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J. Biol. Chem., Vol. 276, Issue 44, 40369-40372, November 2, 2001
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From the
Fueled by fat-rich diets and sedentary
lifestyles, atherosclerosis and obesity are major health issues in the
Western world. Both diseases involve excessive accumulation of
neutral lipids: cholesterol esters in arteries in atherosclerosis and
triglycerides in adipocytes in obesity. The study of these diseases has
sparked interest in the biochemistry and molecular biology of neutral lipid synthesis.
The discovery of acyl-CoA:cholesterol acyltransferase
(ACAT,1 EC 2.3.1.26), a
cholesterol ester synthesis enzyme, dates back to the 1950s (1). ACAT
was identified as an intracellular enzyme in the endoplasmic reticulum
(ER) that covalently joined cholesterol and fatty acyl-CoA molecules to
form cholesterol esters (Fig. 1). ACAT
activity was detected in macrophages and in tissues such as
liver, small intestine, and adrenal glands (2-4). Another ER
enzyme, acyl-CoA:diacylglycerol acyltransferase (DGAT, EC
2.3.1.20), was identified in 1960 (5). The DGAT reaction is similar to that of ACAT except that diacylglycerol is the acyl group acceptor (Fig. 1). In the ensuing 30 years, much was learned about the biochemistry of ACAT and DGAT (2, 3, 6-11). Both enzymes were found to
play important roles in synthesizing neutral lipids for the assembly
and secretion of lipoproteins, and ACAT was found to be responsible for
synthesizing cholesterol esters in arterial macrophage foam cells.
However, these hydrophobic proteins proved difficult to isolate,
slowing progress in their understanding.
Because of the pioneering work of Chang and colleagues (12), the field
of neutral lipid synthesis made great strides during the past decade.
These investigators isolated ACAT by using a clever cloning strategy to
isolate an ACAT cDNA. Thanks to the resultant molecular probes and
to genetic studies in yeast and mice, we now know there are two
mammalian ACAT enzymes and probably more than one DGAT
enzyme.2 A large number of
ACAT- and DGAT-related genes are identifiable in species ranging from
plants (13, 14) to yeast (15-17) to humans. Here we review recent
advances in understanding the function of the mammalian members of this
family, ACAT1, ACAT2, and DGAT.
Characteristics of the human and mouse members of the
ACAT/DGAT gene family are shown in Table
I. The human ACAT1 gene encodes four
mRNAs of 7.0, 4.3, 3.6, and 2.8 kilobases (kb) (12, 18-20); all
contain the same translational reading frame but differ in the length
of the untranslated regions (21). The two shorter mRNAs are
products of a proximal ACAT promoter. The 4.3-kb mRNA is derived
from an unusual RNA recombination mechanism involving trans-splicing of two discontinuous precursor RNAs produced
from chromosomes 1 and 7 (21). The origin of the 7.0-kb transcript is
unknown. The human ACAT2 gene encodes a single mRNA of 2.2 kb, and
the human DGAT gene encodes two mRNAs of 2.0 and 2.4 kb. Regions of
shared sequence identity are present throughout the ACAT and
DGAT proteins, but the greatest similarity is found in their C
termini (Fig. 2). Human and mouse
ACAT2 are ~40% identical to human
ACAT1, and DGAT is ~20% identical to ACAT1.
MINIREVIEW
The Enzymes of Neutral Lipid Synthesis*
§,§¶, and§¶
Gladstone Institute of Cardiovascular
Disease, San Francisco, California 94141-9100 and the
§ Cardiovascular Research Institute and ¶ Department of
Medicine, University of California,
San Francisco, California 94143
INTRODUCTION
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Fig. 1.
The ACAT and DGAT reactions. ACAT
catalyzes the covalent joining of cholesterol (or oxysterols) with long
chain fatty acyl-CoA moieties to form sterol esters. DGAT catalyzes a
similar reaction in which diacylglycerol serves as the acyl acceptor
molecule. Both enzymes function at the ER.
Gene and Protein Structures
Properties of ACAT/DGAT enzymes
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Fig. 2.
Alignment of human ACAT1, ACAT2, and DGAT
proteins. Conserved residues are shown in color.
Asterisks indicate single, fully conserved residues;
colons indicate strongly conserved residues; and
periods indicate weakly conserved residues.
TOP
INTRODUCTION
Gene and Protein StructuresLittle is known about the relationship between protein structure and function in ACAT/DGAT family members. One motif, FYXDWWN (amino acids 403-409 of human ACAT1), is highly conserved in all family members and may be involved in fatty acyl-CoA binding. Another motif, MKXXSF (amino acids 265-270 of human ACAT1), is conserved in ACAT family members. The serine of this motif is required for ACAT activity (22, 23). All three family members have a potential tyrosine phosphorylation motif and at least one N-linked glycosylation site, both of unknown significance. ACAT1 and ACAT2 contain an N-terminal leucine zipper motif. Although ACAT1 functions as a homotetramer (24), it is unknown whether this leucine zipper motif participates in tetramer formation or whether ACAT2 and DGAT act as multimers. ACAT1 and ACAT2 do not form hetero-oligomeric complexes (25).
All ACAT/DGAT proteins possess multiple hydrophobic regions predicted
to serve as transmembrane domains, although there is not yet a
consensus structural model for the proteins. Investigations of human
ACAT1 topology have yielded different results. One study, performed by
inserting epitopes at different positions in the expressed protein
(26), found seven transmembrane domains. Another study, performed by
expressing truncated forms of the protein (22), found five
transmembrane domains. In both studies, the N terminus of the protein
localized to the cytoplasm and the C terminus to the ER lumen (22, 26).
Topologic studies of human ACAT2 performed with the truncation mutant
method also found five transmembrane domains with the N terminus in the
cytoplasm and the C terminus in the ER lumen (22). The latter study
found that a serine residue essential for ACAT activity was located in
the cytoplasm for ACAT1 and in the ER lumen for ACAT2, suggesting that
the active sites of these enzymes reside on opposite sides of the ER
membrane. Several putative transmembrane sequences are conserved in
ACAT1 and ACAT2 but not in DGAT (26), suggesting that these regions are
involved in cholesterol binding. The topology of DGAT has not been
reported, but a putative diacylglycerol binding motif has been
identified (27).
| |
Tissue and Cellular Distributions |
|---|
The tissue distributions of ACAT1 and ACAT2 are largely complementary. ACAT1 mRNA is present in many tissues, with the highest levels in macrophages and in adrenal and sebaceous glands (12, 28, 29), all of which store cholesterol esters in cytoplasmic droplets. ACAT1 is also highly expressed in human atherosclerotic lesions, particularly in macrophage foam cells (30). ACAT2 is expressed predominantly in the liver and small intestine (27, 31, 32). In humans, nonhuman primates, and mice, ACAT2 appears to be the major ACAT in the small intestine (25, 33, 34) and the predominant isozyme in hepatocytes of nonhuman primates and mice (33, 34).
Whether ACAT1 or ACAT2 is the predominant enzyme in human hepatocytes is controversial. Both are expressed in human hepatocytes and HepG2 cells (25). However, immunodepletion experiments found that ACAT1 accounts for ~90% of ACAT activity in human liver (35), whereas ACAT2 accounts for most of the ACAT activity in adult small intestine and fetal liver but only 10-20% of activity in adult liver (25). It is unclear whether the hepatic ACAT1 activity resides in hepatocytes or macrophage-derived Kupffer cells. ACAT1 expression was detected immunohistochemically in both cell types, with stronger staining in Kupffer cells (36). In nonhuman primates, ACAT1 was expressed only in Kupffer cells in the liver (33). A significant proportion of the ACAT1 activity in human liver thus may be attributable to Kupffer cells. Another study found little evidence of ACAT2 expression in human hepatocytes (25).
DGAT mRNA and activity are ubiquitous in mouse and human tissues, with the highest levels in liver, small intestine, and adipose tissue (11, 27, 37, 38) and somewhat lower levels in testis and adrenal gland (11). This wide range of tissue expression is consistent with the involvement of DGAT in the glycerol phosphate pathway of triglyceride synthesis, which is common to most cells. DGAT protein expression in tissues has not been studied because of the lack of suitable antibodies.
The intracellular localization of enzymes in this class has been
examined only for ACAT1. In human melanoma cells and fibroblasts and in
mouse macrophages, ACAT1 is located primarily in the ER (36, 39, 40).
In mouse macrophages, a small portion of ACAT1 immunoreactivity
localizes to a region near the trans-Golgi network (40, 41).
In macrophages, ACAT1 localization may change with different conditions
(36, 40).
| |
Biochemical Activity and Regulation |
|---|
ACAT and DGAT substrates have been identified by expressing the proteins in insect cells or yeast devoid of sterol esterification activity. In insect cells, mouse and human ACAT1 and ACAT2 utilize a variety of oxysterols in addition to cholesterol as substrates (31, 42). Ergosterol and plant sterols are poor substrates (31, 43). Both enzymes also utilize a wide variety of long chain fatty acyl-CoAs as substrates (31), although arachidonyl-CoA appears to be a better substrate for ACAT1 than ACAT2 (31, 43). In insect cells, DGAT utilizes only diacylglycerol as the acyl acceptor (37). DGAT has a broad fatty acyl-CoA specificity (37).
ACAT1 is regulated primarily by post-translational mechanisms (3). In cholesterol-loaded cells, esterification increases without changes in the expression level of ACAT1 mRNA (19, 20, 44) or protein (20, 24, 45). Purified ACAT1 is activated allosterically by cholesterol or oxysterols (46). ACAT1 activity may also be regulated by its intracellular localization. For example, a portion of ACAT1 immunoreactivity in macrophages is found near the trans-Golgi network and the endocytic recycling compartment (41). These cholesterol-rich organelles are involved in membrane traffic with the plasma membrane, and the proximity of ACAT1 to these organelles may be important for cholesterol ester synthesis during the formation of macrophage foam cells. The observation that 30-40% of ACAT1 redistributed from the ER to small vesicles during foam cell formation is consistent with this possibility (36). Regulation by phosphorylation has not been demonstrated.
ACAT1 is also transcriptionally regulated; however, only the expression levels of the shorter ACAT1 mRNAs (2.8 and 3.6 kb) change. In mice (28) and rabbits (18), a fat and cholesterol-rich diet increases ACAT1 mRNA levels 2-3-fold in the liver. In human HepG2 cells, free fatty acids, but not 25-hydroxycholesterol, increase ACAT1 mRNA levels 1.5-2-fold (47). ACAT1 mRNA and protein expression levels also increase during the differentiation of monocytes into macrophages (20, 30). Two factors that induce gene expression during monocyte-macrophage differentiation, 1,25-dihydroxyvitamin D3 and 9-cis-retinoic acid, also increased ACAT1 mRNA, protein, and cholesterol esterification activity in THP-1 cells (48).
Little is known about the regulation of ACAT2 and DGAT. Levels of DGAT
mRNA increase markedly in parallel with enzyme activity in NIH
3T3-L1 cells during their differentiation into adipocytes (37). This
finding suggests that transcription factors involved in adipogenesis
activate DGAT expression. Like other family members, DGAT possesses a
putative tyrosine phosphorylation site. The use of this site in DGAT
regulation has not been demonstrated, although two reports (49, 50)
have indicated that the enzyme may be post-translationally regulated by
a tyrosine kinase.
| |
Functional Analysis of ACAT1 and ACAT2 |
|---|
Gene knockout experiments in mice have provided insights into the
biological roles of ACAT1 and ACAT2. In ACAT1-deficient (ACAT1
/) mice, plasma cholesterol levels, hepatic
cholesterol esterification activity, and intestinal cholesterol
absorption are normal (51), consistent with the presence of a second
ACAT enzyme in the small intestine and liver of mice. ACAT1 deficiency
has its greatest effect in the adrenal glands and macrophages.
Cholesterol esters and cholesterol esterification activity are
virtually undetectable in the adrenal cortex of ACAT1/
mice, although the depletion of cholesterol esters does not affect corticosterone synthesis (51). In addition, peritoneal macrophages from
ACAT1/ mice do not accumulate cholesterol esters when
incubated with cholesterol-containing lipoproteins (51). This finding
provides a unique tool for testing the role of ACAT1 in macrophage foam cell formation and atherosclerosis (see below). Another ACAT1 gene
disruption study in mice confirmed general aspects of the ACAT1/ phenotype and showed that ACAT1 deficiency
reduces cholesterol esterification activity by >95% in testis and
ovary and results in atrophy of the meibomian glands of the eyelids
(52). A naturally occurring mutation in the mouse ACAT1 gene is present
in the AKR strain of inbred mice (53), which are homozygous for the
adrenocortical lipid depletion (ald) allele
(54).
The analysis of ACAT2-deficient mice (ACAT2/) (34)
complemented findings from ACAT1/ mice.
ACAT2/ mice have nearly undetectable ACAT activity and
lack cholesterol esters in the liver and small intestine (34). Because
they cannot synthesize cholesterol esters in the small intestine,
ACAT2/ mice have a reduced capacity to obtain
cholesterol from the diet. As a result, they do not develop
hypercholesterolemia or form cholesterol gallstones when fed a diet
high in fat, cholesterol, and cholic acid (34). ACAT2 deficiency
markedly decreases the cholesterol ester content of apolipoprotein
(apo) B-containing lipoproteins in mice fed either a chow diet or the
above diet (34). Thus, ACAT2 is the cholesterol esterification enzyme
in mouse liver and small intestine and plays a major role in mediating the response to dietary cholesterol.
Gene disruption studies suggest that both ACAT enzymes synthesize
cholesterol esters: ACAT1 for storage in cytosolic droplets and ACAT2
for secretion in apoB-containing lipoproteins. However, these results
may reflect their different tissue distributions rather than inherent
biochemical differences. Both ACAT1 and ACAT2, when expressed in a cell
line deficient in cholesterol esterification activity (AC29 cells),
synthesize cholesterol esters that are stored in cytoplasmic droplets
(25). Also, overexpression of ACAT1 in mouse liver causes both
cholesterol ester storage and secretion (55).
| |
Role of ACAT1 in Atherosclerosis |
|---|
Because cholesterol ester synthesis by ACAT1 is involved in
macrophage foam cell formation, it has been hypothesized that inhibition of ACAT1 may reduce atherosclerosis. To test the hypothesis that ACAT1 deficiency in macrophages inhibits atherosclerosis, ACAT1/ mice were crossed with two strains of mice that
are susceptible to atherosclerosis: low density lipoprotein
receptor-deficient (LDLR/) mice and apoE-deficient
(apoE/) mice (56). ACAT1 deficiency did not prevent
atherosclerotic lesions in either model. Because ACAT1 deficiency also
reduced serum cholesterol levels in both strains of mice, its effect on lesion size was confounded by effects on serum cholesterol levels, and
thus the contribution of ACAT1 to plaque formation could not be
rigorously determined. Qualitative analysis of lesions in the mutant
mice, however, revealed reduced amounts of cholesterol esters and
macrophages (56). These alterations may increase lesion stability (57),
although this hypothesis remains to be tested.
Studies that analyzed the quantitative effect of ACAT1 deficiency on
lesion development have produced different results. Ishibashi and
colleagues (52) crossed a different strain of ACAT1/
mice with LDLR/ and apoE/ mice and
found that ACAT1 deficiency was associated with ~50% reduction in
aortic root lesions in LDLR/ mice and did not decrease
serum cholesterol levels (52). However, Fazio et al. (58)
showed that LDLR/ mice reconstituted with
ACAT1/ macrophages had increased atherosclerotic
lesions that contained more free cholesterol and fewer macrophages than
control lesions. The apparent discrepancies between these studies may
reflect differences in methodology or study design. Ishibashi and
colleagues (52) quantified lesion areas by measuring neutral lipid
staining even though the cholesterol ester content of atherosclerotic
lesions in ACAT1/ mice was significantly diminished
(56, 58). The lesion areas consequently may have been underestimated.
In the study by Fazio et al. (58), selective inhibition of
macrophage ACAT1 may not have reduced lesion size because ACAT activity
was not inhibited in adjacent arterial smooth muscle cells, which can
also become foam cells.
Both complete (52, 56) and macrophage-specific (56) ACAT1 deficiencies
have deleterious effects in hypercholesterolemic mice. ACAT1 deficiency
causes extensive deposition of free cholesterol in the skin (52, 56)
and brain (56) of LDLR/ and apoE/
mice, suggesting an important role for the enzyme in cholesterol metabolism in these tissues when serum sterol levels are elevated. Although the dramatic effects in these models reflect the extreme condition of complete ACAT1 inhibition in the face of severe
hypercholesterolemia, they indicate that selective ACAT1 inhibition can
be detrimental.
| |
Functional Analysis of DGAT |
|---|
Because DGAT catalyzes the final step in the major pathway of
triglyceride synthesis (8, 10), it was speculated that inactivation of
the encoding gene in the mouse (Dgat) would cause severe
morbidity or early lethality. Surprisingly, DGAT-deficient mice are
viable and appear healthy although adult mice develop dry fur and
female mice have a lactation defect (38). Even though these animals
lack triglyceride synthesis in most tissues examined, Dgat/ mice have normal serum triglyceride
levels and triglycerides in white adipose tissue (38). These results
indicate the existence of alternative pathways of triglyceride
synthesis (11).2
Although DGAT deficiency does not prevent triglyceride synthesis,
Dgat/ mice have ~50% reduction in fat pad
content and are resistant to weight gain when fed a high fat diet (38).
Unexpectedly, these findings are associated with an ~15% increase in
daily total energy expenditure, part of which is mediated by increased
physical activity when the mice are fed a high fat diet (38). The
mechanism for the increased energy expenditure is unknown, but the
Dgat/ phenotype indicates that the
disruption of triglyceride synthesis significantly affects energy metabolism.
| |
ACAT and DGAT Enzymes as Pharmaceutical Targets |
|---|
Because ACAT enzymes participate in cholesterol ester synthesis for assembly of atherogenic apoB-containing lipoproteins (59, 60) and in macrophage foam cell formation, ACAT inhibitors have been developed as potential therapeutics (61-64). These agents produced mixed results in several animal models. In cholesterol-fed rabbits and hamsters, ACAT inhibitors reduced atherosclerotic lesion development independently of their effects on serum cholesterol levels (57, 65-67). A study of genetic models of hypercholesterolemia in mice and rabbits suggested that ACAT inhibitors either had no effect or increased aortic sinus lesion size (68). One inhibitor (avasimibe) reduced atherosclerosis in several animal models (57, 69) and is being evaluated in clinical trials. This compound, like most currently available ACAT inhibitors, is not selective for one of the two ACAT enzymes (31, 69). This pan-specificity may be desirable because pharmacologic (68) and genetic studies (56, 58) in animals suggest that specific inhibition of macrophage ACAT1 may increase lesion size, possibly because of toxicity from excess free cholesterol. Selective inactivation of ACAT1 in hypercholesterolemia may also have detrimental consequences (see above). Therefore, selective ACAT1 inhibition should be approached cautiously in humans (70). Partial inhibition of both ACAT enzymes may be a preferable strategy (71). A selective inhibitor of ACAT2 may be useful for preventing diet-induced hypercholesterolemia (34, 72).
Recent findings in Dgat/ mice (38) have
sparked interest in DGAT inhibitors as possible therapeutic agents for
obesity. Several naturally occurring compounds have been identified
(73-75).
| |
FOOTNOTES |
|---|
* This minireview will be reprinted in the 2001 Minireview Compendium, which will be available in December, 2001.
To whom correspondence should be addressed: Gladstone Inst. of
Cardiovascular Disease, P.O. Box 419100, San Francisco, CA 94141-9100. Tel.: 415-826-7500; Fax: 415-285-5632; E-mail:
bfarese@gladstone.ucsf.edu.
Published, JBC Papers in Press, September 5, 2001, DOI 10.1074/jbc.R100050200
2 A second mammalian DGAT gene was recently reported (76).
| |
ABBREVIATIONS |
|---|
The abbreviations used are: ACAT, acyl-CoA:cholesterol acyltransferase; DGAT, acyl-CoA:diacylglycerol acyltransferase; kb, kilobase(s); ER, endoplasmic reticulum; LDLR, low density lipoprotein receptor-deficient; apo, apolipoprotein.
| |
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