Ohashi K

References (10)

Title : The effect of carboxylesterase 1 (CES1) polymorphisms on the pharmacokinetics of oseltamivir in humans - Suzaki_2013_Eur.J.Clin.Pharmacol_69_21
Author(s) : Suzaki Y , Uemura N , Takada M , Ohyama T , Itohda A , Morimoto T , Imai H , Hamasaki H , Inano A , Hosokawa M , Tateishi M , Ohashi K
Ref : European Journal of Clinical Pharmacology , 69 :21 , 2013
Abstract : PURPOSE: The aim of this study was to examine whether carboxylesterase 1 (CES1A) genetic polymorphisms affect the pharmacokinetics of oseltamivir.
METHODS: Thirty healthy Japanese male and female subjects ranging in age from 20 to 36 years voluntarily participated in this study. These subjects were administered a single 75-mg dose of oseltamivir (Tamiflu(R)), and blood samples were collected predose and up to 24 h after oseltamivir administration. Oseltamivir and its active metabolite, oseltamivir carboxylate, were measured by liquid chromatography-time of flight/mass spectrometry with solid-phase extraction. The CES1A diplotypes [a combination of haplotypes A (CES1A3-CES1A1), B (CES1A2-CES1A1), C (CES1A3-CES1A1variant), and D (CES1A2-CES1A1variant)] were determined by PCR-restriction fragment length polymorphism analysis and direct sequencing.
RESULTS: All subjects completed the study according to the protocol, and no clinically meaningful adverse events were attributable to the administration of oseltamivir. No significant differences in the pharmacokinetic parameters of oseltamivir and oseltamivir carboxylate were observed according to CES1A genotype. In one subject, the peak concentration and area under the concentration-time curve (AUC) of oseltamivir were approximately tenfold higher than the mean values of the other subjects.
CONCLUSIONS: In our study, the known interindividual variability in oseltamivir metabolism was not explained by CES1A genetic polymorphisms, but are likely the result of other factors. While one subject was found to exhibit an approximate tenfold higher AUC than the other subjects, no abnormal behaviors were associated with the increased oseltamivir plasma concentrations. Further studies are required to reveal the cause of individual differences in CES1A metabolism and the abnormal behavioral effects of oseltamivir.
ESTHER : Suzaki_2013_Eur.J.Clin.Pharmacol_69_21
PubMedSearch : Suzaki_2013_Eur.J.Clin.Pharmacol_69_21
PubMedID: 22673926

Title : Abrogation of neutral cholesterol ester hydrolytic activity causes adrenal enlargement - Ohta_2011_Biochem.Biophys.Res.Commun_404_254
Author(s) : Ohta K , Sekiya M , Uozaki H , Igarashi M , Takase S , Kumagai M , Takanashi M , Takeuchi Y , Izumida Y , Kubota M , Nishi M , Okazaki H , Iizuka Y , Yahagi N , Yagyu H , Fukayama M , Kadowaki T , Ohashi K , Ishibashi S , Osuga J
Ref : Biochemical & Biophysical Research Communications , 404 :254 , 2011
Abstract : We have previously demonstrated that neutral cholesterol ester hydrolase 1 (Nceh1) regulates foam cell formation and atherogenesis through the catalytic activity of cholesterol ester hydrolysis, and that Nceh1 and hormone-sensitive lipase (Lipe) are responsible for the majority of neutral cholesterol ester hydrolase activity in macrophages. There are several cholesterol ester-metabolizing tissues and cells other than macrophages, among which adrenocortical cells are also known to utilize the intracellular cholesterol for steroidogenesis. It has been believed that the mobilization of intracellular cholesterol ester in adrenal glands was facilitated solely by Lipe. We herein demonstrate that Nceh1 is also involved in cholesterol ester hydrolysis in adrenal glands. While Lipe deficiency remarkably reduced the neutral cholesterol ester hydrolase activity in adrenal glands as previously reported, additional inactivation of Nceh1 gene completely abrogated the activity. Adrenal glands were enlarged in proportion to the degree of reduced neutral cholesterol ester hydrolase activity, and the enlargement of adrenal glands and the accumulation of cholesterol esters were most pronounced in the Nceh1/Lipe double-deficient mice. Thus Nceh1 is involved in the adrenal cholesterol metabolism, and the cholesterol ester hydrolytic activity in adrenal glands is associated with the organ enlargement.
ESTHER : Ohta_2011_Biochem.Biophys.Res.Commun_404_254
PubMedSearch : Ohta_2011_Biochem.Biophys.Res.Commun_404_254
PubMedID: 21111707
Gene_locus related to this paper: human-LIPE , human-NCEH1

Title : The critical role of neutral cholesterol ester hydrolase 1 in cholesterol removal from human macrophages - Igarashi_2010_Circ.Res_107_1387
Author(s) : Igarashi M , Osuga J , Uozaki H , Sekiya M , Nagashima S , Takahashi M , Takase S , Takanashi M , Li Y , Ohta K , Kumagai M , Nishi M , Hosokawa M , Fledelius C , Jacobsen P , Yagyu H , Fukayama M , Nagai R , Kadowaki T , Ohashi K , Ishibashi S
Ref : Circulation Research , 107 :1387 , 2010
Abstract : RATIONALE: Hydrolysis of intracellular cholesterol ester (CE) is the key step in the reverse cholesterol transport in macrophage foam cells. We have recently shown that neutral cholesterol ester hydrolase (Nceh)1 and hormone-sensitive lipase (Lipe) are key regulators of this process in mouse macrophages. However, it remains unknown which enzyme is critical in human macrophages and atherosclerosis. OBJECTIVE: We aimed to identify the enzyme responsible for the CE hydrolysis in human macrophages and to determine its expression in human atherosclerosis. METHODS AND RESULTS: We compared the expression of NCEH1, LIPE, and cholesterol ester hydrolase (CES1) in human monocyte-derived macrophages (HMMs) and examined the effects of inhibition or overexpression of each enzyme in the cholesterol trafficking. The pattern of expression of NCEH1 was similar to that of neutral CE hydrolase activity during the differentiation of HMMs. Overexpression of human NCEH1 increased the hydrolysis of CE, thereby stimulating cholesterol mobilization from THP-1 macrophages. Knockdown of NCEH1 specifically reduced the neutral CE hydrolase activity. Pharmacological inhibition of NCEH1 also increased the cellular CE in HMMs. In contrast, LIPE was barely detectable in HMMs, and its inhibition did not decrease neutral CE hydrolase activity. Neither overexpression nor knockdown of CES1 affected the neutral CE hydrolase activity. NCEH1 was expressed in CD68-positive macrophage foam cells of human atherosclerotic lesions. CONCLUSIONS: NCEH1 is expressed in human atheromatous lesions, where it plays a critical role in the hydrolysis of CE in human macrophage foam cells, thereby contributing to the initial part of reverse cholesterol transport in human atherosclerosis.
ESTHER : Igarashi_2010_Circ.Res_107_1387
PubMedSearch : Igarashi_2010_Circ.Res_107_1387
PubMedID: 20947831

Title : Ablation of neutral cholesterol ester hydrolase 1 accelerates atherosclerosis - Sekiya_2009_Cell.Metab_10_219
Author(s) : Sekiya M , Osuga J , Nagashima S , Ohshiro T , Igarashi M , Okazaki H , Takahashi M , Tazoe F , Wada T , Ohta K , Takanashi M , Kumagai M , Nishi M , Takase S , Yahagi N , Yagyu H , Ohashi K , Nagai R , Kadowaki T , Furukawa Y , Ishibashi S
Ref : Cell Metab , 10 :219 , 2009
Abstract : Cholesterol ester (CE)-laden macrophage foam cells are the hallmark of atherosclerosis, and the hydrolysis of intracellular CE is one of the key steps in foam cell formation. Although hormone-sensitive lipase (LIPE) and cholesterol ester hydrolase (CEH), which is identical to carboxylsterase 1 (CES1, hCE1), were proposed to mediate the neutral CE hydrolase (nCEH) activity in macrophages, recent evidences have suggested the involvement of other enzymes. We have recently reported the identification of a candidate, neutral cholesterol ester hydrolase 1(Nceh1). Here we demonstrate that genetic ablation of Nceh1 promotes foam cell formation and the development of atherosclerosis in mice. We further demonstrate that Nceh1 and Lipe mediate a comparable degree of nCEH activity in macrophages and together account for most of the activity. Mice lacking both Nceh1 and Lipe aggravated atherosclerosis in an additive manner. Thus, Nceh1 is a promising target for the treatment of atherosclerosis.
ESTHER : Sekiya_2009_Cell.Metab_10_219
PubMedSearch : Sekiya_2009_Cell.Metab_10_219
PubMedID: 19723498
Gene_locus related to this paper: human-NCEH1 , mouse-Q8BLF1

Title : Identification of neutral cholesterol ester hydrolase, a key enzyme removing cholesterol from macrophages - Okazaki_2008_J.Biol.Chem_283_33357
Author(s) : Okazaki H , Igarashi M , Nishi M , Sekiya M , Tajima M , Takase S , Takanashi M , Ohta K , Tamura Y , Okazaki S , Yahagi N , Ohashi K , Amemiya-Kudo M , Nakagawa Y , Nagai R , Kadowaki T , Osuga J , Ishibashi S
Ref : Journal of Biological Chemistry , 283 :33357 , 2008
Abstract : Unstable lipid-rich plaques in atherosclerosis are characterized by the accumulation of macrophage foam cells loaded with cholesterol ester (CE). Although hormone-sensitive lipase and cholesteryl ester hydrolase (CEH) have been proposed to mediate the hydrolysis of CE in macrophages, circumstantial evidence suggests the presence of other enzymes with neutral cholesterol ester hydrolase (nCEH) activity. Here we show that the murine orthologue of KIAA1363, designated as neutral cholesterol ester hydrolase (NCEH), is a microsomal nCEH with high expression in murine and human macrophages. The effect of various concentrations of NaCl on its nCEH activity resembles that on endogenous nCEH activity of macrophages. RNA silencing of NCEH decreases nCEH activity at least by 50%; conversely, its overexpression inhibits the CE formation in macrophages. Immunohistochemistry reveals that NCEH is expressed in macrophage foam cells in atherosclerotic lesions. These data indicate that NCEH is responsible for a major part of nCEH activity in macrophages and may be a potential therapeutic target for the prevention of atherosclerosis.
ESTHER : Okazaki_2008_J.Biol.Chem_283_33357
PubMedSearch : Okazaki_2008_J.Biol.Chem_283_33357
PubMedID: 18782767
Gene_locus related to this paper: human-NCEH1

Title : Hormone-sensitive lipase is involved in hepatic cholesteryl ester hydrolysis - Sekiya_2008_J.Lipid.Res_49_1829
Author(s) : Sekiya M , Osuga J , Yahagi N , Okazaki H , Tamura Y , Igarashi M , Takase S , Harada K , Okazaki S , Iizuka Y , Ohashi K , Yagyu H , Okazaki M , Gotoda T , Nagai R , Kadowaki T , Shimano H , Yamada N , Ishibashi S
Ref : J Lipid Res , 49 :1829 , 2008
Abstract : Hormone-sensitive lipase (HSL) regulates the hydrolysis of acylglycerol and cholesteryl ester (CE) in various organs, including adipose tissues. However, the hepatic expression level of HSL has been reported to be almost negligible. In the present study, we found that mice lacking both leptin and HSL (Lep(ob/ob)/HSL(-/-)) showed massive accumulation of CE in the liver compared with Lep(ob/ob)/HSL(+/+) mice, while triacylglycerol (TG) accumulation was modest. Similarly, feeding with a high-cholesterol diet induced hepatic CE accumulation in HSL(-/-) mice. Supporting these observations, we detected significant expression of protein as well as mRNA of HSL in the liver. HSL(-/-) mice showed reduced activity of CE hydrolase, but not of TG lipase, in the liver compared with wild-type mice. Furthermore, we confirmed the expression of HSL in viable parenchymal cells isolated from wild-type mice. The hepatocytes from HSL(-/-) mice showed reduced activity of CE hydrolase and contained more CE than those from HSL(+/+) mice even without the incubation with lipoproteins. Incubation with LDL further augmented the accumulation of CE in the HSL-deficient hepatocytes. From these results, we conclude that HSL is involved in the hydrolysis of CE in hepatocyes.
ESTHER : Sekiya_2008_J.Lipid.Res_49_1829
PubMedSearch : Sekiya_2008_J.Lipid.Res_49_1829
PubMedID: 18480494

Title : Identification of a novel member of the carboxylesterase family that hydrolyzes triacylglycerol: a potential role in adipocyte lipolysis - Okazaki_2006_Diabetes_55_2091
Author(s) : Okazaki H , Igarashi M , Nishi M , Tajima M , Sekiya M , Okazaki S , Yahagi N , Ohashi K , Tsukamoto K , Amemiya-Kudo M , Matsuzaka T , Shimano H , Yamada N , Aoki J , Morikawa R , Takanezawa Y , Arai H , Nagai R , Kadowaki T , Osuga J , Ishibashi S
Ref : Diabetes , 55 :2091 , 2006
Abstract : Molecular mechanisms underlying lipolysis, as defined by mobilization of fatty acids from adipose tissue, are not fully understood. A database search for enzymes with alpha/beta hydrolase folds, the GXSXG motif for serine esterase and the His-Gly dipeptide motif, has provided a previously unannotated gene that is induced during 3T3-L1 adipocytic differentiation. Because of its remarkable structural resemblance to triacylglycerol hydrolase (TGH) with 70.4% identity, we have tentatively designated this enzyme as TGH-2 and the original TGH as TGH-1. TGH-2 is also similar to TGH-1 in terms of tissue distribution, subcellular localization, substrate specificity, and regulation. Both enzymes are predominantly expressed in liver, adipose tissue, and kidney. In adipocytes, they are localized in microsome and fatcake. Both enzymes hydrolyzed p-nitophenyl butyrate, triolein, and monoolein but not diolein, cholesteryl oleate, or phospholipids; hydrolysis of short-chain fatty acid ester was 30,000-fold more efficient than that of long-chain fatty acid triacylglycerol. Fasting increased the expression of both genes in white adipose tissue, whereas refeeding suppressed their expression. RNA silencing of TGH-2 reduced isoproterenol-stimulated glycerol release by 10% in 3T3-L1 adipocytes, while its overexpression increased the glycerol release by 20%. Thus, TGH-2 may make a contribution to adipocyte lipolysis during period of increased energy demand.
ESTHER : Okazaki_2006_Diabetes_55_2091
PubMedSearch : Okazaki_2006_Diabetes_55_2091
PubMedID: 16804080

Title : Mutations in Japanese subjects with primary hyperlipidemia--results from the Research Committee of the Ministry of Health and Welfare of Japan since 1996 - Maruyama_2004_J.Atheroscler.Thromb_11_131
Author(s) : Maruyama T , Yamashita S , Matsuzawa Y , Bujo H , Takahashi K , Saito Y , Ishibashi S , Ohashi K , Shionoiri F , Gotoda T , Yamada N , Kita T
Ref : J Atheroscler Thromb , 11 :131 , 2004
Abstract : Primary hyperlipidemia is caused by various molecular defects in lipid metabolism. The Research Committee on Primary Hyperlipidemia organized by the Ministry of Health and Welfare of Japan (present: the Ministry of Health, Labour and Welfare) has investigated reported mutations in Japanese patients with primary hyperlipidemia and related disorders (including hypolipidemia), and has created a database based on the questionnaire sent to the members of council board of the Japan Atherosclerosis Society. Mutations in the following genes were investigated: low density lipoprotein receptor, lecithin: cholesteryl acyltransferase, lipoprotein lipase (LPL), hepatic lipase, apolipoproteins A-I, A-II, A-IV, B, C-II, C-III and E, microsomal triglyceride transfer protein, and cholesterol ester transfer protein (CETP). Until 1998, 922 patients with primary hyperlipidemia and related disorders has been registered with the Research Committee, and 190 mutations in 15 genes had been reported, showing a marked variation in Japanese patients with primary hyperlipidemia and related disorders. So-called "common mutations" have been described in Japanese patients with familial hypercholesterolemia, LPL deficiency and CETP deficiency. The genetic defect of familial combined hyperlipidemia (FCHL) is still unknown although FCHL is speculated to be the most prevalent genetic hyperlipidemia, and further investigations should be performed to elucidate the molecular mechanisms of FCHL
ESTHER : Maruyama_2004_J.Atheroscler.Thromb_11_131
PubMedSearch : Maruyama_2004_J.Atheroscler.Thromb_11_131
PubMedID: 15256764

Title : Absence of hormone-sensitive lipase inhibits obesity and adipogenesis in Lep ob\/ob mice - Sekiya_2004_J.Biol.Chem_279_15084
Author(s) : Sekiya M , Osuga J , Okazaki H , Yahagi N , Harada K , Shen WJ , Tamura Y , Tomita S , Iizuka Y , Ohashi K , Okazaki M , Sata M , Nagai R , Fujita T , Shimano H , Kraemer FB , Yamada N , Ishibashi S
Ref : Journal of Biological Chemistry , 279 :15084 , 2004
Abstract : Hormone-sensitive lipase (HSL) plays a crucial role in the hydrolysis of triacylglycerol and cholesteryl ester in various tissues including adipose tissues. To explore the role of HSL in the metabolism of fat and carbohydrate, we have generated mice lacking both leptin and HSL (Lep(ob/ob)/HSL(-/-)) by cross-breeding HSL(-/-) mice with genetically obese Lep(ob/ob) mice. Unexpectedly, Lep(ob/ob)/HSL(-/-) mice ate less food, gained less weight, and had lower adiposity than Lep(ob/ob)/HSL(+/+) mice. Lep(ob/ob)/HSL(-/-) mice had massive accumulation of preadipocytes in white adipose tissues with increased expression of preadipocyte-specific genes (CAAT/enhancer-binding protein beta and adipose differentiation-related protein) and decreased expression of genes characteristic of mature adipocytes (CCAAT/enhancer-binding protein alpha, peroxisome proliferator activator receptor gamma, and adipocyte determination and differentiation factor 1/sterol regulatory element-binding protein-1). Consistent with the reduced food intake, hypothalamic expression of neuropeptide Y and agouti-related peptide was decreased. Since HSL is expressed in hypothalamus, we speculate that defective generation of free fatty acids in the hypothalamus due to the absence of HSL mediates the altered expression of these orexigenic neuropeptides. Thus, deficiency of both leptin and HSL has unmasked novel roles of HSL in adipogenesis as well as in feeding behavior.
ESTHER : Sekiya_2004_J.Biol.Chem_279_15084
PubMedSearch : Sekiya_2004_J.Biol.Chem_279_15084
PubMedID: 14752112

Title : Absence of sterol regulatory element-binding protein-1 (SREBP-1) ameliorates fatty livers but not obesity or insulin resistance in Lep(ob)\/Lep(ob) mice - Yahagi_2002_J.Biol.Chem_277_19353
Author(s) : Yahagi N , Shimano H , Hasty AH , Matsuzaka T , Ide T , Yoshikawa T , Amemiya-Kudo M , Tomita S , Okazaki H , Tamura Y , Iizuka Y , Ohashi K , Osuga J , Harada K , Gotoda T , Nagai R , Ishibashi S , Yamada N
Ref : Journal of Biological Chemistry , 277 :19353 , 2002
Abstract : Obesity is a common nutritional problem often associated with diabetes, insulin resistance, and fatty liver (excess fat deposition in liver). Leptin-deficient Lep(ob)/Lep(ob) mice develop obesity and those obesity-related syndromes. Increased lipogenesis in both liver and adipose tissue of these mice has been suggested. We have previously shown that the transcription factor sterol regulatory element-binding protein-1 (SREBP-1) plays a crucial role in the regulation of lipogenesis in vivo. To explore the possible involvement of SREBP-1 in the pathogenesis of obesity and its related syndromes, we generated mice deficient in both leptin and SREBP-1. In doubly mutant Lep(ob/ob) x Srebp-1(-/-) mice, fatty livers were markedly attenuated, but obesity and insulin resistance remained persistent. The mRNA levels of lipogenic enzymes such as fatty acid synthase were proportional to triglyceride accumulation in liver. In contrast, the mRNA abundance of SREBP-1 and lipogenic enzymes in the adipose tissue of Lep(ob)/Lep(ob) mice was profoundly decreased despite sustained fat, which could explain why the SREBP-1 disruption had little effect on obesity. In conclusion, SREBP-1 regulation of lipogenesis is highly involved in the development of fatty livers but does not seem to be a determinant of obesity in Lep(ob)/Lep(ob) mice.
ESTHER : Yahagi_2002_J.Biol.Chem_277_19353
PubMedSearch : Yahagi_2002_J.Biol.Chem_277_19353
PubMedID: 11923308