研究者総覧
永島 秀一 (ﾅｶﾞｼﾏ ｼｭｳｲﾁ)
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Last Updated :2022/06/02
研究者情報
ホームページURL
科研費研究者番号
- 30406136
J-Global ID
研究キーワード
- 肝臓 コレステロール 肝障害 ノックアウト ヒト リポ蛋白リパーゼ マウス マクロファージ アルブミン インスリン抵抗性 肥満 HMG-CoA還元酵素 トリグリセリド 脂肪細胞 IMG-CoA還元酵素 動脈硬化 リパーゼ 脂肪酸 スクワレン合成酵素 遺伝子発現
研究分野
経歴
研究活動情報
論文
- Sakai, Kent, Nagashima, Shuichi, Wakabayashi, Tetsuji, Tumenbayar, Bayasgalan, Hayakawa, Hiroko, Hayakawa, Morisada, Karasawa, Tadayoshi, Ohashi, Ken, Yamazaki, Hisataka, Takei, Akihito, Takei, Shoko, Yamamuro, Daisuke, Takahashi, Manabu, Yagyu, Hiroaki, Osuga, Jun-ichi, Takahashi, Masafumi, Tominaga, Shin-ichi, Ishibashi, ShunARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 38 11 2590 - 2600 LIPPINCOTT WILLIAMS & WILKINS 2018年11月 [査読有り][通常論文]
Objective- Inhibition of HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) is atheroprotective primarily by decreasing plasma LDL (low-density lipoprotein)-cholesterol. However, it is unknown whether inhibition of HMGCR in myeloid cells contributes to this atheroprotection. We sought to determine the role of myeloid HMGCR in the development of atherosclerosis. Approach and Results- We generated mice with genetically reduced Hmgcr in myeloid cells ( Hmgcr m-/m-) using LysM (Cre) and compared various functions of their macrophages to those of Hmgcr fl/fl control mice. We further compared the extent of atherosclerosis in Hmgcr m-/ m- and Hmgcr fl/fl mice in the absence of Ldlr (LDL receptor). Hmgcr m-/ m- macrophages and granulocytes had significantly lower Hmgcr mRNA expression and cholesterol biosynthesis than Hmgcr fl/fl cells. In vitro, Hmgcr m-/ m- monocytes/macrophages had reduced ability to migrate, proliferate, and survive compared with Hmgcr fl/fl monocytes/macrophages. However, there was no difference in ability to adhere, phagocytose, store lipids, or polarize to M1 macrophages between the 2 types of macrophages. The amounts of plasma membrane-associated small GTPase proteins, such as RhoA (RAS homolog family member A), were increased in Hmgcr m-/ m- macrophages. In the setting of Ldlr deficiency, Hmgcr m-/ m- mice developed significantly smaller atherosclerotic lesions than Hmgcr fl/fl mice. However, there were no differences between the 2 types of mice either in plasma lipoprotein profiles or in the numbers of proliferating or apoptotic cells in the lesions in vivo. The in vivo migration of Hmgcr m-/ m- macrophages to the lesions was reduced compared with Hmgcr fl/fl macrophages. Conclusions- Genetic reduction of HMGCR in myeloid cells may exert atheroprotective effects primarily by decreasing the migratory activity of monocytes/macrophages to the lesions. - Kenta Okada, Hiroaki Yagyu, Kazuhiko Kotani, Hisataka Yamazaki, Kazufumi Ozaki, Manabu Takahashi, Shuichi Nagashima, Jun-Ichi Osuga, Shun IshibashiEndocrine journal 60 7 913 - 22 2013年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.
- Shuichi Nagashima, Hiroaki Yagyu, Nirei Takahashi, Tomoyuki Kurashina, Manabu Takahashi, Takeshi Tsuchita, Fumiko Tazoe, Xiao Li Wang, Tumenbayar Bayasgalan, Naoko Sato, Kenta Okada, Shoichiro Nagasaka, Takaya Gotoh, Masayuki Kojima, Masanobu Hyodo, Hisanaga Horie, Yoshinori Hosoya, Masaki Okada, Yoshikazu Yasuda, Hiroyuki Fujiwara, Michitaka Ohwada, Sadahiko Iwamoto, Mitsuaki Suzuki, Hideo Nagai, Shun IshibashiJOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS 18 3 190 - 199 2011年 [査読有り][通常論文]
Aim: Adipocyte lipolysis is mediated by a family of triglyceride (TG) lipases consisting of hormone-sensitive lipase (LIPE), adipose triglyceride lipase (PNPLA2) and carboxylesterase 1 (CES1); however, little is known about the relationship between the expression of each gene in different depots and TG lipase activity or obesity Method: We measured both mRNA expression levels of the lipolytic enzymes (LIPE, PNPLA2 and CES1) and TG lipase activities of biopsy samples obtained from subcutaneous, omental and mesenteric adipose tissues of 34 patients who underwent abdominal surgery. The results were correlated with clinical parameters: adiposity measures, parameters for insulin resistance and plasma lipid levels. Results: PNPLA2 mRNA levels were slightly higher in omental fat than subcutaneous fat. Cytosolic TG lipase activities were positively correlated with the mRNA levels of CES1 in subcutaneous fat and mesenteric fat, while they were correlated with those of PNPLA2 in omental fat. The mRNA levels of LIPE were negatively correlated with various measures of adiposity in subcutaneous fat. The mRNA levels of CES1 were positively correlated with various measures of adiposity, particularly those estimated by CT in the three depots; they were also positively correlated with plasma LDL-cholesterol levels in omental fat. In contrast, the mRNA levels of PNPLA2 were not significantly associated with adiposity. Conclusions: The positive correlations of the expression of CES1 with cytosolic TG lipase activities as well as with adiposity suggest that CES1 is involved in lipolysis, thereby contributing to the development of obesity-associated phenotypes. On the other hand, the expression of LIPE is negatively correlated with adiposity. These distinct regulatory patterns of lipolytic genes may underlie the complex phenotypes associated with human obesity. - Lkhagvasuren Munkhtulga, Shuichi Nagashima, Kazuhiro Nakayama, Nanami Utsumi, Yoshiko Yanagisawa, Takaya Gotoh, Toshinori Omi, Maki Kumada, Khadbaatar Zolzaya, Tserenkhuu Lkhagvasuren, Yasuo Kagawa, Hiroyuki Fujiwara, Yoshinori Hosoya, Masanobu Hyodo, Hisanaga Horie, Masayuki Kojima, Shun Ishibashi, Sadahiko IwamotoObesity (Silver Spring, Md.) 18 5 1006 - 14 2010年05月Retinol-binding protein 4 (RBP4) is a recently identified adipokine that was involved in insulin resistance. RBP4 is predominantly expressed from the liver in normal metabolic state to transport retinoids throughout the body, but the exact physiological function and the regulatory mechanisms of adipocyte-derived RBP4 have not been revealed. We conducted the genetic analysis about metabolic parameters in Japanese and Mongolian; the minor allele carriers of regulatory single-nucleotide polymorphism (SNP -803G>A) showed significantly higher BMI in Japanese men (P = 0.009) and women (P = 0.017), and in Mongolian women (P = 0.009). Relative quantification of RBP4 transcripts in -803GA heterozygotes showed that the minor allele-linked haplotype-derived mRNA was significantly more abundant than the transcript from major allele. RBP4 promoter assay in 3T3L1 adipocytes revealed that the minor allele increased the promoter activity double to triple and the administration of 9-cis-retinoic acid (RA) and 8-bromo-cyclic adenosine monophosphate (8-Br-cAMP) enhanced the activity. Multiple alignment analysis of human, mouse, rat, and cattle RBP4 promoter suggested conserved seven transcription factor binding motifs. Electrophoretic mobility shift assay showed the -803G>A SNP modulate the affinity against unidentified DNA-binding factor, which was assumed to be a suppressive factor. These results collectively suggested that the minor allele of RBP4 regulatory SNP enhanced the expression in adipocytes, which may be associated with the adipogenesis.
- Motohiro Sekiya, Jun-Ichi Osuga, Shuichi Nagashima, Taichi Ohshiro, Masaki Igarashi, Hiroaki Okazaki, Manabu Takahashi, Fumiko Tazoe, Taeko Wada, Keisuke Ohta, Mikio Takanashi, Masayoshi Kumagai, Makiko Nishi, Satoru Takase, Naoya Yahagi, Hiroaki Yagyu, Ken Ohashi, Ryozo Nagai, Takashi Kadowaki, Yusuke Furukawa, Shun IshibashiCell metabolism 10 3 219 - 28 2009年09月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.