes liver X receptor-stimulated fecal neutral sterol loss. Enzyme SOAT2-driven cholesterol esterification interplays with fecal cholesterol disposal and high density lipoprotein metabolism. Potential role for SOAT2 as a regulator of reverse cholesterol transport (RCT) called transintestinal cholesterol excretion
physiological function
the enzyme plays a critical role in the formation of cholesteryl esters from cholesterol and fatty acids
physiological function
ACAT1/2 overexpression partially inhibits the differentiation of 3T3-L1 preadipocytes. In mature adipocytes, increased ACAT activity reduces the size of lipid droplets and inhibits lipolysis and insulin signaling. The amount of free cholesterol increases on the surface of lipid droplets in ACAT1/2-overexpressing adipocytes, accompanied by increased lipid droplet localization of caveolin-1. Cholesterol depletion in adipocytes induces changes in cholesterol distribution that are similar to those caused by ACAT1/2 overexpression
physiological function
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SOAT1 activity is attenuated by miRNAs gga-miR-181a-5pand gga-miR-429-3p through directly inhibiting TGFBR1 in the TGFbeta signaling pathway
physiological function
zebrafish embryos injected with pyripyropene A or morpholino oligo against SOAT2 in the yolk show significantly larger yolk when compared with wild-type embryos. Overexpression of SOAT2 increases the intracellular lipid droplets
physiological function
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acyl-CoA:cholesterol acyltransferase 1 mediates liver fibrosis by regulating free cholesterol accumulation in hepatic stellate cells, role of ACAT1 in the pathogenesis of liver fibrosis, overview
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additional information
no significant change in the amount of ACAT1 mRNA when the cells are treated with apolipoprotein AI and its lysine deletion variants with respect to control. The treatment of murine macrophages with apolipoprotein A-I mutant DELTAK107, i.e. apoA-I Helsinki, produces an increment of more than ten folds in the ACAT1 cellular level detected by western-blotting with a specific antibody. This effect is specific for the variant with the lysine deletion at the central region, since it is not produced by the lysine deletion at the C-terminus (DELTAK226) or the wild-type apoA-I. ACAT1 protein accumulation evoked by DELTAK107 in RAW cells is independent of cholesterol-loading conditions. ACAT1 protein accumulation is not accompanied by an enhanced mRNA level, but it is due to an increased translation rate or to a decreased protein degradation rate
additional information
two human ACAT2 gene polymorphisms have significant effects on 41A-G (Glu14Gly, rs9658625) and 734C-T (Thr254Ile, rs2272296), on plasma lipid levels and coronary artery disease susceptibility
additional information
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two human ACAT2 gene polymorphisms have significant effects on 41A-G (Glu14Gly, rs9658625) and 734C-T (Thr254Ile, rs2272296), on plasma lipid levels and coronary artery disease susceptibility