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Dive into the research topics where Katsumi Aragane is active.

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Featured researches published by Katsumi Aragane.


Circulation | 2001

Acyl-CoA:Cholesterol Acyltransferase Inhibition Reduces Atherosclerosis in Apolipoprotein E–Deficient Mice

Jun Kusunoki; Dipal K. Hansoty; Katsumi Aragane; John T. Fallon; Juan J. Badimon; Edward A. Fisher

Background—Acyl-CoA:cholesterol acyltransferase (ACAT) converts cholesterol to cholesteryl esters. The form of ACAT in macrophages, ACAT1, contributes to foam cell formation in the arterial wall and the development of atherosclerosis. Recent studies in a mouse model of atherosclerosis (the apolipoprotein E [apoE]-deficient mouse), however, have suggested that complete deficiency of ACAT1 activity is not antiatherogenic, in part because of toxicity resulting from adverse effects on tissue cholesterol homeostasis. We have tested whether partial inhibition of ACAT1 and ACAT2 (expressed in liver and intestine) activities reduces atherosclerosis development in apoE-deficient mice and avoids toxicity. Methods and Results—ApoE-deficient mice were maintained for 17 weeks on a Western-type diet without (control) or with the ACAT inhibitor F-1394 (effective against ACAT1 and ACAT2) at doses of either 300 (low) or 900 (high) mg/kg. Intimal lesion area at the aortic sinus in controls was 0.69±0.06 mm2. F-1394 treatment significantly decreased lesional area by 39% (low) or 45% (high). F-1394 treatment also reduced lesional immunostaining for macrophages by 61% (low) or 83% (high). En face analysis showed that surface lipid staining in control aortas was 20.0±2.8%; F-1394 treatment reduced this by 46% (low) or 62% (high). There were no obvious signs of systemic or vessel wall toxicity associated with F-1394 treatment. Conclusions—Partial ACAT inhibition by F-1394 had antiatherogenic effects in apoE-deficient mice that were achieved without obvious toxicity. Partial ACAT inhibition may have therapeutic potential in the clinical treatment of atherosclerosis.


Molecular and Cellular Biology | 2007

Hepatic De Novo Lipogenesis Is Present in Liver-Specific ACC1-Deficient Mice

Naomoto Harada; Zenjun Oda; Yoshikazu Hara; Koji Fujinami; Mayumi Okawa; Katsuya Ohbuchi; Mari Yonemoto; Yuika Ikeda; Kenji Ohwaki; Katsumi Aragane; Yoshitaka Tamai; Jun Kusunoki

ABSTRACT Acetyl coenzyme A (acetyl-CoA) carboxylase (ACC) catalyzes carboxylation of acetyl-CoA to form malonyl-CoA. In mammals, two isozymes exist with distinct physiological roles: cytosolic ACC1 participates in de novo lipogenesis (DNL), and mitochondrial ACC2 is involved in negative regulation of mitochondrial β-oxidation. Since systemic ACC1 null mice were embryonic lethal, to clarify the physiological role of ACC1 in hepatic DNL, we generated the liver-specific ACC1 null mouse by crossbreeding of an Acc1lox(ex46) mouse, in which exon 46 of Acc1 was flanked by two loxP sequences and the liver-specific Cre transgenic mouse. In liver-specific ACC1 null mice, neither hepatic Acc1 mRNA nor protein was detected. However, to compensate for ACC1 function, hepatic ACC2 protein and activity were induced 1.4 and 2.2 times, respectively. Surprisingly, hepatic DNL and malonyl-CoA were maintained at the same physiological levels as in wild-type mice. Furthermore, hepatic DNL was completely inhibited by an ACC1/2 dual inhibitor, 5-tetradecyloxyl-2-furancarboxylic acid. These results strongly demonstrate that malonyl-CoA from ACC2 can access fatty acid synthase and become the substrate for the DNL pathway under the unphysiological circumstances that result with ACC1 disruption. Therefore, there does not appear to be strict compartmentalization of malonyl-CoA from either of the ACC isozymes in the liver.


Biochemical and Biophysical Research Communications | 2009

Role of MGAT2 and DGAT1 in the release of gut peptides after triglyceride ingestion

Mayumi Okawa; Kenji Fujii; Katsuya Ohbuchi; Mayumi Okumoto; Katsumi Aragane; Hiromu Sato; Yoshitaka Tamai; Toru Seo; Yoshiki Itoh; Ryo Yoshimoto

Triglyceride ingestion releases gut peptides from enteroendocrine cells located in the intestinal epithelia and provides feedback regulations of gastrointestinal function. The precise mechanisms sensing lipids in the intestinal wall, however, are not well characterized. In the current study, we investigated the release of gut peptides following oral triglyceride loading in mice deficient for monoacylglycerol acyltransferase 2 (MGAT2KO) and diacylglycerol acyltransferase 1 (DGAT1KO), enzymes that sequentially re-synthesize triglyceride to secrete as chylomicron at the small intestine. In wild-type (Wt) mice, oral triglyceride loading resulted in hypertriglycemia. In addition, plasma glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were significantly increased 30 min after triglyceride loading, before decaying in 2h. In MGAT2KO and DGAT1KO mice, oral triglyceride loading did not result in hypertriglycemia and the increase in GIP was significantly suppressed in both KO mouse strains. In contrast, the increases in plasma GLP-1 and PYY in both KO mouse strains were comparable to Wt mice 30 min after triglyceride loading, however, they remained elevated in DGAT1KO mice even 2h after triglyceride loading. In parallel to the changes in GLP-1 and PYY, gastric emptying was delayed after oral triglyceride loading in MGAT2KO mice comparably to Wt type mice and was further delayed in DGAT1KO mice. STC-1 and GLUTag, GLP-1-producing intestinal endocrine L-cell lines, displayed a significant level of DGAT1 activity but not MGAT activity. These findings suggest that synthesis and/or secretion of triglyceride-rich lipoproteins play an important role in the release of GIP. Moreover, DGAT1 may directly regulate the release of GLP-1 and PYY in L-cells.


Arteriosclerosis, Thrombosis, and Vascular Biology | 2000

Postprandial Hyperlipidemia in Streptozotocin-Induced Diabetic Rats Is Due to Abnormal Increase in Intestinal Acyl Coenzyme A:Cholesterol Acyltransferase Activity

Jun Kusunoki; Katsumi Aragane; Tetsuya Kitamine; Hideki Kozono; Kyoko Kano; Kouji Fujinami; Kazuhiro Kojima; Tsuyoshi Chiwata; Yasuo Sekine

Postprandial hyperlipidemia (PH) is recognized as a significant risk factor for cardiovascular disease. The present study, involving rats with streptozotocin (STZ)-induced diabetes, was performed to establish a PH model and to examine the relation between small intestinal acyl-coenzyme A:cholesterol acyltransferase (ACAT) activity and serum lipid levels in the postprandial state. The small intestinal ACAT activities in normal rats during the experimental period were 4 to 5 pmol/mg protein per minute. In contrast, in the diabetic rats, the ACAT activities were 2 to 3 times higher than activities seen in normal rats from 7 to 21 days after the STZ injection in the absence of a high fat diet and hyperplasia in the gut. In an oral fat-loading test that used diabetic rats that had been injected with STZ (60 mg/kg) intravenously 14 days previously, the postloading changes in the serum concentrations of total cholesterol (TC) and triglyceride (TG) were significantly greater in the diabetic rats than in normal rats. Single oral administration of (1s,2s)-2-[3-(2,2-dimethylpropyl)-3-nonylureido]cyclohexane- 1-yl 3-[(4R)-N-(2,2,5,5-tetramethyl-1, 3-dioxane-4-carbonyl)amino]propionate (F-1394, 3 to 30 mg/kg), a potent ACAT inhibitor, suppressed the post-fat-loading elevation of serum TC levels in the diabetic rats in a dose-dependent manner without affecting serum glucose levels. Furthermore, the small intestinal ACAT activity, serum TG levels, and lymphatic absorption of TC and TG in the rats that were administered F-1394 (30 mg/kg) were reduced by approximately 90%, 70%, 30%, and 15%, respectively. This is the first evidence that elevated ACAT activity in the gut, unlike hyperplasia and hyperphagia, induces PH in rats. Our results strongly suggest that F-1394 may be a potential treatment for PH in humans.


British Journal of Pharmacology | 2001

Direct effect of an acyl-CoA:cholesterol acyltransferase inhibitor, F-1394, on atherosclerosis in apolipoprotein E and low density lipoprotein receptor double knockout mice.

Tsuyoshi Chiwata; Katsumi Aragane; Koji Fujinami; Kazuhiro Kojima; Shun Ishibashi; Nobuhiro Yamada; Jun Kusunoki

The acyl‐CoA:cholesterol acyltransferase (ACAT) enzyme is thought to be responsible for foam cell formation and the subsequent progression of atherosclerosis. The apolipoprotein E and low density lipoprotein receptor double knockout (apoE/LDLr‐DKO) mouse is an animal model that develops severe hyperlipidaemia and atherosclerosis. Here we have examined the effect of oral administration of an ACAT inhibitor, F‐1394, on atherosclerosis in apoE/LDLr‐DKO mice fed a regular chow diet. In en face analysis, a dose of 10, 30, or 100 mg kg−1 day−1 F‐1394 for 10 weeks reduced the extent of lesions visible in the aorta by 24, 28 and 38%, respectively, as detected by staining with oil red O, without affecting serum cholesterol level in these mice. At the highest dose 100 mg kg−1 day−1 of F‐1394, the reduction was statistically significant. For quantitative analysis of the cellular and non‐cellular components comprising the lesions at the aortic sinus, the effects of an oral dose of 100 mg kg−1 day−1 F‐1394 for 15 weeks were studied. There was a significant reduction (31.9%) in the oil‐red O‐stained area in cross‐sections of the aortic sinus. In addition, the neointimal area, as well as levels of ACAT‐1 protein tended to be decreased (15.2 and 25.8%, respectively, not significant). However, the areas containing macrophages, smooth muscle cells, and collagen were not affected by F‐1394. In vitro, F‐1394 attenuated foam cell formation in mouse peritoneal macrophages. These results indicate that ACAT may be primarily responsible for lipid accumulation in atherosclerotic lesions, and that its inhibition diminishes the lipid deposition via a direct effect on macrophages in the arterial wall.


Atherosclerosis | 2001

Effect of F-1394, an acyl-CoA:cholesterol acyltransferase inhibitor, on atherosclerosis induced by high cholesterol diet in rabbits

Katsumi Aragane; Kazuhiro Kojima; Koji Fujinami; Junzo Kamei; Jun Kusunoki

Cholesterol-fed rabbits were used to study the anti-atherosclerotic effect of (1S,2S)-2-[3-(2,2-dimethylpropyl)-3-nonylureido]cyclohexane-1-yl 3-[(4R)-N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionate (F-1394), an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor. To test its effect on the development of atherosclerosis, rabbits were fed a high-cholesterol diet (HCD) for 6 weeks, followed by regular chow (RC) for 12 weeks plus 0 or 100 mg/kg per day F-1394. Serum total cholesterol (TC) rose to approximately 2000 mg/dl on HCD and then declined gradually after the change in diet in both groups. F-1394 significantly reduced the extent of the atherosclerotic lesions and the total and esterified cholesterol contents of the aorta (by 57,38, and 59%, respectively), without affecting the serum TC level. To clarify whether F-1394 accelerates the regression of preexisting atherosclerosis, rabbits were fed HCD for the first 6 weeks and then RC for the next 6 weeks. Then, the rabbits were given 0 or 100 x 2 mg/kg per day F-1394 for another 12 weeks while on RC. F-1394 significantly reduced the extent of the atherosclerotic lesions and the total and esterified cholesterol content in the aorta (by 31, 31, and 43%, respectively), without affecting the serum TC level. These results demonstrate that F-1394 both prevents the formation of atherosclerosis and accelerates its regression without affecting the serum TC level, indicating that F-1394 acts directly on the arterial wall.


European Journal of Pharmacology | 2010

Discovery and characterization of a novel potent, selective and orally active inhibitor for mammalian ELOVL6

Ken Shimamura; Yasuhisa Miyamoto; Hidefumi Kitazawa; Maki Kanesaka; Ryo Yoshimoto; Katsumi Aragane; Naomi Morita; Tomoyuki Ohe; Toshiyuki Takahashi; Tsuyoshi Nagase; Nagaaki Sato; Shigeru Tokita

The elongase of long chain fatty acids family 6 (ELOVL6) is a rate-limiting enzyme for the elongation of saturated and monounsaturated long chain fatty acids. ELOVL6 is abundantly expressed in lipogenic tissues such as liver, and its mRNA expression is up-regulated in obese model animals. ELOVL6 deficient mice are protected from high-fat-diet-induced insulin resistance, suggesting that ELOVL6 might be a new therapeutic target for diabetes. We previously identified an indoledione compound, Compound A, as the first inhibitor for mammalian ELOVL6. In this study, we discovered a novel compound, Compound B, and characterized its biochemical and pharmacological properties. Compound B has a more appropriate profile for use as a pharmacological tool compared to Compound A. Chronic treatment with Compound B in model animals, diet-induced obesity (DIO) and KKAy mice, showed significant reduction in hepatic fatty acid composition, suggesting that it effectively inhibits ELOVL6 activity in the liver. However, no improvement in insulin resistance by ELOVL6 inhibition was found in these model animals. Further studies need to address the impact of ELOVL6 inhibition on pharmacological abnormalities in several model animals. This is the first report on pharmacology data from chronic studies using a selective ELOVL6 inhibitor. Compound B appears to be a useful tool to further understand the physiological roles of ELOVL6 and to evaluate the therapeutic potential of ELOVL6 inhibitors.


Journal of Medicinal Chemistry | 2009

Synthesis and evaluation of a novel indoledione class of long chain fatty acid elongase 6 (ELOVL6) inhibitors.

Toshiyuki Takahashi; Tsuyoshi Nagase; Takahide Sasaki; Ken Shimamura; Yasuhisa Miyamoto; Hidefumi Kitazawa; Maki Kanesaka; Ryo Yoshimoto; Katsumi Aragane; Shigeru Tokita; Nagaaki Sato

Novel indoledione derivatives were synthesized and evaluated as long chain fatty acid elongase 6 (ELOVL6) inhibitors. Systematic optimization of an indole class of lead 1 led to the identification of potent ELOVL6 selective inhibitors. Representative inhibitor 37 showed sustained plasma exposure and good liver penetrability in mice. After oral administration, 37 potently inhibited ELOVL6 activity in the liver in mice.


Journal of Medicinal Chemistry | 2009

Synthesis and Biological Evaluation of a Novel 3-Sulfonyl-8-azabicyclo[3.2.1]octane Class of Long Chain Fatty Acid Elongase 6 (ELOVL6) Inhibitors

Tsuyoshi Nagase; Toshiyuki Takahashi; Takahide Sasaki; Ken Shimamura; Yasuhisa Miyamoto; Hidefumi Kitazawa; Maki Kanesaka; Ryo Yoshimoto; Katsumi Aragane; Shigeru Tokita; Nagaaki Sato

Long chain fatty acid elongase 6 (ELOVL6) catalyzes the elongation of long chain fatty acyl-CoAs and is a potential target for the treatment of metabolic disorders. The ultrahigh throughput screen of our corporate chemical collections resulted in the identification of a novel 3-sulfonyl-8-azabicyclo[3.2.1]octane class of ELOVL6 inhibitor 1a. Optimization of lead 1a led to the identification of the potent, selective, and orally available ELOVL6 inhibitor 1w.


Folia Pharmacologica Japonica | 1997

ヒト腸上皮細胞株Caco-2のacyl-CoA:cholesterol acyltransferase(ACAT)活性とコレステロールエステル分泌に対するACAT阻害薬,F-1394の作用

Jun Kusunoki; Katsumi Aragane; Tetsuya Kitamine; Tetsuaki Yamaura; Haruo Ohnishi

The present study was conducted to investigate the inhibitory effect of F-1394, a potent and selective inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), on incorporation of 14C-oleic acid into cholesteryl ester in cultured Caco-2 cells, a human intestinal cell line, and compare its effect to those of other ACAT inhibitors and hypolipidemic agents. The cholesterol esterification in Caco-2 cells was strongly inhibited by F-1394 in a concentration-dependent manner with the estimated IC50 value of 71 nM. In contrast, the estimated IC50 values of the other ACAT inhibitors such as YM-17E, CI-976, CL-277,082 and DL-melinamide are 121 nM, 702 nM, 21.5 microM and 20.9 microM, respectively. Simvastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, also inhibited the ACAT activity in Caco-2 cells with an IC50 value of 22.5 microM, whereas pravastatin Na, probucol and clofibrate did not affect the activity. Furthermore, F-1394 at a concentration of 100 nM inhibited the basolateral secretion of cholesteryl ester by 90% from differentiated Caco-2 cells that were cultured on a membrane filter. These results demonstrate that F-1394 strongly inhibits human intestinal ACAT activity and basolateral secretion of cholesterol from Caco-2 cells. Therefore, F-1394 may have a therapeutic potential for dietary hyperlipidemic subjects.

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Haruo Ohnishi

Mochida Pharmaceutical Co.

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