Alzheimer's disease (AD) is the most common form of dementia in older adults. Currently, there is no cure for AD. The hallmark of AD is the accumulation of extracellular amyloid plaques composed of ...amyloid-β (Aβ) peptides (especially Aβ1-42) and neurofibrillary tangles, composed of hyperphosphorylated tau and accompanied by chronic neuroinflammation. Aβ peptides are derived from the amyloid precursor protein (APP). The oligomeric form of Aβ peptides is probably the most neurotoxic species; its accumulation eventually forms the insoluble and aggregated amyloid plaques. ApoE is the major apolipoprotein of the lipoprotein(s) present in the CNS. ApoE has three alleles, of which the Apoe4 allele constitutes the major risk factor for late-onset AD. Here we describe the complex relationship between ApoE4, oligomeric Aβ peptides, and cholesterol homeostasis. The review consists of four parts: 1) key elements involved in cellular cholesterol metabolism and regulation; 2) key elements involved in intracellular cholesterol trafficking; 3) links between ApoE4, Aβ peptides, and disturbance of cholesterol homeostasis in the CNS; 4) potential lipid-based therapeutic targets to treat AD. At the end, we recommend several research topics that we believe would help in better understanding the connection between cholesterol and AD for further investigations.
Sterol O-acyltransferase 1 (SOAT1) is an endoplasmic reticulum (ER) resident, multi-transmembrane enzyme that belongs to the membrane-bound O-acyltransferase (MBOAT) family. It catalyzes the ...esterification of cholesterol to generate cholesteryl esters for cholesterol storage. SOAT1 is a target to treat several human diseases. However, its structure and mechanism remain elusive since its discovery. Here, we report the structure of human SOAT1 (hSOAT1) determined by cryo-EM. hSOAT1 is a tetramer consisted of a dimer of dimer. The structure of hSOAT1 dimer at 3.5 Å resolution reveals that a small molecule inhibitor CI-976 binds inside the catalytic chamber and blocks the accessibility of the active site residues H460, N421 and W420. Our results pave the way for future mechanistic study and rational drug design targeting hSOAT1 and other mammalian MBOAT family members.
Acyl-coenzyme A:cholesterol acyltransferases Chang, Ta-Yuan; Li, Bo-Liang; Chang, Catherine C. Y ...
American journal of physiology: endocrinology and metabolism,
07/2009, Volume:
297, Issue:
1
Journal Article
Peer reviewed
Open access
1 Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire; 2 State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for ...Biological Sciences, Chinese Academy of Sciences, Shanghai, China
Submitted 12 November 2008
; accepted in final form 12 January 2009
ABSTRACT
The enzymes acyl-coenzyme A (CoA):cholesterol acyltransferases (ACATs) are membrane-bound proteins that utilize long-chain fatty acyl-CoA and cholesterol as substrates to form cholesteryl esters. In mammals, two isoenzymes, ACAT1 and ACAT2, encoded by two different genes, exist. ACATs play important roles in cellular cholesterol homeostasis in various tissues. This chapter summarizes the current knowledge on ACAT-related research in two areas: 1 ) ACAT genes and proteins and 2 ) ACAT enzymes as drug targets for atherosclerosis and for Alzheimer's disease.
acyl-coenzyme A:cholesterol acyltransferase inhibitors; atherosclerosis; Alzheimer's disease
Address for reprint requests and other correspondence: T. Y. Chang, Dept. of Biochemistry, Dartmouth Medical School, 1 Rope Ferry Rd., Hanover, NH 03755-1404 (e-mail: Ta.Yuan.Chang{at}Dartmouth.edu )
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•A respirable-dust module was developed by AI algorithms and three low-cost sensors.•Random forest regression was identified as the best model than other 19 methods.•The accuracy of ...this module was 94% compared with that by a gold sampling approach.•Its data completeness was 99.7% during the continuous two-week monitoring period.
The Internet of Things (IoT) and low-cost sensor technology have become common tools for environmental exposure monitoring; however, their application in measuring respirable dust (RD) in the workplace remains limited. This study aimed to develop a predictive model for RD using artificial intelligence (AI) algorithms and low-cost sensors and subsequently assess its validity using a standard sampling approach. Various low-cost sensors were combined into an RD sensor module and mounted on a portable aerosol monitor (GRIMM 11-D) for two weeks. AI algorithms were used to capture data per minute over 14 days to establish predictive RD models. The best-fitting model was validated using an aluminum cyclone equipped with an air pump and polytetrafluoroethylene filters to sample the 8-hour RD for 5 days at an aircraft manufacturing company. This module was continuously monitored for two weeks to evaluate its stability. The RD concentration measured by GRIMM 11-D in a general outdoor environment over two weeks was 28.1 ± 16.1 μg/m3 (range: 2.4–85.3 μg/m3). Among the various established models, random forest regression was observed to have the best prediction capacity (R2 = 0.97 and root mean square error = 2.82 μg/m3) in comparison to the other 19 methods. Field-based validation revealed that the predicted RD concentration (35.9 ± 4.1 μg/m3, range: 32.7–42.9 μg/m3) closely approximated the results obtained by the traditional method (38.1 ± 8.9 μg/m3, range: 28.1–52.5 μg/m3), and a strong positive Spearman correlation was observed between the two (rs = 0.70). The average bias was −2.2 μg/m3 and the precision was 5.8 μg/m3, resulting in an accuracy of 6.2 μg/m3 (94.2 %). Data completeness was 99.7 % during the continuous two-week monitoring period. The developed sensor module of RD exhibited excellent predictive performance and good data stability that can be applied to exposure assessments in occupational epidemiological studies.
Ubiquitin linkage to cysteine is an unconventional modification targeting protein for degradation. However, the physiological regulation of cysteine ubiquitylation is still mysterious. Here we found ...that ACAT2, a cellular enzyme converting cholesterol and fatty acid to cholesteryl esters, was ubiquitylated on Cys277 for degradation when the lipid level was low. gp78-Insigs catalysed Lys48-linked polyubiquitylation on this Cys277. A high concentration of cholesterol and fatty acid, however, induced cellular reactive oxygen species (ROS) that oxidized Cys277, resulting in ACAT2 stabilization and subsequently elevated cholesteryl esters. Furthermore, ACAT2 knockout mice were more susceptible to high-fat diet-associated insulin resistance. By contrast, expression of a constitutively stable form of ACAT2 (C277A) resulted in higher insulin sensitivity. Together, these data indicate that lipid-induced stabilization of ACAT2 ameliorates lipotoxicity from excessive cholesterol and fatty acid. This unconventional cysteine ubiquitylation of ACAT2 constitutes an important mechanism for sensing lipid-overload-induced ROS and fine-tuning lipid homeostasis.
Few studies have applied land-use regression to predict road traffic noise exposure, and there are few predictive models for different frequencies. This study aimed to measure 24-h average road ...traffic noise levels and to analyze the frequency components over one year to establish land-use regression models of noise exposure. Fifty monitoring stations were set up to conduct 3 measurements for A-weighted equivalent sound pressure levels over 24 h (Leq,24h) and night equivalent sound pressure levels (Lnight), as well as octave-band analyses, during the 2013–2014 period. Noise measurements were integrated with land-use types, road and traffic information, meteorological data and geographic information systems to construct land-use regression models. Leave-one-out cross-validation was performed to test the validity of the predictive models. The annual means of Leq,24h and Lnight were 66.4 ± 4.7 A-weighed decibels (dBA) and 62.1 ± 6.0 dBA, respectively. Octave-band frequency analyses revealed that the highest means over 24 h and at night were 61.4 ± 5.3 decibels (dB) and 56.7 ± 6.6 dB (both at 1000 Hz), respectively. The model-explained variance (R2) of the full-frequency noise was 0.83 for Leq,24h and 0.79 for Lnight. The R2 values for octave-band-frequency noise ranged from 0.67 to 0.88 for Leq,24h and 0.65 to 0.85 for Lnight, with the highest R2 at 250 Hz for Leq,24h and at 125 Hz for Lnight. The differences between the model R2 and the leave-one-out cross-validation R2 ranged from 5% to 15% for both Leq,24h and Lnight at all frequencies. In the validation, the root mean squared error was 2.09 dBA and 2.80 dBA for the full-frequency Leq,24 and Lnight, respectively, and ranged from 1.89 to 2.62 dB and from 2.51 to 3.28 dB for the octave-band-frequency Leq,24h and Lnight, respectively. This study observed that the annual means of the measured Leq,24h and Lnight in Taichung were both above 60 dBA and had the highest level at 1000 Hz. The developed land-use regression models of Leq,24 and Lnight both had good predictive capacity for the full frequency spectrum and within octave bands and can therefore be applied for epidemiological studies.
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•The highest annual means of Leq,24h and Lnight both are measured at 1000 Hz.•The model-explained variance (R2) is 0.83 for Leq,24h and 0.79 for Lnight.•The highest R2 is 0.88 at 250 Hz for Leq,24h and 0.85 at 125 Hz for Lnight.•The root mean squared error is 2.09 dBA and 2.80 dBA for Leq,24 and Lnight.•Models with good performance are built to estimate levels of road traffic noise.
CD8(+) T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment. Reactivating the cytotoxicity of CD8(+) T cells is of great clinical ...interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8(+) T cells can be potentiated by modulating cholesterol metabolism. Inhibiting cholesterol esterification in T cells by genetic ablation or pharmacological inhibition of ACAT1, a key cholesterol esterification enzyme, led to potentiated effector function and enhanced proliferation of CD8(+) but not CD4(+) T cells. This is due to the increase in the plasma membrane cholesterol level of CD8(+) T cells, which causes enhanced T-cell receptor clustering and signalling as well as more efficient formation of the immunological synapse. ACAT1-deficient CD8(+) T cells were better than wild-type CD8(+) T cells at controlling melanoma growth and metastasis in mice. We used the ACAT inhibitor avasimibe, which was previously tested in clinical trials for treating atherosclerosis and showed a good human safety profile, to treat melanoma in mice and observed a good antitumour effect. A combined therapy of avasimibe plus an anti-PD-1 antibody showed better efficacy than monotherapies in controlling tumour progression. ACAT1, an established target for atherosclerosis, is therefore also a potential target for cancer immunotherapy.
Acyl-CoA:cholesterol acyltransferase 1 (ACAT1) is a resident endoplasmic reticulum enzyme that prevents the buildup of cholesterol in membranes by converting it to cholesterol esters. Blocking ACAT1 ...pharmacologically or by Acat1 gene knock-out (KO) decreases amyloidopathy in mouse models for Alzheimer's disease. However, the beneficial actions of ACAT1 blockage to treat Alzheimer's disease remained not well understood. Microglia play essential roles in the proteolytic clearance of amyloid β (Aβ) peptides. Here we show that Acat1 gene KO in mouse increases phagocytic uptake of oligomeric Aβ1-42 and stimulates lysosomal Aβ1-42 degradation in cultured microglia and in vivo. Additional results show that Acat1 gene KO or a specific ACAT1 inhibitor K604 stimulates autophagosome formation and transcription factor EB-mediated lysosomal proteolysis. Surprisingly, the effect of ACAT1 blockage does not alter mTOR signaling or endoplasmic reticulum stress response but can be modulated by agents that disrupt cholesterol biosynthesis. To our knowledge, our current study provides the first example that a small molecule (K604) can promote autophagy in an mTOR-independent manner to activate the coordinated lysosomal expression and regulation network. Autophagy is needed to degrade misfolded proteins/peptides. Our results implicate that blocking ACAT1 may provide a new way to benefit multiple neurodegenerative diseases.
Mammalian cells acquire cholesterol from low-density lipoprotein (LDL) and from endogenous biosynthesis. The roles of the Niemann-Pick type C1 protein in mediating the endosomal transport of ...LDL-derived cholesterol and endogenously synthesized cholesterol are discussed. Excess cellular cholesterol is converted to cholesteryl esters by the enzyme acyl-coenzyme A:cholesterol acyltransferase (ACAT) 1 or is removed from a cell by cellular cholesterol efflux at the plasma membrane. A close relationship between the ACAT substrate pool and the cholesterol efflux pool is proposed. Sterol-sensing domains (SSDs) are present in several membrane proteins, including NPC1, HMG-CoA reductase, and the SREBP cleavage-activating protein. The functions of SSDs are described. ACAT1 is an endoplasmic reticulum cholesterol sensor and contains a signature motif characteristic of the membrane-bound acyltransferase family. The nonvesicular cholesterol translocation processes involve the START domain proteins and the oxysterol binding protein-related proteins (ORPs). The properties of these proteins are summarized.
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