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ABSTRACT: Postprandial hyperglycemia and/or hyperlipidemia can contribute to development of atherosclerosis in patients with type 2 diabetes mellitus (T2DM). The objective of this study was to compare the effects of miglitol and sitagliptin on postprandial glucose and lipid metabolism in patients with T2DM. Thirty-five patients with T2DM were randomized to 2 groups receiving miglitol (150 mg/day) or sitagliptin (50 mg/day). Serum variables related to glucose and lipid metabolism were measured before and after treatment for 10 weeks and at 0, 60, and 120 min using a cookie-loading test (CLT). After 10 weeks of treatment, miglitol (n = 16) and sitagliptin (n = 18) caused a similarly significant decrease in hemoglobin A1c (mean: 7.6% to 7.3% versus 8.0% to 7.6%) and a significant increase in fasting insulin levels, with a greater increase observed in the miglitol group than in the sitagliptin group (p=0.03). In addition, a significant decrease in the change in glucose levels after the CLT was observed in both groups, with a greater decrease observed in the miglitol group than in the sitagliptin group (p=0.02). The miglitol group also showed a greater decrease in the change in insulin levels after the CLT than the sitagliptin group (p<0.01). The lipid and lipoprotein levels did not show any significant differences between the groups after the CLT. Our results suggested that miglitol and sitagliptin treatment resulted in similar glycemic control but that a greater decrease in postprandial glucose and insulin levels was observed with miglitol compared with sitagliptin in patients with T2DM.
Endocrine Journal 04/2013; · 2.03 Impact Factor
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Satoru Takase, Jun-Ichi Osuga,
Hayato Fujita,
Kazuo Hara,
Motohiro Sekiya,
Masaki Igarashi,
Mikio Takanashi,
Yoshinori Takeuchi,
Yoshihiko Izumida,
Keisuke Ohta, [......],
Yoko Iizuka,
Ken Ohashi,
Hiroshi Yoshida,
Hidekatsu Yanai,
Norio Tada,
Takanari Gotoda,
Shun Ishibashi,
Takashi Kadowaki,
Hiroaki Okazaki,
Naoya Yahagi
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ABSTRACT: Aim: Familial apolipoprotein C-II (apoC-II) deficiency is a rare autosomal recessive disorder with marked hypertriglyceridemia resulting from impaired activation of lipoprotein lipase. In most cases of apoC-II deficiency, causative mutations have been found in the protein-coding region of APOC2; however, several atypical cases of apoC-II deficiency were reported to have markedly reduced, but detectable levels of plasma apoC-II protein (hereafter referred to as hypoapoC-II), which resulted from decreased promoter activity or improper splicing of apoC-II mRNA due to homozygous mutations in APOC2. Here we aim to dissect the molecular bases of a new case of hypoapoC-II.Methods: We performed detailed biochemical/genetic analyses of our new case of hypoapoC-II, manifesting severe hypertriglyceridemia (plasma triglycerides, 3235 mg·dL-1) with markedly reduced levels of plasma apoC-II (0.6 mg·dL-1).Results: We took advantage of a monocyte/macrophage culture system to prove that transcription of apoC-II mRNA was decreased in the patient's cells, which is compatible with the reported features of hypoapoC-II. Concomitantly, transcriptional activity of the minigene reporter construct of the patient's APOC2 gene was decreased; however, no rare variant was detected in the patient's APOC2 gene. Fifty single nucleotide variants were detected in the patient's APOC2, but all were common variants (allele frequencies ＞35%) that are supposedly not causative.Conclusions: A case of apoC-II deficiency was found that is phenotypically identical to hypoapoC-II but with no causative mutations in APOC2, implying that other genes regulate apoC-II levels. The clinical entity of hypoapoC-II is discussed.
Journal of atherosclerosis and thrombosis 03/2013; · 2.69 Impact Factor
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ABSTRACT: The role of macrophage lipoprotein lipase (LpL) in the development of atherosclerosis and adiposity was examined in macrophage LpL knockout (MLpLKO) mice. MLpLKO mice were generated using cre-loxP gene targeting. Loss of LpL in macrophages did not alter plasma LpL activity or lipoprotein levels. Incubation of apolipoprotein E (ApoE)-deficient β-VLDL with peritoneal macrophages from ApoE knockout mice lacking macrophage LpL (MLpLKO/ApoEKO) led to less cholesteryl ester formation than that found with ApoEKO macrophages. MLpLKO/ApoEKO macrophages had reduced intracellular triglyceride levels, with decreased CD36 and carnitine palmitoyltransferase-1 mRNA levels compared to ApoEKO macrophages, when incubated with VLDL. Although both MLpLKO/ApoEKO and ApoEKO mice developed comparable hypercholesterolemia in response to feeding with a Western-type diet for 12 weeks, atherosclerosis was less in MLpLKO/ApoEKO mice. Epididymal fat mass and gene expression levels associated with inflammation did not differ between the two groups. In conclusion, macrophage LpL plays an important role in the development of atherosclerosis, but not adiposity.
The Journal of Lipid Research 02/2013; · 5.56 Impact Factor
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ABSTRACT: There are very few clinical reports that have compared the association between cigarette smoking and microangiopathy in Asian patients with type 1 diabetes mellitus (T1DM). The objective of this study was to assess the relationships between urinary protein concentrations and smoking and gender-based risk factors among patients with T1DM.
A cross-sectional study of 259 patients with T1DM (men/women = 90/169; mean age, 50.7 years) who visited our hospital for more than 1 year between October 2010 and April 2011 was conducted. Participants completed a questionnaire about their smoking habits. Patient characteristics included gender, age, body mass index, blood pressure, hemoglobin A1c, lipid parameters, and microangiopathy. Diabetic nephropathy (DN) was categorized as normoalbuminuria (NA), microalbuminuria (MA), or overt albuminuria (OA) on the basis of the following urinary albumin/creatinine ratio (ACR) levels: NA, ACR levels less than 30 mg/g creatinine (Cr); MA, ACR levels between 30 and 299 mg/g Cr; and OA, ACR levels over 300 mg/g Cr.
The percentages of current nonsmokers and current smokers with T1DM were 73.0% (n = 189) and 27.0% (n = 70), respectively. In addition, the percentage of males was higher than that of females (52.2% versus 13.6%) in the current smoking population. The percentage of DN was 61.8% (n = 160) in patients with NA, 21.6% (n = 56) in patients with MA, and 16.6% (n = 43) in patients with OA. The percentage of males among OA patients was also higher than that of females (24.4% versus 12.4%). However, current smoking status was associated with OA in females with T1DM only [unadjusted odds ratio (OR), 4.13; 95% confidence interval (CI), 1.45-11.73, P < 0.01; multivariate-adjusted OR, 5.41; 95% CI, 1.69-17.30, P < 0.01].
Based on our results in this cross-sectional study of Asian patients with T1DM, smoking might be a risk factor for OA among female patients. Further research is needed of these gender-specific results.
Tobacco Induced Diseases 08/2012; 10(1):12.
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ABSTRACT: To address the effects of ezetimibe on high-density lipoprotein (HDL) metabolism, the HDL subclasses, cholesteryl ester transfer protein (CETP), and lecithin-cholesterol acyltransferase (LCAT) were measured in patients with type 2 diabetes mellitus (T2DM). Twenty-three hypercholesterolemic patients with T2DM were treated with 10 mg of ezetimibe daily for 12 weeks. Plasma total cholesterol (TC), low-density lipoprotein (LDL)-cholesterol (C), HDL-C, HDL(2)-C, HDL(3)-C, CETP mass, and LCAT activity were measured. HDL-C and HDL(2)-C increased by 5% (p<0.05) and 12% (p<0.01), respectively, in response to ezetimibe. Of the 23 patients, 21 had decreased CETP mass, which led to an average reduction of 20% (p<0.0001). LCAT activity also decreased by 6% (p<0.01). A significant positive correlation was found in the changes from baseline between HDL(2)-C and CETP mass, whereas a significant inverse relationship was observed between HDL(3)-C and CETP mass. Furthermore, the change in HDL-C was positively correlated with the change in LCAT activity. In conclusion, ezetimibe may affect HDL metabolism and reverse cholesterol transport, especially CETP, in T2DM. These observations may provide some insights into how ezetimibe prevents atherosclerosis.
Endocrine Journal 07/2012; · 2.03 Impact Factor
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Shuichi Nagashima,
Hiroaki Yagyu,
Ken Ohashi,
Fumiko Tazoe,
Manabu Takahashi,
Taichi Ohshiro,
Tumenbayar Bayasgalan,
Kenta Okada,
Motohiro Sekiya, Jun-ichi Osuga,
Shun Ishibashi
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ABSTRACT: 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) catalyzes the rate-limiting step in cholesterol biosynthesis and has proven to be an effective target of lipid-lowering drugs, statins. The aim of this study was to understand the role of hepatic HMGCR in vivo.
To disrupt the HMGCR gene in liver, we generated mice homozygous for a floxed HMGCR allele and heterozygous for a transgene encoding Cre recombinase under the control of the albumin promoter (liver-specific HMGCR knockout mice). Ninety-six percent of male and 71% of female mice died by 6 weeks of age, probably as a result of liver failure or hypoglycemia. At 5 weeks of age, liver-specific HMGCR knockout mice showed severe hepatic steatosis with apoptotic cells, hypercholesterolemia, and hypoglycemia. The hepatic steatosis and death were completely reversed by providing the animals with mevalonate, indicating its essential role in normal liver function. There was a modest decrease in hepatic cholesterol synthesis in liver-specific HMGCR knockout mice. Instead, they showed a robust increase in the fatty acid synthesis, independent of sterol regulatory element binding protein-1c.
Hepatocyte HMGCR is essential for the survival of mice, and its abrogation elicits hepatic steatosis with jaundice and hypoglycemia.
Arteriosclerosis Thrombosis and Vascular Biology 06/2012; 32(8):1824-31. · 6.37 Impact Factor
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ABSTRACT: The combination of pegylated interferon-α2b (PEG-IFNα) and ribavirin (RBV) is a standard treatment for chronic hepatitis C. The case of a patient with chronic hepatitis C who developed Hashitoxicosis followed by type 1 diabetes mellitus (T1DM) with PEG-IFNα plus RBV combination therapy, but not IFNα alone, is presented.
Diabetes research and clinical practice 12/2011; 95(3):e52-4. · 2.16 Impact Factor
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Michiyo Amemiya-Kudo,
Junko Oka,
Yoshinori Takeuchi,
Hiroaki Okazaki,
Takashi Yamamoto,
Naoya Yahagi,
Kaori Matsuzaka,
Sachiko Okazaki, Jun-ichi Osuga,
Nobuhiro Yamada,
Toshio Murase,
Hitoshi Shimano
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ABSTRACT: Overexpression of sterol regulatory element-binding protein-1c (SREBP-1c) in β cells causes impaired insulin secretion and β cell dysfunction associated with diminished pancreatic duodenal homeodomain transcription factor-1 (PDX-1) expression in vitro and in vivo. To identify the molecular mechanism responsible for this effect, the mouse Pdx-1 gene promoter (2.7 kb) was analyzed in β cell and non-β cell lines. Despite no apparent sterol regulatory element-binding protein-binding sites, the Pdx-1 promoter was suppressed by SREBP-1c in β cells in a dose-dependent manner. PDX-1 activated its own promoter. The E-box (-104/-99 bp) in the proximal region, occupied by ubiquitously expressed upstream stimulatory factors (USFs), was crucial for the PDX-1-positive autoregulatory loop through direct PDX-1·USF binding. This positive feedback activation was a prerequisite for SREBP-1c suppression of the promoter in non-β cells. SREBP-1c and PDX-1 directly interact through basic helix-loop-helix and homeobox domains, respectively. This robust SREBP-1c·PDX-1 complex interferes with PDX-1·USF formation and inhibits the recruitment of PDX-1 coactivators. SREBP-1c also inhibits PDX-1 binding to the previously described PDX-1-binding site (-2721/-2646 bp) in the distal enhancer region of the Pdx-1 promoter. Endogenous up-regulation of SREBP-1c in INS-1 cells through the activation of liver X receptor and retinoid X receptor by 9-cis-retinoic acid and 22-hydroxycholesterol inhibited PDX-1 mRNA and protein expression. Conversely, SREBP-1c RNAi restored Pdx-1 mRNA and protein levels. Through these multiple mechanisms, SREBP-1c, when induced in a lipotoxic state, repressed PDX-1 expression contributing to the inhibition of insulin expression and β cell dysfunction.
Journal of Biological Chemistry 06/2011; 286(32):27902-14. · 4.77 Impact Factor
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Xiao Li Wang, Jun-ichi Osuga,
Fumiko Tazoe,
Kenta Okada,
Shuichi Nagashima,
Manabu Takahashi,
Taichi Ohshiro,
Tumenbayar Bayasgalan,
Hiroaki Yagyu,
Koji Okada,
Shun Ishibashi
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ABSTRACT: Lecithin-cholesterol acyltransferase (LCAT) is an important enzyme involved in the esterification of cholesterol. Here, we report a novel point mutation in the LCAT gene of a 63-year-old female with characteristics of classic familial LCAT deficiency. The patient's clinical manifestations included corneal opacity, mild anemia, mild proteinuria and normal renal function. She had no sign of coronary heart disease. Her LCAT activity was extremely low. DNA sequencing revealed a point mutation in exon 5 of the LCAT gene: a G to C substitution converting Gly(179) to an Arg, located in one of the catalytic triads of the enzyme. In vitro expression of recombinant LCAT proteins in HEK293 cells showed that the mutant G179R protein was present in the cell lysate, but not the culture medium. LCAT activity was barely detectable in the cell lysate or medium of the cells expressing the G179R mutant. This novel missense mutation seems to cause a complete loss of catalytic activity of LCAT, which is also defective in secretion.
Journal of atherosclerosis and thrombosis 05/2011; 18(8):713-9. · 2.69 Impact Factor
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ABSTRACT: Cholesterol ester-laden macrophage foam cells are a hallmark of atherosclerosis. The cycle of esterification and hydrolysis of cholesterol esters is one of the key steps in macrophage cholesterol trafficking. In the process of foam cell formation, excess free cholesterol undergoes esterification by acyl coenzyme A: acylcholesterol transferase 1 (ACAT-1), and fatty acid sterol esters are stored in cytoplasmic lipid droplets. The actions of ACAT-1 are opposed by neutral cholesterol ester hydrolase (nCEH), which generates free cholesterol and fatty acids. The resulting free cholesterol is a preferential source for cholesterol efflux into the extracellular space. Despite the important role of nCEH in protection against foam cell formation and atherosclerosis, the molecular identity of nCEH has long been debated. Although hormone-sensitive lipase (LIPE) has been proposed to be the nCEH in macrophages, recent evidence suggested the existence of other nCEH(s). We have recently identified a novel nCEH, neutral cholesterol ester hydrolase 1 (NCEH1), and demonstrated that NCEH1, in addition to LIPE, primarily mediates the hydrolysis of CE in macrophages. This review focuses on the protective roles of nCEHs in atherosclerosis, with special emphasis on the role of NCEH1.
Journal of atherosclerosis and thrombosis 04/2011; 18(5):359-64. · 2.69 Impact Factor
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Keisuke Ohta,
Motohiro Sekiya,
Hiroshi Uozaki,
Masaki Igarashi,
Satoru Takase,
Masayoshi Kumagai,
Mikio Takanashi,
Yoshinori Takeuchi,
Yoshihiko Izumida,
Midori Kubota,
Makiko Nishi,
Hiroaki Okazaki,
Yoko Iizuka,
Naoya Yahagi,
Hiroaki Yagyu,
Masashi Fukayama,
Takashi Kadowaki,
Ken Ohashi,
Shun Ishibashi, Jun-ichi Osuga
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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.
Biochemical and Biophysical Research Communications 01/2011; 404(1):254-60. · 2.48 Impact Factor
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Masaki Igarashi, Jun-ichi Osuga,
Hiroshi Uozaki,
Motohiro Sekiya,
Shuichi Nagashima,
Manabu Takahashi,
Satoru Takase,
Mikio Takanashi,
Yongxue Li,
Keisuke Ohta, [......],
Makiko Nishi,
Masakiyo Hosokawa,
Christian Fledelius,
Poul Jacobsen,
Hiroaki Yagyu,
Masashi Fukayama,
Ryozo Nagai,
Takashi Kadowaki,
Ken Ohashi,
Shun Ishibashi
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ABSTRACT: 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.
We aimed to identify the enzyme responsible for the CE hydrolysis in human macrophages and to determine its expression in human atherosclerosis.
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.
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.
Circulation Research 11/2010; 107(11):1387-95. · 9.49 Impact Factor
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ABSTRACT: A 59-year-old female with type 1 diabetes and RS3PE had HLA types known to be associated with both diseases. Type 1 diabetes patients suffering from polyarthritis and pitting edema should be examined for possible RS3PE and glucocorticoid therapy may be indicated despite the diabetes.
Diabetes research and clinical practice 10/2010; 91(2):e43-4. · 2.16 Impact Factor
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Yoshinori Takeuchi,
Naoya Yahagi,
Yoshihiko Izumida,
Makiko Nishi,
Midori Kubota,
Yuji Teraoka,
Takashi Yamamoto,
Takashi Matsuzaka,
Yoshimi Nakagawa,
Motohiro Sekiya, [......],
Ken Ohashi, Jun-ichi Osuga,
Takanari Gotoda,
Shun Ishibashi,
Keiji Itaka,
Kazunori Kataoka,
Ryozo Nagai,
Nobuhiro Yamada,
Takashi Kadowaki,
Hitoshi Shimano
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ABSTRACT: Sterol regulatory element-binding protein (SREBP)-1 is a key transcription factor for the regulation of lipogenic enzyme genes
in the liver. Polyunsaturated fatty acids (PUFA) selectively suppress hepatic SREBP-1, but molecular mechanisms remain largely
unknown. To gain insight into this regulation, we established in vivo reporter assays to assess the activities of Srebf1c transcription and proteolytic processing. Using these in vivo reporter assays, we showed that the primary mechanism for PUFA suppression of SREBP-1 is at the proteolytic processing level
and that this suppression in turn decreases the mRNA transcription through lowering SREBP-1 binding to the SREBP-binding element
on the promoter (“autoloop regulatory circuit”), although liver X receptor, an activator for Srebf1c transcription, is not involved in this regulation by PUFA. The mechanisms for PUFA suppression of SREBP-1 confirm that the
autoloop regulation for transcription is crucial for the nutritional regulation of triglyceride synthesis.
Journal of Biological Chemistry 04/2010; 285(15):11681-11691. · 4.77 Impact Factor
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Yoshinori Takeuchi,
Naoya Yahagi,
Yoshihiko Izumida,
Makiko Nishi,
Midori Kubota,
Yuji Teraoka,
Takashi Yamamoto,
Takashi Matsuzaka,
Yoshimi Nakagawa,
Motohiro Sekiya, [......],
Ken Ohashi, Jun-ichi Osuga,
Takanari Gotoda,
Shun Ishibashi,
Keiji Itaka,
Kazunori Kataoka,
Ryozo Nagai,
Nobuhiro Yamada,
Takashi Kadowaki,
Hitoshi Shimano
[show abstract]
[hide abstract]
ABSTRACT: Sterol regulatory element-binding protein (SREBP)-1 is a key transcription factor for the regulation of lipogenic enzyme genes in the liver. Polyunsaturated fatty acids (PUFA) selectively suppress hepatic SREBP-1, but molecular mechanisms remain largely unknown. To gain insight into this regulation, we established in vivo reporter assays to assess the activities of Srebf1c transcription and proteolytic processing. Using these in vivo reporter assays, we showed that the primary mechanism for PUFA suppression of SREBP-1 is at the proteolytic processing level and that this suppression in turn decreases the mRNA transcription through lowering SREBP-1 binding to the SREBP-binding element on the promoter ("autoloop regulatory circuit"), although liver X receptor, an activator for Srebf1c transcription, is not involved in this regulation by PUFA. The mechanisms for PUFA suppression of SREBP-1 confirm that the autoloop regulation for transcription is crucial for the nutritional regulation of triglyceride synthesis.
Journal of Biological Chemistry 02/2010; 285(15):11681-91. · 4.77 Impact Factor
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ABSTRACT: To date, there are very few clinical reports that have compared the effects of ezetimibe on lipid parameters between hypercholesterolemic patients with and without type 2 diabetes mellitus (T2DM). In this study, we recruited patients for hypercholesterolemic groups with T2DM (n = 42; men/women = 24/18; HbA1c = 6.7 ± 5.4%) and without T2DM (n = 21; men/women = 7/14; HbA1c = 5.3 ± 0.4%). Patients were prescribed ezetimibe at a dose of 10 mg/daily for the course of the 12-week study. At baseline and after 12 weeks of treatment, several lipid parameters, including serum low-density-lipoprotein cholesterol (LDL-C), non-high-density-lipoprotein cholesterol (non-HDL-C), high-sensitivity C-reactive protein (hs-CRP), and cholesterol synthesis/absorption-related markers, were measured. Compared with those at the baseline, the levels of LDL-C, non-HDL-C, campesterol, and sitosterol were significantly reduced after 12 weeks of ezetimibe treatment in both groups. After adjusting for confounding factors, such as age, gender, smoking, and BMI, the levels of LDL-C and non-HDL-C displayed significantly greater reductions in the patients with T2DM (-25.1 ± 13.6% in LDL-C, -20.5 ± 11.2% in non-HDL-C) than those without T2DM (-20.5 ± 7.8% in LDL-C, P < 0.05; -17.4 ± 7.6% in non-HDL-C, P < 0.05). The reduction of the level of cholestanol was significantly and positively correlated with those of LDL-C and non-HDL-C in the patients with T2DM. Taken together, these findings indicate that ezetimibe could reduce the levels of atherogenic lipoproteins to a greater extent in hypercholesterolemic patients with T2DM than in those without T2DM.
Endocrine Journal 01/2010; 57(10):903-8. · 2.03 Impact Factor
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Motohiro Sekiya, Jun-Ichi Osuga,
Shuichi Nagashima,
Taichi Ohshiro,
Masaki Igarashi,
Hiroaki Okazaki,
Manabu Takahashi,
Fumiko Tazoe,
Taeko Wada,
Keisuke Ohta, [......],
Masayoshi Kumagai,
Makiko Nishi,
Satoru Takase,
Naoya Yahagi,
Hiroaki Yagyu,
Ken Ohashi,
Ryozo Nagai,
Takashi Kadowaki,
Yusuke Furukawa,
Shun Ishibashi
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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.
Cell metabolism 10/2009; 10(3):219-28. · 17.35 Impact Factor
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Jinya Suzuki,
Masami Ueno,
Miyuki Uno,
Yoshikazu Hirose,
Yasuo Zenimaru,
Sadao Takahashi, Jun-Ichi Osuga,
Shun Ishibashi,
Masafumi Takahashi,
Masamichi Hirose,
Mitsuhiko Yamada,
Fredric B Kraemer,
Isamu Miyamori
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ABSTRACT: Increased fatty acid (FA) flux and intracellular lipid accumulation (steatosis) give rise to cardiac lipotoxicity in both pathological and physiological conditions. Since hormone-sensitive lipase (HSL) contributes to intracellular lipolysis in adipose tissue and heart, we investigated the impact of HSL disruption on cardiac energy metabolism in response to fasting and refeeding. HSL-knockout (KO) mice and wild-type (WT) littermates were fasted for 24 h, followed by ∼6 h of refeeding. Plasma FA concentration in WT mice was elevated twofold with fasting, whereas KO mice lacked this elevation, resulting in twofold lower cardiac FA uptake compared with WT mice. Echocardiography showed that fractional shortening was 15% decreased during fasting in WT mice and was associated with steatosis, whereas both of these changes were absent in KO mice. Compared with Langendorff-perfused hearts isolated from fasted WT mice, the isolated KO hearts also displayed higher contractile function and a blunted response to FA. Although cardiac glucose uptake in KO mice was comparable with WT mice under all conditions tested, cardiac VLDL uptake and lipoprotein lipase (LPL) activity were twofold higher in KO mice during fasting. The KO hearts showed undetectable activity of neutral cholesteryl esterase and 40% lower non-LPL triglyceride lipase activity compared with WT hearts in refed conditions accompanied by overt steatosis, normal cardiac function, and increased mRNA expression of adipose differentiation-related protein. Thus, the dissociation between cardiac steatosis and functional sequelae observed in HSL-KO mice suggests that excess FA influx, rather than steatosis per se, appears to play an important role in the pathogenesis of cardiac lipotoxicity.
AJP Endocrinology and Metabolism 09/2009; 297(5):E1115-24. · 4.75 Impact Factor
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Motohiro Sekiya,
Naoya Yahagi,
Yoshiaki Tamura,
Hiroaki Okazaki,
Masaki Igarashi,
Keisuke Ohta,
Mikio Takanashi,
Masayoshi Kumagai,
Satoru Takase,
Makiko Nishi, [......],
Ken Ohashi,
Yoko Iizuka,
Hiroaki Yagyu,
Takanari Gotoda,
Ryozo Nagai,
Hitoshi Shimano,
Nobuhiro Yamada,
Takashi Kadowaki,
Shun Ishibashi, Jun-ichi Osuga
[show abstract]
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ABSTRACT: It has long been a matter of debate whether the hormone-sensitive lipase (HSL)-mediated lipolysis in pancreatic beta-cells can affect insulin secretion through the alteration of lipotoxicity. We generated mice lacking both leptin and HSL Lep(ob/ob)/HSL(-/-) and explored the role of HSL in pancreatic beta-cells in the setting of obesity. Lep(ob/ob)/HSL(-/-) developed elevated blood glucose levels and reduced plasma insulin levels compared with Lep(ob/ob)/HSL(+/+) in a fed state, while the deficiency of HSL did not affect glucose homeostasis in Lep(+/+) background. The deficiency of HSL exacerbated the accumulation of triglycerides in Lep(ob/ob) islets, leading to reduced glucose-stimulated insulin secretion. The deficiency of HSL also diminished the islet mass in Lep(ob/ob) mice due to decreased cell proliferation. In conclusion, HSL affects insulin secretary capacity especially in the setting of obesity.
Biochemical and Biophysical Research Communications 08/2009; 387(3):511-5. · 2.48 Impact Factor
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Masaki Igarashi, Jun-Ichi Osuga,
Masashi Isshiki,
Motohiro Sekiya,
Hiroaki Okazaki,
Satoru Takase,
Mikio Takanashi,
Keisuke Ohta,
Masayoshi Kumagai,
Makiko Nishi,
Toshiro Fujita,
Ryozo Nagai,
Takashi Kadowaki,
Shun Ishibashi
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ABSTRACT: Neutral cholesterol ester hydrolase (NCEH) accounts for a large part of the nCEH activity in macrophage foam cells, a hallmark of atherosclerosis, but its subcellular localization and structure-function relationship are unknown. Here, we determined subcellular localization, glycosylation, and nCEH activity of a series of NCEH mutants expressed in macrophages. NCEH is a single-membrane-spanning type II membrane protein comprising three domains: N-terminal, catalytic, and lipid-binding domains. The N-terminal domain serves as a type II signal anchor sequence to recruit NCEH to the endoplasmic reticulum (ER) with its catalytic domain within the lumen. All of the putative N-linked glycosylation sites (Asn(270), Asn(367), and Asn(389)) of NCEH are glycosylated. Glycosylation at Asn(270), which is located closest to the catalytic serine motif, is important for the enzymatic activity. Cholesterol loading by incubation with acetyl-LDL does not change the ER localization of NCEH. In conclusion, NCEH is targeted to the ER of macrophages, where it hydrolyzes CE to deliver cholesterol for efflux out of the cells.
The Journal of Lipid Research 08/2009; 51(2):274-85. · 5.56 Impact Factor
