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Information on EC 2.3.1.26 - sterol O-acyltransferase and Organism(s) Mus musculus and UniProt Accession Q61263
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2.3.1.26 sterol O-acyltransferaseIUBMB Comments
The enzyme catalyses the formation of sterol esters from a sterol and long-chain fatty acyl-coenzyme A. The enzyme from yeast, but not from mammals, prefers monounsaturated acyl-CoA. In mammals the enzyme acts mainly on cholesterol and forms cholesterol esters that are stored in cytosolic droplets, which may serve to protect cells from the toxicity of free cholesterol. In macrophages, the accumulation of cytosolic droplets of cholesterol esters results in the formation of `foam cells', a hallmark of early atherosclerotic lesions. In hepatocytes and enterocytes, cholesterol esters can be incorporated into apolipoprotein B-containing lipoproteins for secretion from the cell.
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- 2.3.1.26
- keratinocytes
- lipoprotein
-
immortalize
- tnf
- dermal
- esterification
- psoriasis
-
esterify
- erk
- mapks
- chemokine
- collagen
-
atopic
-
uvb-induced
- nanoparticles
- atherosclerosis
- keratin
-
cosmetic
- dermatitis
- caspase-3
- drug development
-
radiation-induced
-
photoaging
-
macrophage-derived
- cox-2
- filaggrin
-
7alpha-hydroxylase
- hairless
-
sunscreen
- nutrition
-
scratch
- pharmacology
- sunburn
-
antiatherosclerotic
- phototoxicity
-
hypocholesterolemic
-
foam
- hmg-coa
-
photoprotective
-
desmogleins
-
dermatology
-
keratinocyte-derived
-
ad-like
-
suprabasal
- medicine
-
cholesterol-fed
-
hyperproliferation
-
transdermal
- mmp-1
- analysis
- imiquimod
-
uvb-irradiated
- involucrin
-
cyclobutane
-
re-epithelialization
The taxonomic range for the selected organisms is: Mus musculus
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
hacat, acat1, acat2, acyl-coa:cholesterol acyltransferase, acat-1, acyl-coa cholesterol acyltransferase, soat1, cholesterol acyltransferase, acyl-coenzyme a:cholesterol acyltransferase, acat-2, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
ACAT
acyl coenzyme A-cholesterol-O-acyltransferase
-
-
-
-
acyl-CoA:cholesterol acyltransferase
acylcoenzyme A:cholesterol O-acyltransferase
-
-
-
-
acyltransferase, cholesterol
-
-
-
-
cholesterol acyltransferase
-
-
-
-
cholesterol ester synthase
-
-
-
-
cholesterol ester synthetase
-
-
-
-
cholesteryl ester synthetase
-
-
-
-
sterol-ester synthase
-
-
-
-
sterol-ester synthetase
-
-
-
-
ACAT
-
-
-
-
acyl-CoA:cholesterol acyltransferase
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Acyl group transfer
Acyl group transfer
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
long-chain acyl-CoA:sterol O-acyltransferase
The enzyme catalyses the formation of sterol esters from a sterol and long-chain fatty acyl-coenzyme A. The enzyme from yeast, but not from mammals, prefers monounsaturated acyl-CoA. In mammals the enzyme acts mainly on cholesterol and forms cholesterol esters that are stored in cytosolic droplets, which may serve to protect cells from the toxicity of free cholesterol. In macrophages, the accumulation of cytosolic droplets of cholesterol esters results in the formation of `foam cells', a hallmark of early atherosclerotic lesions. In hepatocytes and enterocytes, cholesterol esters can be incorporated into apolipoprotein B-containing lipoproteins for secretion from the cell.
CAS REGISTRY NUMBER
COMMENTARY
9027-63-8
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
acyl-CoA + cholesterol
CoA + cholesterol ester
cholesterol is the preferred acceptor substrate, and for ACAT1, the preferred fatty acyl-CoA is oleoyl coenzyme A
-
-
?
oleoyl-CoA + cholesterol
CoA + cholesteryl oleate
cholesterol is the preferred acceptor substrate, and for ACAT1, the preferred fatty acyl-CoA is oleoyl coenzyme A
-
-
?
acyl-CoA + cholesterol
CoA + cholesterol ester
cholesterol is the preferred acceptor substrate
-
-
?
long-chain fatty acyl-CoA + cholesterol
CoA + cholesteryl long-chain fatty acyl ester
-
-
-
?
long-chain fatty acyl-CoA + cholesterol
CoA + cholesteryl long-chain fatty acyl ester
-
may play an important role in regulation of the accumulation of cholesterol esters within smooth muscle cells of the artery wall during atherogenesis and in synthesis of cholesterol esters during hepatic very low-density lipoprotein synthesis and secretion
-
?
long-chain fatty acyl-CoA + cholesterol
CoA + cholesteryl long-chain fatty acyl ester
-
responsible for cellular synthesis of cholesterol esters in various cell types
-
?
additional information
?
-
the enzyme contains two different binding sites for steroidal molecules. In addition to cholesterol, other sterols that possess the 3-beta OH at C-3, including pregnenolone, oxysterols such as 24(S)-hydroxycholesterol and 27-hydroxycholesterol, etc., and various plant sterols, can all be ACAT substrates. Pregnenolone can only be an ACAT substrate because it lacks the iso-octyl side chain required to be an ACAT activator. The unnatural cholesterol analogs epi-cholesterol (with 3-alpha OH in steroid ring B) and ent-cholesterol (the mirror image of cholesterol) contain the iso-octyl side chain but do not have the 3-beta OH at C-3. Thus, they can only serve as activators and cannot serve as substrates
-
-
?
additional information
?
-
the enzyme contains two different binding sites for steroidal molecules. In addition to cholesterol, other sterols that possess the 3-beta OH at C-3, including pregnenolone, oxysterols such as 24(S)-hydroxycholesterol and 27-hydroxycholesterol, etc., and various plant sterols, can all be ACAT substrates. Pregnenolone can only be an ACAT substrate because it lacks the iso-octyl side chain required to be an ACAT activator. The unnatural cholesterol analogs epi-cholesterol (with 3-alpha OH in steroid ring B) and ent-cholesterol (the mirror image of cholesterol) contain the iso-octyl side chain but do not have the 3-beta OH at C-3. Thus, they can only serve as activators and cannot serve as substrates
-
-
?
additional information
?
-
hepatic ACAT2 plays a critical role in driving the production of atherogenic lipoproteins
-
-
?
additional information
?
-
the enzyme contains two different binding sites for steroidal molecules. In addition to cholesterol, other sterols that possess the 3-beta OH at C-3, including pregnenolone, oxysterols such as 24(S)-hydroxycholesterol and 27-hydroxycholesterol, etc., and various plant sterols, can all be ACAT substrates. Pregnenolone can only be an ACAT substrate because it lacks the iso-octyl side chain required to be an ACAT activator. The unnatural cholesterol analogs epi-cholesterol (with 3-alpha OH in steroid ring B) and ent-cholesterol (the mirror image of cholesterol) contain the iso-octyl side chain but do not have the 3-beta OH at C-3. Thus, they can only serve as activators and cannot serve as substrates
-
-
?
additional information
?
-
the enzyme contains two different binding sites for steroidal molecules. In addition to cholesterol, other sterols that possess the 3-beta OH at C-3, including pregnenolone, oxysterols such as 24(S)-hydroxycholesterol and 27-hydroxycholesterol, etc., and various plant sterols, can all be ACAT substrates. Pregnenolone can only be an ACAT substrate because it lacks the iso-octyl side chain required to be an ACAT activator. The unnatural cholesterol analogs epi-cholesterol (with 3-alpha OH in steroid ring B) and ent-cholesterol (the mirror image of cholesterol) contain the iso-octyl side chain but do not have the 3-beta OH at C-3. Thus, they can only serve as activators and cannot serve as substrates
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
long-chain fatty acyl-CoA + cholesterol
CoA + cholesteryl long-chain fatty acyl ester
-
-
-
?
long-chain fatty acyl-CoA + cholesterol
CoA + cholesteryl long-chain fatty acyl ester
-
may play an important role in regulation of the accumulation of cholesterol esters within smooth muscle cells of the artery wall during atherogenesis and in synthesis of cholesterol esters during hepatic very low-density lipoprotein synthesis and secretion
-
?
long-chain fatty acyl-CoA + cholesterol
CoA + cholesteryl long-chain fatty acyl ester
-
responsible for cellular synthesis of cholesterol esters in various cell types
-
?
additional information
?
-
the enzyme contains two different binding sites for steroidal molecules. In addition to cholesterol, other sterols that possess the 3-beta OH at C-3, including pregnenolone, oxysterols such as 24(S)-hydroxycholesterol and 27-hydroxycholesterol, etc., and various plant sterols, can all be ACAT substrates. Pregnenolone can only be an ACAT substrate because it lacks the iso-octyl side chain required to be an ACAT activator. The unnatural cholesterol analogs epi-cholesterol (with 3-alpha OH in steroid ring B) and ent-cholesterol (the mirror image of cholesterol) contain the iso-octyl side chain but do not have the 3-beta OH at C-3. Thus, they can only serve as activators and cannot serve as substrates
-
-
?
additional information
?
-
the enzyme contains two different binding sites for steroidal molecules. In addition to cholesterol, other sterols that possess the 3-beta OH at C-3, including pregnenolone, oxysterols such as 24(S)-hydroxycholesterol and 27-hydroxycholesterol, etc., and various plant sterols, can all be ACAT substrates. Pregnenolone can only be an ACAT substrate because it lacks the iso-octyl side chain required to be an ACAT activator. The unnatural cholesterol analogs epi-cholesterol (with 3-alpha OH in steroid ring B) and ent-cholesterol (the mirror image of cholesterol) contain the iso-octyl side chain but do not have the 3-beta OH at C-3. Thus, they can only serve as activators and cannot serve as substrates
-
-
?
additional information
?
-
hepatic ACAT2 plays a critical role in driving the production of atherogenic lipoproteins
-
-
?
additional information
?
-
the enzyme contains two different binding sites for steroidal molecules. In addition to cholesterol, other sterols that possess the 3-beta OH at C-3, including pregnenolone, oxysterols such as 24(S)-hydroxycholesterol and 27-hydroxycholesterol, etc., and various plant sterols, can all be ACAT substrates. Pregnenolone can only be an ACAT substrate because it lacks the iso-octyl side chain required to be an ACAT activator. The unnatural cholesterol analogs epi-cholesterol (with 3-alpha OH in steroid ring B) and ent-cholesterol (the mirror image of cholesterol) contain the iso-octyl side chain but do not have the 3-beta OH at C-3. Thus, they can only serve as activators and cannot serve as substrates
-
-
?
additional information
?
-
the enzyme contains two different binding sites for steroidal molecules. In addition to cholesterol, other sterols that possess the 3-beta OH at C-3, including pregnenolone, oxysterols such as 24(S)-hydroxycholesterol and 27-hydroxycholesterol, etc., and various plant sterols, can all be ACAT substrates. Pregnenolone can only be an ACAT substrate because it lacks the iso-octyl side chain required to be an ACAT activator. The unnatural cholesterol analogs epi-cholesterol (with 3-alpha OH in steroid ring B) and ent-cholesterol (the mirror image of cholesterol) contain the iso-octyl side chain but do not have the 3-beta OH at C-3. Thus, they can only serve as activators and cannot serve as substrates
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
K-604
selective for isoform ACAT-1, use to measure the individual enzymatic activities of isoforms ACAT-1 and ACAT-2
AM-251
-
selective antagonist of cannobinoid receptor CB1. Additionally, reatment of cells reduces cholesteryl ester synthesis in unstimulated and acetylated low densitixy lipoprotein-stimulated Raw 264.7 macrophages, CB2 +/+ and CB2-/- peritoneal macrophages, as well as in vitro, in mouse liver microsomes. Consistent with inhibition of ACAT, the development of foam cell characteristics in macrophages by treatment with acetylated low density lipoprotein is reduced
K-604
selective for isoform ACAT-1, use to measure the individual enzymatic activities of isoforms ACAT-1 and ACAT-2
SR144528
-
selective antagonist of cannobinoid receptor CB1. Additionally, reatment of cells reduces cholesteryl ester synthesis in unstimulated and acetylated low densitixy lipoprotein-stimulated Raw 264.7 macrophages, CB2 +/+ and CB2-/- peritoneal macrophages, as well as in vitro, in mouse liver microsomes. Consistent with inhibition of ACAT, the development of foam cell characteristics in macrophages by treatment with acetylated low density lipoprotein is reduced
additional information
-
poly(ADP-ribose) polymerase inhibition in foam cells resulted in significant sensitization to 7-ketocholesterol by increasing cellular-toxic-free cholesterol, potentially through a down-regulation of ACAT-1 expression
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
enzyme ACAT1 can be activated by a variety of sterols. All sterols that possess the iso-octyl side chain including cholesterol, oxysterols, various plant sterols can all be activators of ACAT. Pregnenolone can only be an ACAT substrate because it lacks the iso-octyl side chain required to be an ACAT activator. The unnatural cholesterol analogs epi-cholesterol (with 3-alpha OH in steroid ring B) and ent-cholesterol (the mirror image of cholesterol) contain the iso-octyl side chain but do not have the 3-beta OH at C-3. Thus, they can only serve as activators and cannot serve as substrates
-
additional information
enzyme ACAT1 can be activated by a variety of sterols. All sterols that possess the iso-octyl side chain including cholesterol, oxysterols, various plant sterols can all be activators of ACAT. Pregnenolone can only be an ACAT substrate because it lacks the iso-octyl side chain required to be an ACAT activator. The unnatural cholesterol analogs epi-cholesterol (with 3-alpha OH in steroid ring B) and ent-cholesterol (the mirror image of cholesterol) contain the iso-octyl side chain but do not have the 3-beta OH at C-3. Thus, they can only serve as activators and cannot serve as substrates
-
additional information
enzyme ACAT1 can be activated by a variety of sterols. All sterols that possess the iso-octyl side chain including cholesterol, oxysterols, various plant sterols can all be activators of ACAT. Pregnenolone can only be an ACAT substrate because it lacks the iso-octyl side chain required to be an ACAT activator. The unnatural cholesterol analogs epi-cholesterol (with 3-alpha OH in steroid ring B) and ent-cholesterol (the mirror image of cholesterol) contain the iso-octyl side chain but do not have the 3-beta OH at C-3. Thus, they can only serve as activators and cannot serve as substrates
-
additional information
enzyme ACAT1 can be activated by a variety of sterols. All sterols that possess the iso-octyl side chain including cholesterol, oxysterols, various plant sterols can all be activators of ACAT. Pregnenolone can only be an ACAT substrate because it lacks the iso-octyl side chain required to be an ACAT activator. The unnatural cholesterol analogs epi-cholesterol (with 3-alpha OH in steroid ring B) and ent-cholesterol (the mirror image of cholesterol) contain the iso-octyl side chain but do not have the 3-beta OH at C-3. Thus, they can only serve as activators and cannot serve as substrates
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
ACAT1 is an allosteric enzyme, modeling, overview
-
additional information
additional information
ACAT1 is an allosteric enzyme, modeling, overview
-
additional information
additional information
ACAT2 is an allosteric enzyme, modeling, overview
-
additional information
additional information
ACAT2 is an allosteric enzyme, modeling, overview
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.000144
additional information
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
ACAT1 expression is significantly increased in the adipose tissue of ob/ob mice
hepatic ACAT2 plays a critical role in driving the production of atherogenic lipoproteins
-
loss of ACAT activity in macrophages, either by pharmacological inhibition or by genetic knockout of ACAT-1, results in reduced induction of apoptosis in response to 7-ketocholesterol or oxidized low density lipoproteins. The apoptotic signal generated in macrophages by ACAT may be an arachidonyl oxysterol
additional information
effect of an atherogenic diet upon hepatic and intestinal enzyme mRNA expression and on enzyme mRNA expression in aorta and peritoneal macrophages. Enzyme activity in the liver is regulated at least in part by enzyme mRNA abundance
additional information
-
effect of an atherogenic diet upon hepatic and intestinal enzyme mRNA expression and on enzyme mRNA expression in aorta and peritoneal macrophages. Enzyme activity in the liver is regulated at least in part by enzyme mRNA abundance
additional information
ACAT1 is the major isozyme in mouse primary hepatic stellate cells, and ACAT2 is the major isozyme in mouse primary hepatocytes and Kupffer cells
additional information
ACAT1 is ubiquitously expressed in essentially all tissues examined
additional information
ACAT1 is ubiquitously expressed in essentially all tissues examined
additional information
ACAT2 is mainly expressed in the intestines and hepatocytes. It is also expressed in various other tissues, but at much lower levels than ACAT1
additional information
ACAT2 is mainly expressed in the intestines and hepatocytes. It is also expressed in various other tissues, but at much lower levels than ACAT1
additional information
tissue-specific expression and physiological function of the isozyme SOAT2
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
ACAT1 is a resident enzyme at the endoplasmic reticulum
-
approximately 10-15% of the enzyme in freshly harvested, non-attached macrophages is exposed to the extracellular space
additional information
additional information
ACAT1 is in a position to esterify cholesterol and various cholesterol metabolites (i.e., oxysterols, pregnenolone etc.) traversing through the mitochondria and endoplasmic reticulum membranes
-
additional information
ACAT1 is in a position to esterify cholesterol and various cholesterol metabolites (i.e., oxysterols, pregnenolone etc.) traversing through the mitochondria and endoplasmic reticulum membranes
-
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
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
physiological function
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
metabolism
physiological function
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
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
blocking ACAT enzyme activity with ACAT inhibitors, or with genetic ablation of ACAT1, significantly increases macrophage apoptosis
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. 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
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
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
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
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 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
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
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
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
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). SOAT1_MOUSE
540
8
63799
Swiss-Prot
other Location (Reliability: 2)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
two potential N-glycosylation sites close to the C-terminal end of the polypeptide identified
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
generation of tissue-specific SOAT2 knockouts in liver and small intestine, i.e. SOAT2L-/L- and SOAT2SI-/SI- mice, phenotypes, overview. Floxed mice (LoxP sites flanked exons 11 through 13 of the SOAT2 gene on chromosome 15) are designated as SOAT2fl/fl. SOAT2 wild-type control mice (SOAT2+/+LDLr?/?) and SOAT2 floxed mice (SOAT2fl/flLDLr?/?) have similar levels of cholesterol absorption. SOAT2 total body knockout mice (SOAT2?/?LDLr?/?) and intestinal SOAT2 knockout mice (SOAT2SI?/SI?LDLr?/?) have significantly decreased levels of cholesterol absorption, overview. SOAT2 knockout mice have lower plasma VLDL and LDL cholesterol concentrations
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene ACAT1, in mouse the Acat1 gene is located solely on chromosome 1 and contains 17 exons
RENATURED/Commentary
ORGANISM
UNIPROT
LITERATURE
solubilization of enzyme activity from Ehrlich ascites cells, the solubilized activity can be reconstituted as a liposome complex after the detergent is removed
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
analysis
use of inhibitor K-604, selective for isoform ACAT-1, to measure the individual enzymatic activities of isoforms ACAT-1 and ACAT-2 in semniferous tubule
drug development
regulation of ACAT1 activities in hepatic stellate cells can be a target for treatment of liver fibrosis
analysis
use of inhibitor K-604, selective for isoform ACAT-1, to measure the individual enzymatic activities of isoforms ACAT-1 and ACAT-2 in semniferous tubule
drug development
selective inhibitors of the cholesterol esterifying enzyme sterol-O acyltransferase 2 (SOAT2) hold great promise as effective atherosclerotic cardiovascular disease therapeutics
medicine
pharmacology
-
the results strongly support the idea that CS-505 could be promising as a therapeutic agent for the treatment of atherosclerosis
medicine
hepatic ACAT2 plays a critical role in driving the production of atherogenic lipoproteins, and therapeutic interventions, such as the ACAT2-specific antisense oligonucleotide used here, which reduce acyltransferase 2 (ACAT2) function in the liver without affecting ACAT1, may provide clinical benefit for cardiovascular disease prevention
medicine
-
the study provides evidence that purified esculeogenin A significantly suppresses the activity of ACAT protein and leads to reduction of atherogenesis
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Chang, T.Y.; Doolittle, G.M.
Acyl coenzyme A:cholesterol O-acyltransferase
The Enzymes, 3rd Ed. (Boyer, P. D. , ed. )
16
523-539
1983
Cavia porcellus, Cricetulus griseus, Columba sp., Oryctolagus cuniculus, Homo sapiens, Platyrrhini, Mus musculus, Rattus norvegicus, Sus scrofa
-
Kaduce, T.L.; Schmidt, R.W.; Spector, A.A.
Acylcoenzyme A:cholesterol acyltransferase activity: solubilization and reconstitution in liposomes
Biochem. Biophys. Res. Commun.
81
462-468
1978
Mus musculus
Uelmen, P.J.; Oka, K.; Sullivan, M.; Chang, C.C.Y.; Chang, T.Y.; Chan, L.
Tissue-specific expression and cholesterol regulation of acylcoenzyme A:cholesterol acyltransferase (ACAT) in mice
J. Biol. Chem.
270
26192-26201
1995
Mus musculus (Q61263), Mus musculus
Green, S.; Steinberg, D.; Quehenberger, O.
Cloning and expression in Xenopus Oocytes of a mouse homologue of the human acylcoenzyme A:cholesterol acyltransferase and its potential role in metabolism of oxidized LDL
Biochem. Biophys. Res. Commun.
218
924-929
1996
Mus musculus
Chang, T.Y.; Chang, C.C.Y.; Cheng, D.
Acyl-coenzyme A:cholesterol acyltransferase
Annu. Rev. Biochem.
66
613-638
1997
Cavia porcellus, Cricetulus griseus, Columba sp., Oryctolagus cuniculus, Homo sapiens, Platyrrhini, Mus musculus, Rattus norvegicus, Sus scrofa
Khelef, N.; Buton, X.; Beatini, N.; Wang, H.; Meiner, V.; Chang, T.; Farese, R.V.; Maxfield, F.R.; Tabas, I.
Immunolocalization of acyl-coenzyme A:cholesterol O-acyltransferase in macrophages
J. Biol. Chem.
273
11218-11224
1998
Mus musculus
Bell, T.A.; Brown, J.M.; Graham, M.J.; Lemonidis, K.M.; Crooke, R.M.; Rudel, L.L.
Liver-specific inhibition of acyl-coenzyme A:cholesterol acyltransferase 2 with antisense oligonucleotides limits atherosclerosis development in apolipoprotein B100-only low-density lipoprotein receptor-/- mice
Arterioscler. Thromb. Vasc. Biol.
26
1814-1820
2006
Mus musculus (O88908)
Ohshiro, T.; Rudel, L.L.; Omura, S.; Tomoda, H.
Selectivity of microbial acyl-CoA: cholesterol acyltransferase inhibitors toward isozymes
J. Antibiot.
60
43-51
2007
Chlorocebus aethiops, Cricetulus griseus, Mus musculus, Rattus norvegicus
Freeman, N.E.; Rusinol, A.E.; Linton, M.; Hachey, D.L.; Fazio, S.; Sinensky, M.S.; Thewke, D.
Acyl-coenzyme A:cholesterol acyltransferase promotes oxidized LDL/oxysterol-induced apoptosis in macrophages
J. Lipid Res.
46
1933-1943
2005
Mus musculus
Bose, C.; Bhuvaneswaran, C.; Udupa, K.B.
Age-related alteration in hepatic acyl-CoA: cholesterol acyltransferase and its relation to LDL receptor and MAPK
Mech. Ageing Dev.
126
740-751
2005
Mus musculus, Mus musculus C57/BL6
Fujiwara, Y.; Kiyota, N.; Hori, M.; Matsushita, S.; Iijima, Y.; Aoki, K.; Shibata, D.; Takeya, M.; Ikeda, T.; Nohara, T.; Nagai, R.
Esculeogenin A, a new tomato sapogenol, ameliorates hyperlipidemia and atherosclerosis in ApoE-deficient mice by inhibiting ACAT
Arterioscler. Thromb. Vasc. Biol.
27
2400-2406
2007
Homo sapiens, Mus musculus
Terasaka, N.; Miyazaki, A.; Kasanuki, N.; Ito, K.; Ubukata, N.; Koieyama, T.; Kitayama, K.; Tanimoto, T.; Maeda, N.; Inaba, T.
ACAT inhibitor pactimibe sulfate (CS-505) reduces and stabilizes atherosclerotic lesions by cholesterol-lowering and direct effects in apolipoprotein E-deficient mice
Atherosclerosis
190
239-247
2007
Homo sapiens, Mus musculus, Rattus norvegicus
Hans, C.P.; Zerfaoui, M.; Naura, A.S.; Catling, A.; Boulares, A.H.
Differential effects of PARP inhibition on vascular cell survival and ACAT-1 expression favouring atherosclerotic plaque stability
Cardiovasc. Res.
78
429-439
2008
Mus musculus
Thewke, D.; Freeman-Anderson, N.; Pickle, T.; Netherland, C.; Chilton, C.
AM-251 and SR144528 are acyl CoA:cholesterol acyltransferase inhibitors
Biochem. Biophys. Res. Commun.
381
181-186
2009
Mus musculus
Chen, L.; Lafond, J.; Pelletier, R.M.
A novel technical approach for the measurement of individual ACAT-1 and ACAT-2 enzymatic activity in the testis
Methods Mol. Biol.
550
169-177
2009
Mus musculus (O88908), Mus musculus (Q61263), Mus musculus
Zhang, J.; Sawyer, J.K.; Marshall, S.M.; Kelley, K.L.; Davis, M.A.; Wilson, M.D.; Brown, J.M.; Rudel, L.L.
Cholesterol esters (CE) derived from hepatic sterol O-acyltransferase 2 (SOAT2) are associated with more atherosclerosis than CE from intestinal SOAT2
Circ. Res.
115
826-833
2014
Mus musculus (O88908)
Tomita, K.; Teratani, T.; Suzuki, T.; Shimizu, M.; Sato, H.; Narimatsu, K.; Usui, S.; Furuhashi, H.; Kimura, A.; Nishiyama, K.; Maejima, T.; Okada, Y.; Kurihara, C.; Shimamura, K.; Ebinuma, H.; Saito, H.; Yokoyama, H.; Watanabe, C.; Komoto, S.; Nagao, S.; Sugiyama, K.; Aosasa, S.; Hatsuse, K.; Yamamoto, J.; Hibi, T.; Miura, S.; Hokari, R.; Kanai, T.
Acyl-CoA:cholesterol acyltransferase 1 mediates liver fibrosis by regulating free cholesterol accumulation in hepatic stellate cells
J. Hepatol.
61
98-106
2014
Homo sapiens (P35610), Mus musculus (Q61263), Mus musculus C57BL/6 (Q61263)
Rogers, M.A.; Liu, J.; Song, B.L.; Li, B.L.; Chang, C.C.; Chang, T.Y.
Acyl-CoA:cholesterol acyltransferases (ACATs/SOATs): enzymes with multiple sterols as substrates and as activators
J. Steroid Biochem. Mol. Biol.
151
102-107
2015
Homo sapiens (O75908), Homo sapiens (P35610), Homo sapiens, Mus musculus (O88908), Mus musculus (Q61263)
Warrier, M.; Zhang, J.; Bura, K.; Kelley, K.; Wilson, M.D.; Rudel, L.L.; Brown, J.M.
Sterol O-acyltransferase 2-driven cholesterol esterification opposes liver X receptor-stimulated fecal neutral sterol loss
Lipids
51
151-157
2016
Mus musculus (O88908), Mus musculus
Toledo, J.D.; Garda, H.A.; Cabaleiro, L.V.; Cuellar, A.; Pellon-Maison, M.; Gonzalez-Baro, M.R.; Gonzalez, M.C.
Apolipoprotein A-I Helsinki promotes intracellular acyl-CoA cholesterol acyltransferase (ACAT) protein accumulation
Mol. Cell. Biochem.
377
197-205
2013
Mus musculus (Q61263)
Lopez, A.M.; Jones, R.D.; Repa, J.J.; Turley, S.D.
Niemann-Pick C1-deficient mice lacking sterol O-acyltransferase 2 have less hepatic cholesterol entrapment and improved liver function
Am. J. Physiol. Gastrointest. Liver Physiol.
315
G454-G463
2018
Mus musculus (O88908)
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