The Experts below are selected from a list of 5139 Experts worldwide ranked by ideXlab platform
Tayuan Chang - One of the best experts on this subject based on the ideXlab platform.
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structural insights into the inhibition mechanism of human sterol o acyltransferase 1 by a competitive inhibitor
Nature Communications, 2020Co-Authors: Chengcheng Guan, Yange Niu, Sicong Chen, Yunlu Kang, Koji Nishi, Catherine C Y Chang, Tayuan Chang, Tuoping Luo, Lei ChenAbstract: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 A 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. Sterol O-acyltransferase 1 (SOAT1, also named ACAT1) is an endoplasmic reticulum resident enzyme which catalyzes the esterification of cholesterol to generate Cholesteryl Esters. Here, authors report cryo-EM structures of human SOAT1 which reveal the binding site of the competitive inhibitor CI-976.
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acyl coenzyme a cholesterol acyltransferases
American Journal of Physiology-endocrinology and Metabolism, 2009Co-Authors: Tayuan Chang, Catherine C Y Chang, Yasuomi UranoAbstract: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.
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human acyl coa cholesterol acyltransferase acat and its potential as a target for pharmaceutical intervention against atherosclerosis
Acta Biochimica et Biophysica Sinica, 2006Co-Authors: Catherine C Y Chang, Akira Miyazaki, Ruhong Dong, Naomi Sakashita, Yi Zhang, Jay Liu, Michael Guo, Tayuan ChangAbstract:Acyl-CoA:cholesterol acyltransferase (ACAT) catalyzes the formation of Cholesteryl Esters from cholesterol and long-chain fatty-acyl-coenzyme A. At the single-cell level, ACAT serves as a regulator of intracellular cholesterol homeostasis. In addition, ACAT supplies Cholesteryl Esters for lipoprotein assembly in the liver and small intestine. Under pathological conditions, the accumulation of Cholesteryl Esters produced by ACAT in macrophages contributes to foam cell formation, a hallmark of the early stage of atherosclerosis. Several reviews addressing various aspects of ACAT and ACAT inhibitors are available [1-8]. This review briefly outlines the current knowledge on the biochemical properties of human ACATs, and then focuses on discussing the merit of ACAT as a drug target for pharmaceutical interventions against atherosclerosis.
Robert Salvayre - One of the best experts on this subject based on the ideXlab platform.
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new pathogenetic hypothesis for wolman disease possible role of oxidized low density lipoproteins in adrenal necrosis and calcification
Biochemical Journal, 1994Co-Authors: Geraldine Fitoussi, Anne Negresalvayre, Marietherese Pieraggi, Robert SalvayreAbstract:Wolman disease in an inherited metabolic disease, characterized by a severe deficiency of the acid lipase and a massive lysosomal storage of triacylglycerols and Cholesteryl Esters, associated with hepatosplenomegaly, adrenal calcification and nearly always fatal in the first year of life. Cultured human lymphoblastoid cells and human adrenal cells are able to promote the formation of mildly oxidized low-density lipoproteins (LDL), which in turn exhibit a non-negligible cytotoxic effect on these cells. In contrast, fibroblasts induce only very low levels of LDL oxidation. Comparative experiments have shown that the cytotoxic effect of oxidized LDL was higher to Wolman-disease cells than to controls. The oxidative ability of Wolman cells was similar to that of normal ones. The over-cytotoxicity of mildly oxidized LDL to Wolman cells resulted from the higher uptake of mildly oxidized LDL through the LDL-receptor pathway, which is only poorly down-regulated in Wolman cells subsequently to the block of the lysosomal degradation of LDL-Cholesteryl Esters. In cultured adrenal cells, oxidized LDL induced a sustained rise in intracellular [Ca2+] which is directly involved in the cellular damage and cell death induced by oxidized LDL [Negre-Salvayre and Salvayre (1992) Biochim. Biophys. Acta 1123, 207-215]. This Ca2+ peak is followed by a dramatic deposition of calcium in damaged or/and dead cultured adrenal cells, quite similar to that observed in Wolman-disease adrenal cortex. The cell-induced LDL oxidation and the subsequent cytotoxic effect can be prevented, at least in part, by antioxidants such as alpha-tocopherol and nordihydroguaiaretic acid. These findings support the hypothesis that the Wolman-disease adrenal damage (necrosis and calcification) could result from the association of the following events: mild oxidation of LDL by adrenal cells, over-uptake of mildly oxidized LDL by Wolman cells (resulting from the block of the lysosomal degradation of Cholesteryl Esters in Wolman cells), and cytotoxicity related to the amount of mildly oxidized LDL internalized by cells. The reported data also suggest that LDL oxidation induced by adrenal cells and their subsequent cytotoxicity can be prevented (in part) by antioxidants, and the potential therapeutic use of antioxidants in Wolman disease is discussed.
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New pathogenetic hypothesis for Wolman disease: possible role of oxidized low-density lipoproteins in adrenal necrosis and calcification.
The Biochemical journal, 1994Co-Authors: Geraldine Fitoussi, Marietherese Pieraggi, Anne Nègre-salvayre, Robert SalvayreAbstract:Wolman disease in an inherited metabolic disease, characterized by a severe deficiency of the acid lipase and a massive lysosomal storage of triacylglycerols and Cholesteryl Esters, associated with hepatosplenomegaly, adrenal calcification and nearly always fatal in the first year of life. Cultured human lymphoblastoid cells and human adrenal cells are able to promote the formation of mildly oxidized low-density lipoproteins (LDL), which in turn exhibit a non-negligible cytotoxic effect on these cells. In contrast, fibroblasts induce only very low levels of LDL oxidation. Comparative experiments have shown that the cytotoxic effect of oxidized LDL was higher to Wolman-disease cells than to controls. The oxidative ability of Wolman cells was similar to that of normal ones. The over-cytotoxicity of mildly oxidized LDL to Wolman cells resulted from the higher uptake of mildly oxidized LDL through the LDL-receptor pathway, which is only poorly down-regulated in Wolman cells subsequently to the block of the lysosomal degradation of LDL-Cholesteryl Esters. In cultured adrenal cells, oxidized LDL induced a sustained rise in intracellular [Ca2+] which is directly involved in the cellular damage and cell death induced by oxidized LDL [Nègre-Salvayre and Salvayre (1992) Biochim. Biophys. Acta 1123, 207-215]. This Ca2+ peak is followed by a dramatic deposition of calcium in damaged or/and dead cultured adrenal cells, quite similar to that observed in Wolman-disease adrenal cortex. The cell-induced LDL oxidation and the subsequent cytotoxic effect can be prevented, at least in part, by antioxidants such as alpha-tocopherol and nordihydroguaiaretic acid. These findings support the hypothesis that the Wolman-disease adrenal damage (necrosis and calcification) could result from the association of the following events: mild oxidation of LDL by adrenal cells, over-uptake of mildly oxidized LDL by Wolman cells (resulting from the block of the lysosomal degradation of Cholesteryl Esters in Wolman cells), and cytotoxicity related to the amount of mildly oxidized LDL internalized by cells. The reported data also suggest that LDL oxidation induced by adrenal cells and their subsequent cytotoxicity can be prevented (in part) by antioxidants, and the potential therapeutic use of antioxidants in Wolman disease is discussed.
Catherine C Y Chang - One of the best experts on this subject based on the ideXlab platform.
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structural insights into the inhibition mechanism of human sterol o acyltransferase 1 by a competitive inhibitor
Nature Communications, 2020Co-Authors: Chengcheng Guan, Yange Niu, Sicong Chen, Yunlu Kang, Koji Nishi, Catherine C Y Chang, Tayuan Chang, Tuoping Luo, Lei ChenAbstract: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 A 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. Sterol O-acyltransferase 1 (SOAT1, also named ACAT1) is an endoplasmic reticulum resident enzyme which catalyzes the esterification of cholesterol to generate Cholesteryl Esters. Here, authors report cryo-EM structures of human SOAT1 which reveal the binding site of the competitive inhibitor CI-976.
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acyl coenzyme a cholesterol acyltransferases
American Journal of Physiology-endocrinology and Metabolism, 2009Co-Authors: Tayuan Chang, Catherine C Y Chang, Yasuomi UranoAbstract: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.
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human acyl coa cholesterol acyltransferase acat and its potential as a target for pharmaceutical intervention against atherosclerosis
Acta Biochimica et Biophysica Sinica, 2006Co-Authors: Catherine C Y Chang, Akira Miyazaki, Ruhong Dong, Naomi Sakashita, Yi Zhang, Jay Liu, Michael Guo, Tayuan ChangAbstract:Acyl-CoA:cholesterol acyltransferase (ACAT) catalyzes the formation of Cholesteryl Esters from cholesterol and long-chain fatty-acyl-coenzyme A. At the single-cell level, ACAT serves as a regulator of intracellular cholesterol homeostasis. In addition, ACAT supplies Cholesteryl Esters for lipoprotein assembly in the liver and small intestine. Under pathological conditions, the accumulation of Cholesteryl Esters produced by ACAT in macrophages contributes to foam cell formation, a hallmark of the early stage of atherosclerosis. Several reviews addressing various aspects of ACAT and ACAT inhibitors are available [1-8]. This review briefly outlines the current knowledge on the biochemical properties of human ACATs, and then focuses on discussing the merit of ACAT as a drug target for pharmaceutical interventions against atherosclerosis.
Herbert Y Meltzer - One of the best experts on this subject based on the ideXlab platform.
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lowered ω3 polyunsaturated fatty acids in serum phospholipids and Cholesteryl Esters of depressed patients
Psychiatry Research-neuroimaging, 1999Co-Authors: Michael Maes, Armand Christophe, Joris R Delanghe, Carlo Altamura, Hugo Neels, Herbert Y MeltzerAbstract:Depression is associated with a lowered degree of esterification of serum cholesterol, an increased C20:4ω6/C20:5ω3 ratio and decreases in ω3 fractions in fatty acids (FAs) or in the red blood cell membrane. The aims of the present study were to examine: (i) serum phospholipid and Cholesteryl ester compositions of individual saturated fatty acids (SFAs), monounsaturated FAs (MUFAs) and polyunsaturated FAs (PUFAs) in major depressed patients vs. healthy volunteers; (ii) the relationships between the above FAs and lowered serum zinc (Zn), a marker of the inflammatory response in depression; and (iii) the effects of subchronic treatment with antidepressants on FAs in depression. The composition of the FAs was determined by means of thin layer chromatography in conjunction with gas chromatography. Lipid concentrations were assayed by enzymatic colorimetric methods. The oxidative potential index (OPI) of FAs was computed in 34 major depressed inpatients and 14 normal volunteers. Major depression was associated with: increased MUFA and C22:5ω3 proportions and increased C20:4ω6/C20:5ω3 and C22:5ω6/C22:6ω3 ratios; lower C22:4ω6, C20:5ω3 and C22:5ω3 fractions in phospholipids; lower C18:3ω3, C20:5ω3 and total (Σ)ω3 FAs, and higher C20:4ω6/C20:5ω3 and Σω6/Σω3 ratios in Cholesteryl Esters; lower serum concentrations of phospholipids and Cholesteryl Esters; and a decreased OPI. In depression, there were significant and positive correlations between serum Zn and C20:5ω3 and C22:6ω3 fractions in phospholipids; and significant inverse correlations between serum Zn and the Σω6/Σω3, C20:4ω6/C20:5ω3, and C22:5ω6/C22:6ω3 ratios in phospholipids. There was no significant effect of antidepressive treatment on any of the FAs. The results show that, in major depression, there is a deficiency of ω3 PUFAs and a compensatory increase in MUFAs and C22:5ω6 in phospholipids. The results suggest that: (i) there is an abnormal metabolism of ω3 PUFAs in depression; (ii) the FA alterations in depression are related to the inflammatory response in that illness; and (iii) the disorders may persist despite successful antidepressant treatment.
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fatty acid composition in major depression decreased ω3 fractions in Cholesteryl Esters and increased c20 4ω6c20 5ω3 ratio in Cholesteryl Esters and phospholipids
Journal of Affective Disorders, 1996Co-Authors: Michael Maes, Ronald Smith, Armand Christophe, P Cosyns, Roger Desnyder, Herbert Y MeltzerAbstract:Abstract Recently, there were some reports that major depression may be accompanied by alterations in serum total cholesterol, cholesterol ester and ω3 essential fatty acid levels and by an increased C 20: 4ω6 C 20: 5ω3 i.e., arachidonic acid/eicosapentaenoic, ratio. The present study aimed to examine fatty acid composition of serum Cholesteryl Esters and phospholipids in 36 major depressed, 14 minor depressed and 24 normal subjects. Individual saturated (e.g., C14:0; C16:0, C18:0) and unsaturated (e.g., C18:1, C18:2; C20:4) fatty acids in phospholipid and Cholesteryl ester fractions were assayed and the sums of the percentages of ω6 and ω3, saturated, branched chain and odd chain fatty acids, monoenes as well as the ratios ω6 ω3 and C 20:4ω6 C 20:5ω3 were calculated. Major depressed subjects had significantly higher C 20:4ω6 C 20:5ω3 ratio in both serum Cholesteryl Esters and phospholipids and a significantly increased ω6 ω3 ratio in Cholesteryl ester fraction than healthy volunteers and minor depressed subjects. Major depressed subjects had significantly lower C18:3ω3 in Cholesteryl Esters than normal controls. Major depressed subjects showed significantly lower total ω3 polyunsaturated fatty acids in Cholesteryl Esters and significantly lower C20:5ω3 in serum Cholesteryl Esters and phospholipids than minor depressed subjects and healthy controls. These findings suggest an abnormal intake or metabolism of essential fatty acids in conjunction with decreased formation of Cholesteryl Esters in major depression.
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fatty acid composition in major depression decreased omega 3 fractions in Cholesteryl Esters and increased c20 4 omega 6 c20 5 omega 3 ratio in Cholesteryl Esters and phospholipids
Journal of Affective Disorders, 1996Co-Authors: Michael Maes, Ronald Smith, Armand Christophe, P Cosyns, Roger Desnyder, Herbert Y MeltzerAbstract:Recently, there were some reports that major depression may be accompanied by alterations in serum total cholesterol, cholesterol ester and omega 3 essential fatty acid levels and by an increased C20: 4 omega 6/C20: 5 omega 3, i.e., arachidonic acid/eicosapentaenoic, ratio. The present study aimed to examine fatty acid composition of serum Cholesteryl Esters and phospholipids in 36 major depressed, 14 minor depressed and 24 normal subjects. Individual saturated (e.g., C14:0; C16:0, C18:0) and unsaturated (e.g., C18:1, C18:2, C20:4) fatty acids in phospholipid and Cholesteryl ester fractions were assayed and the sums of the percentages of omega 6 and omega 3, saturated, branched chain and odd chain fatty acids, monoenes as well as the ratios omega 6/omega 3 and C20:4 omega 6/C20:5 omega 3 were calculated. Major depressed subjects had significantly higher C20:4 omega 6/C20:5 omega 3 ratio in both serum Cholesteryl Esters and phospholipids and a significantly increased omega 6/omega 3 ratio in Cholesteryl ester fraction than healthy volunteers and minor depressed subjects. Major depressed subjects had significantly lower C18:3 omega 3 in Cholesteryl Esters than normal controls. Major depressed subjects showed significantly lower total omega 3 polyunsaturated fatty acids in Cholesteryl Esters and significantly lower C20:5 omega 3 in serum Cholesteryl Esters and phospholipids than minor depressed subjects and healthy controls. These findings suggest an abnormal intake or metabolism of essential fatty acids in conjunction with decreased formation of Cholesteryl Esters in major depression.
Abdeljabar El Andaloussi - One of the best experts on this subject based on the ideXlab platform.
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acyl coenzyme a cholesterol acyltransferase inhibitor avasimibe affect survival and proliferation of glioma tumor cell lines
Cancer Biology & Therapy, 2010Co-Authors: Sana Bemlih, Mariedenise Poirier, Abdeljabar El AndaloussiAbstract:Glioblastoma is the most common primary brain tumor in adults and one of its hallmarks is resistance to apoptosis. Acyl-CoA: cholesterol acyltransferase (ACAT) is an intracellular membrane-bound enzyme that uses cholesterol and long chain fatty acyl-CoA as substrates to produce Cholesteryl Esters. The presence of Cholesteryl Esters in glioblastoma may be related to vascular and/or cell neoplastic proliferation in the tumor mass, two prerequisites for tumor cell growth. ACAT activity has been detected in glioblastoma cell homogenates. The present study is the first report on the effect of Avasimibe, a specific inhibitor of ACAT, on glioma cell lines (U87, A172, and GL261). Our results showed that Avasimibe inhibited ACAT-1 expression and cholesterol ester synthesis in glioma cell lines. Moreover, Avasimibe inhibited the growth of the cells by inducing cell cycle arrest and induced apoptosis as a result of caspase-8 and caspase-3 activation. Also, Our findings provide proof of principle that targeting ACAT-...
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acyl coenzyme a cholesterol acyltransferase inhibitor avasimibe affect survival and proliferation of glioma tumor cell lines
Cancer Biology & Therapy, 2010Co-Authors: Sana Bemlih, Mariedenise Poirier, Abdeljabar El AndaloussiAbstract:Glioblastoma is the most common primary brain tumor in adults and one of its hallmarks is resistance to apoptosis. Acyl-CoA: cholesterol acyltransferase (ACAT) is an intracellular membrane-bound enzyme that uses cholesterol and long chain fatty acyl-CoA as substrates to produce Cholesteryl Esters. The presence of Cholesteryl Esters in glioblastoma may be related to vascular and/or cell neoplastic proliferation in the tumor mass, two prerequisites for tumor cell growth. ACAT activity has been detected in glioblastoma cell homogenates. The present study is the first report on the effect of Avasimibe, a specific inhibitor of ACAT, on glioma cell lines (U87, A172 and GL261). Our results showed that Avasimibe inhibited ACAT-1 expression and cholesterol ester synthesis in glioma cell lines. Moreover, Avasimibe inhibited the growth of the cells by inducing cell cycle arrest and induced apoptosis as a result of caspase-8 and caspase-3 activation. Also, Our findings provide proof of principle that targeting ACAT-1 with the inhibitor Avasimibe could be an efficient therapy in the treatment of glioblastoma.