Mammalian acyl-CoA:cholesterol acyltransferases

Buhman, Kimberly K.; Accad, Michel; Farese, Robert V.

doi:10.1016/s1388-1981(00)00144-x

Cited by 194 publications

(149 citation statements)

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“…In mammals, two ACAT genes have been identified (reviewed in Refs. [1][2][3][4]. The first ACAT gene, acat1, was identified by isolating a human cDNA (ACAT cDNA K1) that functionally complements a Chinese hamster ovary cell mutant (clone AC29) lacking endogenous ACAT activity (5).…”

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confidence: 99%

Human Acyl-Coenzyme A:Cholesterol Acyltransferase 1 (acat1) Sequences Located in Two Different Chromosomes (7 and 1) Are Required to Produce a Novel ACAT1 Isoenzyme with Additional Sequence at the N Terminus

Yang

Lee

Chen

et al. 2004

Journal of Biological Chemistry

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A rare form of human ACAT1 mRNA, containing the optional long 5 -untranslated region, is produced as a 4.3-kelonucleotide chimeric mRNA through a novel interchromosomal trans-splicing of two discontinuous RNAs transcribed from chromosomes 1 and 7 (Li, B. L., Li, X. L., Duan, Z. J., Lee, O., Lin, S., Ma, Z. M., Chang, C. C., Yang, X. Y., Park, J. P., Mohandas, T. K., Noll, W., Chan, L., and Chang, T. Y. (1999) J. Biol. Chem. 274, 11060 -11071). To investigate its function, we express the chimeric ACAT1 mRNA in Chinese hamster ovary cells and show that it can produce a larger ACAT1 protein, with an apparent molecular mass of 56 kDa on SDS-PAGE, in addition to the normal, 50-kDa ACAT1 protein, which is produced from the ACAT1 mRNAs without the optional long 5 -untranslated repeat. To produce the 56-kDa ACAT1, acat1 sequences located at both chromosomes 7 and 1 are required. The 56-kDa ACAT1 can be recognized by specific antibodies prepared against the predicted additional amino acid sequence located upstream of the N-terminal of the ACAT1 ORF . The translation initiation codon for the 56-kDa protein is GGC, which encodes for glycine, as deduced by mutation analysis and mass spectrometry. Similar to the 50-kDa protein, when expressed alone, the 56-kDa ACAT1 is located in the endoplasmic reticulum and is enzymatically active. The 56-kDa ACAT1 is present in native human cells, including human monocyte-derived macrophages. Our current results show that the function of the chimeric ACAT1 mRNA is to increase the ACAT enzyme diversity by producing a novel isoenzyme. To our knowledge, our result provides the first mammalian example that a trans-spliced mRNA produces a functional protein.Acyl-coenzyme A:cholesterol acyltransferase (ACAT) 1 is an intracellular enzyme that plays important roles in lipid metabolism. It catalyzes the formation of cholesteryl esters, using long-chain fatty acyl coenzyme A and cholesterol as the two substrates. In mammals, two ACAT genes have been identified (reviewed in Refs. 1-4). The first ACAT gene, acat1, was identified by isolating a human cDNA (ACAT cDNA K1) that functionally complements a Chinese hamster ovary cell mutant (clone AC29) lacking endogenous ACAT activity (5). The second ACAT gene, acat2, was identified by homology cloning, based on the nucleotide sequence of ACAT1 cDNA. The ACAT1 and ACAT2 proteins share extensive sequence homology at their C-terminal halves but not at their N-terminals. Both enzymes are integral membrane proteins. Human ACAT1 (hACAT1) contains seven transmembranes (6), whereas hACAT2 contains only two detectable transmembranes (7). A conserved histidine (His-460 in hACAT1 and His-432 in hACAT2), located within a long stretch of hydrophobic residues, may serve as an active site for ACAT catalysis (7,8). Human ACAT1 message and protein are present in many tissues and various cell types examined, including adrenal, kidney, hepatocytes, Kupffer cells, intestinal enterocytes, fibroblasts, macrophages, and neurons in the brain (5, 9 -12). In contrast, abundant ACA...

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confidence: 99%

Human Acyl-Coenzyme A:Cholesterol Acyltransferase 1 (acat1) Sequences Located in Two Different Chromosomes (7 and 1) Are Required to Produce a Novel ACAT1 Isoenzyme with Additional Sequence at the N Terminus

Yang

Lee

Chen

et al. 2004

Journal of Biological Chemistry

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“…In other words, although the cholesterol content of the aortic arch strongly correlates with the degree of atherosclerosis shown by the morphometric technique, the biological and clinical significance obtained by these procedures may markedly differ (19). Acyl CoA:cholesterol acyltransferase (ACAT) catalyzes the intracellular cholesterol esterification (27,28). Histological analyses of tissues and atherosclerotic lesions have shown that double KO mice for ACAT1 and for apoE, or for LDLR, develop atherosclerotic lesions.…”

Section: Methods Choicementioning

confidence: 99%

Pitfalls in the assessment of murine atherosclerosis

Catanozi

Rocha

Passarelli

et al. 2009

Braz J Med Biol Res

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This review provides examples of the fact that different procedures for the measurement of atherosclerosis in mice may lead to interpretation of the extent of atherosclerosis having markedly different biological and clinical significance for humans: 1) aortic cholesterol measurement is highly sensitive for the detection of early and advanced atherosclerosis lesions, but misses the identification of the location and complexity of these lesions that are so critical for humans; 2) the histological analysis of the aortic root lesions in simvastatin-treated and control mice reveals similar lesion morphology in spite of the remarkable simvastatin-induced reduction of the aortic cholesteryl ester content; 3) in histological analyses, chemical fixation and inclusion may extract the tissue fat and also shrink and distort tissue structures. Thus, the method may be less sensitive for the detection of slight differences among the experimental groups, unless a more suitable procedure employing physical fixation with histological sample freezing using optimal cutting temperature and liquid nitrogen is employed. Thus, when measuring experimental atherosclerosis in mice, investigators should be aware of several previously unreported pitfalls regarding the extent, location and complexity of the arterial lesion that may not be suitable for extrapolation to human pathology.

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“…acyltransferase 1 (DGAT1) (19). These enzymes are founding members of the membrane-bound O-acyltransferase enzyme family (MBOAT).…”

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“…In addition to ACAT and DGAT1, other MBOATs include ghrelin octanoylcoenzyme A acyltransferase (22)(23)(24), and lysophospholipid acyltransferases (25). Two ACAT isoforms exist in mammals: ACAT1 and ACAT2 (reviewed in (19,26,27). ACAT1 is ubiquitously expressed, whereas ACAT2 is mainly expressed in intestinal enterocytes and in hepatocytes (28)(29)(30).…”

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confidence: 99%

Neuronal cholesterol esterification by ACAT1 in Alzheimer's disease

Chang

Bryleva

et al. 2010

IUBMB Life

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SummaryCholesterol has been implicated in various neurodegenerative diseases. Here we review the connection between cholesterol and Alzheimer's disease (AD), focusing on a recent study that links neuronal cholesterol esterification with biosynthesis of 24(S)-hydroxycholesterol and the fate of human amyloid precursor protein in a mouse model of AD. We also briefly evaluate the potential of ACAT1 as a drug target for AD.

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Mammalian acyl-CoA:cholesterol acyltransferases

Cited by 194 publications

References 80 publications

Human Acyl-Coenzyme A:Cholesterol Acyltransferase 1 (acat1) Sequences Located in Two Different Chromosomes (7 and 1) Are Required to Produce a Novel ACAT1 Isoenzyme with Additional Sequence at the N Terminus

Human Acyl-Coenzyme A:Cholesterol Acyltransferase 1 (acat1) Sequences Located in Two Different Chromosomes (7 and 1) Are Required to Produce a Novel ACAT1 Isoenzyme with Additional Sequence at the N Terminus

Pitfalls in the assessment of murine atherosclerosis

Neuronal cholesterol esterification by ACAT1 in Alzheimer's disease

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