Faculty Profiles - SONE, Hirohito

Papers - SONE, Hirohito

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Risk of Cardiovascular Diseases Is Increased Even with Mild Diabetic Retinopathy The Japan Diabetes Complications Study Reviewed

Ryo Kawasaki, Shiro Tanaka, Sachiko Tanaka, Sachi Abe, Hirohito Sone, Koutaro Yokote, Shun Ishibashi, Shigehiro Katayama, Yasuo Ohashi, Yasuo Akanuma, Nobuhiro Yamada, Hidetoshi Yamashita

OPHTHALMOLOGY 120 ( 3 ) 574 - 582 2013.3

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Objective: Diabetic retinopathy (DR) is linked to cardiovascular risk in diabetic patients. This study examined whether mild-stage DR is associated with risk of coronary heart disease (CHD) and stroke in type 2 diabetic patients of the Japan Diabetes Complications Study (JDCS).
Design: Prospective cohort study.
Participants: In the JDCS, there were 2033 Japanese persons with type 2 diabetes free of cardiovascular diseases at baseline.
Methods: Diabetic retinopathy was ascertained from clinical and photographic grading (70%) following the international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Incident CHD and stroke were followed up prospectively annually up to 8 years.
Main Outcome Measures: Eight-year incidence of CHD and stroke compared between persons with or without DR.
Results: After adjusting for traditional cardiovascular risk factors, persons with mild to moderate nonproliferative DR had a higher risk of CHD (hazard ratio [HR], 1.69; 95% confidence interval [CI], 1.17-2.97) and stroke (HR, 2.69; 95% CI, 1.03-4.86). Presence of retinal hemorrhages or microaneurysms was associated with risk of CHD (HR, 1.63; 95% CI, 1.04-2.56) but was not associated with stroke (P = 0.06). Presence of cotton-wool spots was associated with risk of incident stroke (HR, 2.39; 95% CI, 1.35-4.24) but was not associated with CHD (P = 0.66). When information about DR was added in the prediction models for CHD and stroke based on traditional cardiovascular risk factors, the area under the receiver operating curve improved from 0.682 to 0.692 and 0.640 to 0.677, and 9% and 13% of persons were reclassified correctly for CHD and stroke, respectively.
Conclusions: Type 2 diabetic patients with even a mild stage of DR, such as dot hemorrhages, are already at higher risk of CHD and stroke independent of traditional risk factors.
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2013;120:574-582 (C) 2013 by the American Academy of Ophthalmology.

DOI： 10.1016/j.ophtha.2012.08.029

Comparison of Education-Only versus Group-Based Intervention in Promoting Weight Loss: A Randomised Controlled Trial (vol 4, pg 222, 2011)

Nakata, Yoshio, Okada, Masafumi, Hashimoto, Koichi, Harada, Yoshinori, Sone, Hirohito, Tanaka, Kiyoji

OBESITY FACTS 6 ( 1 ) 89 - 90 2013.3

The hyperglycemia stimulated myocardial endoplasmic reticulum (ER) stress contributes to diabetic cardiomyopathy in the transgenic-non-obese type 2 diabetic rats: A differential role of unfolded protein response (UPR) signaling proteins Reviewed

Arun Prasath Lakshmanan, Meilei Harima, Kenji Suzuki, Vivian Soetikno, Masaki Nagata, Takashi Nakamura, Toshihiro Takahashi, Hirohito Sone, Hiroshi Kawachi, Kenichi Watanabe

INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY 45 ( 2 ) 438 - 447 2013.2

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

It has been well demonstrated that excessive blood glucose level could be detrimental to the myocardial function through the variety of mechanisms, of which endoplasmic reticulum stress (ERS) could play an unprecedented role through the activation of unfolded protein response (UPR). Recently, reports are coming out with the evidences that UPR signaling proteins are regulated differentially depend on the experimental conditions and cell types. In addition, ERS has been proposed to be closely associated with the regulation of lipogenesis. Therefore, in this study we tried to find out the expressions of myocardial UPR signaling proteins as well as proteins involved in lipid and glucose metabolism in non-obese type 2 diabetic mellitus (DM) condition using Spontaneous Diabetic Toni (SDT) rat. We have found the significant up-regulation of oxidative, nitrosative and ERS marker proteins in the myocardium of the SDT rats, in comparison to its normal (Sprague-Dawley - SD) rats. In addition, the sub-arm-of UPR signaling proteins, such as p-PERK, p-eIF2 alpha, ATF6, CHOP/GADD153, TRAF2, apoptotic signaling proteins, such as BAD, cytochrome C, cleaved caspase-7 and -12, were significantly up-regulated in the SDT rats, in comparison to the SD rats. Interestingly, there were no significant changes in the phosphorylation of IRE-1 alpha, and XBP-1 protein expression. In addition, the proteins involved in lipid and glucose metabolisms, such as PPAR alpha, PPAR gamma, CPT1, PGC-1 alpha except GLUT4, and the proteins involved in insulin signaling, such as p-Akt and p-PI3K were shown significant attenuation in its expressions in the SDT rats, when compared with the SD rats. Taken together, it is suggested that the activation of PERK and ATF6 pathway are the major determinant rather than the IRE-1 alpha-XBP1 pathway for the ERS-mediated metabolic dysfunction, which might eventually leads to diabetic cardiomyopathy in non-obese type 2 DM. (c) 2012 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.biocel.2012.09.017

Association Between Physical Activity and Risk of All-Cause Mortality and Cardiovascular Disease in Patients With Diabetes A meta-analysis Reviewed

Satoru Kodama, Shiro Tanaka, Yoriko Heianza, Kazuya Fujihara, Chika Horikawa, Hitoshi Shimano, Kazumi Saito, Nobuhiro Yamada, Yasuo Ohashi, Hirohito Sone

DIABETES CARE 36 ( 2 ) 471 - 479 2013.2

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：AMER DIABETES ASSOC

OBJECTIVE-The association between habitual physical activity (PA) and lowered risk of all-cause mortality (ACM) and cardiovascular disease (CVD) has been suggested in patients with diabetes. This meta-analysis summarizes the risk reduction in relation to PA, focusing on clarifying dose-response associations.
RESEARCH DESIGN AND METHODS-Electronic literature searches were conducted for cohort studies that examined relative risk (RR) of ACM or CVD in relation to PA in patients with diabetes. For the qualitative assessment, RR for the highest versus the lowest PA category in each study was pooled with a random-effects model. We added linear and spline regression analyses to assess the quantitative relationship between increases in PA and ACM and CVD risk.
RESULTS-There were 17 eligible studies. Qualitatively, the highest PA category had a lower RR [95% CI] for ACM (0.61 [0.52-0.70]) and CVD (0.71 [0.60-0.84]) than the lowest PA category. The linear regression model indicated a high goodness of fit for the risk of ACM (adjusted R-2 = 0.44, P = 0.001) and CVD (adjusted R-2 = 0.51, P = 0.001), with the result that a 1 MET-h/day incrementally higher PA was associated with 9.5% (5.0-13.8%) and 7.9% (4.3-11.4%) reductions in ACM and CVD risk, respectively. The spline regression model was not significantly different from the linear model in goodness of fit (P = 0.14 for ACM risk; P = 0.60 for CVD risk).
CONCLUSIONS-More PA was associated with a larger reduction in future ACM and CVD risk in patients with diabetes. Nevertheless, any amount of habitual PA was better than inactivity. Diabetes Care 36:471-479, 2013

DOI： 10.2337/dc12-0783

Metabolic predictors of ischemic heart disease and cerebrovascular attack in elderly diabetic individuals: Difference in risk by age Reviewed

Toshio Hayashi, Atsushi Araki, Seinosuke Kawashima, Hirohito Sone, Hiroshi Watanabe, Takashi Ohrui, Koutaro Yokote, Minoru Takemoto, Kiyoshi Kubota, Mitsuhiko Noda, Hiroshi Noto, Koichiro Ina, Hideki Nomura

Cardiovascular Diabetology 12 ( 1 ) 10 2013.1

Language：English Publishing type：Research paper (scientific journal)

Background: High LDL-cholesterol (LDL-C) and glucose levels are risk factors for ischemic heart disease (IHD) in middle-aged diabetic individuals
however, the risk among the elderly, especially the very elderly, is not well known. The aim of this study was to identify factors that predict IHD and cerebrovascular attack (CVA) in the elderly and to investigate their differences by age.Methods: We performed a prospective cohort study (Japan Cholesterol and Diabetes Mellitus Study) with 5.5 years of follow-up. A total of 4,014 patients with type 2 diabetes and without previous IHD or CVA (1,936 women
age 67.4 ± 9.5 years, median 70 years
&lt
65 years old, n = 1,261
65 to 74 years old, n = 1,731
and ≥ 75 years old, n = 1,016) were recruited on a consecutive outpatient basis from 40 hospitals throughout Japan. Lipids, glucose, and other factors related to IHD or CVA risk, such as blood pressure (BP), were investigated using the multivariate Cox hazard model.Results: One hundred fifty-three cases of IHD and 104 CVAs (7.8 and 5.7/1,000 people per year, respectively) occurred over 5.5 years. Lower HDL-cholesterol (HDL-C) and female gender were correlated with IHD in patients ≥75 years old (hazard ratio (HR):0.629, P &lt
0.01 and 1.132, P &lt
0.05, respectively). In contrast, systolic BP (SBP), HbA1C, LDL-C and non-HDL-C were correlated with IHD in subjects &lt
65 years old (P &lt
0.05), and the LDL-C/HDL-C ratio was correlated with IHD in all subjects. HDL-C was correlated with CVA in patients ≥75 years old (HR: 0.536, P &lt
0.01). Kaplan-Meier estimator curves showed that IHD occurred more frequently in patients &lt
65 years old in the highest quartile of the LDL-C/HDL-C ratio. In patients ≥75 years old, IHD and CVA were both the most frequent among those with the lowest HDL-C levels.Conclusions: IHD and CVA in late elderly diabetic patients were predicted by HDL-C. LDL-C, HbA1C, SBP and non-HDL-C are risk factors for IHD in the non-elderly. The LDL-C/HDL-C ratio may represent the effects of both LDL-C and HDL-C. These age-dependent differences in risk are important for developing individualized strategies to prevent atherosclerotic disease.Trial registration: UMIN-CTR, UMIN00000516. © 2013 Hayashi et al
licensee BioMed Central Ltd.

DOI： 10.1186/1475-2840-12-10

Diabetes and Risk of Hearing Impairment in Adults: A Meta-Analysis Reviewed

Chika Horikawa, Satoru Kodama, Shiro Tanaka, Kazuya Fujihara, Reiko Hirasawa, Yoko Yachi, Hitoshi Shimano, Nobuhiro Yamada, Kazumi Saito, Hirohito Sone

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 98 ( 1 ) 51 - 58 2013.1

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：ENDOCRINE SOC

Context: Recently, several studies have investigated the relationship between diabetes and hearing impairment, but results were inconsistent.
Objective: Our objective was to compare the prevalence of hearing impairment between diabetic and nondiabetic adults. Data Sources : We performed a systematic literature search using MEDLINE (1950 to May 30, 2011) and EMBASE (1974 to May 30, 2011).
Study Selection: Cross-sectional studies were included if data on numbers of hearing-impaired and non-hearing-impaired cases with diabetes were presented. Hearing impairment was limited to that assessed by pure-tone audiometry that included at least 2 kHz of frequency range and was defined as progressive, chronic, sensorineural, or without specified cause.
Data Extraction: Two authors independently extracted relevant data. Odd ratios (ORs) of hearing impairment related to diabetes calculated in each study were pooled with the random-effects model.
Data Synthesis: Data were obtained from 13 eligible studies (20,194 participants and 7,377 cases). Overall pooled OR (95% confidence interval) of hearing impairment for diabetic participants compared with nondiabetic participants was 2.15 (1.72-2.68). OR was higher in younger participants (mean age, <= 60 yr) than in those over 60 yr among which the OR remained significant (2.61 and 1.58, P = 0.008). The strength of the association between diabetes and prevalence of hearing impairment was not significantly influenced by whether participants were matched for age and gender (P = 0.68) or whether participants chronically exposed to noisy environments were excluded (P = 0.19).
Conclusions: Current meta-analysis suggests that the higher prevalence of hearing impairment in diabetic patients compared with nondiabetic patients was consistent regardless of age. (J Clin Endocrinol Metab 98: 51-58, 2013)

DOI： 10.1210/jc.2012-2119

Nutrition education in Japanese medical schools: A follow-up survey Reviewed

Hideo Orimo, Takahiro Ueno, Hiroshi Yoshida, Hirohito Sone, Akira Tanaka, Hiroshige Itakura

Asia Pacific Journal of Clinical Nutrition 22 ( 1 ) 144 - 149 2013.1

Language：English Publishing type：Research paper (scientific journal)

A questionnaire survey was used to determine the status of nutrition education in Japanese medical schools in 2009. A similar survey was conducted in 2004, at which time nutritional education was determined to be inadequate in Japanese medical schools. The current questionnaire was sent to the directors of Centers for Medical Education of 80 medical schools, who represented all medical schools in Japan. Sixty-seven medical schools (83.8%) responded, of which 25 schools (37.3%) offered dedicated nutrition courses and 36 schools (53.7%) did not offer dedicated nutrition courses but offered something related to nutrition in other courses
six schools (9.0%) did not offer any nutrition education. Overall, 61 schools (91.0%) offered at least some nutritional topics in their undergraduate education. Nevertheless, only 11 schools (16.4%) seem to dedicate more than 5 hours to substantial nutrition education as judged by their syllabi. Although the mean length of the course was 11 hours, substantial nutrition education accounted for only 4.2 hours. Of the 25 medical schools that offered dedicated nutrition courses, seven schools offered the nutrition course as a stand-alone course and 18 schools offered it as an integrated course. In conclusion, the status of nutrition education in Japan has improved slightly but is still inadequate.

DOI： 10.6133/apjcn.2013.22.1.13

TFE3 inhibits myoblast differentiation in C2C12 cells via down-regulating gene expression of myogenin Reviewed

Ayano Naka, Kaoruko Tada Iida, Yoshimi Nakagawa, Hitoshi Iwasaki, Yoshinori Takeuchi, Aoi Satoh, Takashi Matsuzaka, Kiyo-aki Ishii, Kazuto Kobayashi, Shigeru Yatoh, Masako Shimada, Naoya Yahagi, Hiroaki Suzuki, Hirohito Sone, Nobuhiro Yamada, Hitoshi Shimano

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 430 ( 2 ) 664 - 669 2013.1

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Transcription factor E3 (TFE3) belongs to a basic-helix-loop-helix family, and is involved in the biology of osteoclasts, melanocytes and their malignancies. We previously reported the metabolic effects of TFE3 on insulin in the liver and skeletal muscles in animal models. In the present study, we explored a novel role for TFE3 in a skeletal muscle cell line. When TFE3 was overexpressed in C2C12 myoblasts by adenovirus before induction of differentiation, myogenic differentiation of C2C12 cells was significantly inhibited. Adenovirus-mediated TFE3 overexpression also suppressed the gene expression of muscle regulatory factors (MRFs), such as MyoD and myogenin, during C2C12 differentiation. In contrast, knockdown of TFE3 using adenovirus encoding short-hairpin RNAi specific for TFE3 dramatically promoted myoblast differentiation associated with significantly increased expression of MRFs. Consistent with these findings, promoter analyses via luciferase reporter assay and electrophoretic mobility shift assay suggestid that TFE3 negatively regulated myogenin promoter activity by direct binding to an E-box, E2, in the myogenin promoter. These findings indicated that TFE3 has a regulatory role in myoblast differentiation, and that transcriptional suppression of myogenin expression may be part of the mechanism of action. (C) 2012 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2012.11.094

Low BMI at age 20years predicts gestational diabetes independent of BMI in early pregnancy in Japan: Tanaka Women's Clinic Study Reviewed

Y. Yachi, Y. Tanaka, I. Nishibata, A. Sugawara, S. Kodama, K. Saito, H. Sone

Diabetic Medicine 30 ( 1 ) 70 - 73 2013.1

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

Aims Maternal obesity and weight gain since early adulthood are known predictors of gestational diabetes in Western countries. However, their impact has not been evaluated well in Asia, where mean BMI levels are generally lower than in Western countries. We therefore examined the associations of BMI at age 20years and BMI change since age 20years with the risk of gestational diabetes in Japanese pregnant women. Methods Six hundred and twenty-four consecutive pregnant women without recognized diabetes before pregnancy, whose initial obstetric clinic visit was before 13weeks' gestation, were prospectively observed. Weight at age 20years was self-reported. Baseline height and weight measurements were obtained at the initial obstetric visit. Multivariate logistic regression analysis estimated the risk of incident gestational diabetes for BMI change since 20years and BMI at age 20years. Results Twenty-eight women developed incident gestational diabetes. By multivariate logistic regression analysis that adjusted for maternal age, parity and baseline BMI, we observed a statistically significant inverse association between BMI at age 20years and incidence of gestational diabetes (odds ratio 0.68, 95% CI 0.51-0.92). Similarly, when we assessed the association of BMI change since age 20years, adjusted for maternal age and parity, BMI change was associated with an increased risk of gestational diabetes (odds ratio 1.26, 95%CI 1.03-1.53). When we focused on the threshold of risk of gestational diabetes, women with BMI at 20years of less than 18kg/m2 had a 6.30-fold (2.26-17.59) greater risk than women with both BMI at age 20years of 18kg/m2 or more and BMI change since age 20years of less than 1.85. Conclusions Both low BMI at age 20years and BMI change since age 20years were significantly associated with increased risk of incident gestational diabetes. © 2012 Diabetes UK.

DOI： 10.1111/j.1464-5491.2012.03712.x

The Relationship between Diabetic Neuropathy and Sleep Apnea Syndrome: A Meta-Analysis. Reviewed International journal

Kazuya Fujihara, Satoru Kodama, Chika Horikawa, Sakiko Yoshizawa, Ayumi Sugawara, Reiko Hirasawa, Hitoshi Shimano, Yoko Yachi, Akiko Suzuki, Osamu Hanyu, Hirohito Sone

Sleep disorders 2013 150371 - 150371 2013

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

Aims. High prevalence of sleep apnea syndrome (SAS) has been reported in patients with diabetes. However, whether diabetic neuropathy (DN) contributes to this high prevalence is controversial. Our aim of this study is to compare the prevalence of SAS between patients with and without DN. Methods. Systematic literature searches were conducted for cross-sectional studies that reported the number of patients with DN and SAS using MEDLINE (from 1966 to Nov 5, 2012) and EMBASE (from 1974 to Nov 5, 2012). Odds ratios (ORs) of SAS related to DN were pooled with the Mantel-Haenszel method. Results. Data were obtained from 5 eligible studies (including 6 data sets, 880 participants, and 429 cases). Overall, the pooled OR of SAS in patients with DN compared with that in non-DN patients was significant (OR (95% CI), -1.95 (1.03-3.70)). The pooled OR of SAS was 1.90 (0.97-3.71) in patients with type 2 diabetes. Excluding data on patients with type 1 diabetes, a higher OR was observed in younger patients (mean age <60 years) than in those ≥60 years among whom the OR remained significant (3.82; 95% CI, 2.24-6.51 and 1.17; 95% CI, 0.81-1.68). Conclusions. Current meta-analysis suggested the association of some elements of neuropathy with SAS in type 2 diabetes. Further investigations are needed to clarify whether the association is also true for patients with type 1 diabetes.

DOI： 10.1155/2013/150371

Carotid artery plaque and LDL-to-HDL cholesterol ratio predict atherosclerotic status in coronary arteries in asymptomatic patients with type 2 diabetes mellitus Reviewed

Kazuya Fujihara, Hiroaki Suzuki, Akira Sato, Satoru Kodama, Yoriko Heianza, Kazumi Saito, Hitoshi Iwasaki, Kazuto Kobayashi, Shigeru Yatoh, Akimitsu Takahashi, Nobuhiro Yamada, Hirohito Sone, Hitoshi Shimano

Journal of Atherosclerosis and Thrombosis 20 ( 5 ) 452 - 464 2013

Language：English Publishing type：Research paper (scientific journal)

Aims: To investigate the clinical predictors of coronary atherosclerosis and to assess the utility of maximum-IMT for predicting coronary atherosclerosis in asymptomatic type 2 diabetic patients. Methods: One hundred one Japanese patients with type 2 diabetes underwent computed tomography coronary angiography. Definitions of coronary artery stenosis and vulnerable coronary plaque were luminal narrowing of ≥50% and any coronary plaque with positive vessel remodeling and low attenuation, respectively. Carotid intima-media thickness (IMT) was assessed using B-mode ultrasound. Results: Of the 101 patients, 40 had coronary artery stenosis without vulnerable coronary plaque, 7 had vulnerable coronary plaque without coronary artery stenosis, and 23 had coronary artery stenosis with vulnerable coronary plaque. Male sex (p= 0.031), duration of diabetes (p= 0.024), systolic blood pressure (SBP) (p=0.039), and the LDL/HDL ratio (LDL/HDL) (p=0.013) were independent predictors of coronary artery stenosis and the LDL/HDL (p=0.042) independently predicted vulnerable coronary plaque by logistic regression analyses. Areas under the curves in receiver operating characteristic curve analysis of the maximum-IMT, LDL/HDL, and these two parameters combined were 0.711 (95% CI 0.601-0.820), 0.618 (0.508-0.728), and 0.732 (0.632-0.831), respectively, for predicting coronary artery stenosis and 0.655 (0.537-0.773), 0.629 (0.504-0.754), and 0.710 (0.601- 0.818), respectively, for predicting vulnerable coronary plaque. Conclusions: Male sex, duration of diabetes, elevated SBP, and LDL/HDL were independent predictors of coronary artery stenosis. LDL/HDL was an independent predictor of vulnerable coronary plaque. Maximum-IMT predicted both coronary stenosis and vulnerable coronary plaque. Adding LDL/HDL improved the prediction of coronary artery stenosis and vulnerable coronary plaque.

DOI： 10.5551/jat.14977

Various Components of Blood Pressure as Stroke Risk in Japanese Patients With Type 2 Diabetes: Analysis from the Japan Diabetes Complications Study (JDCS)

Hirohito Sone

Diabetes 2013

Combined Risk of Alcohol Intake and Smoking for Development of Type 2 Diabetes in the General Population in Japan: The Ibaraki Prefectural Health Study

Hirohito Sone

Diabetes 2013

Effects of Recommendation Notices for Clinic Visits by Nationwide Health Screening System in Japan

Hirohito Sone

Diabetes 2013

Elovl6 Promotes Nonalcoholic Steatohepatitis Reviewed

Takashi Matsuzaka, Ayaka Atsumi, Rie Matsumori, Tang Nie, Haruna Shinozaki, Noriko Suzuki-Kemuriyama, Motoko Kuba, Yoshimi Nakagawa, Kiyoaki Ishii, Masako Shimada, Kazuto Kobayashi, Shigeru Yatoh, Akimitsu Takahashi, Kazuhiro Takekoshi, Hirohito Sone, Naoya Yahagi, Hiroaki Suzuki, Soichiro Murata, Makoto Nakamuta, Nobuhiro Yamada, Hitoshi Shimano

HEPATOLOGY 56 ( 6 ) 2199 - 2208 2012.12

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Nonalcoholic steatohepatitis (NASH) is associated with obesity and type 2 diabetes, and an increased risk for liver cirrhosis and cancer. ELOVL family member 6, elongation of very long chain fatty acids (Elovl6), is a microsomal enzyme that regulates the elongation of C12-16 saturated and monounsaturated fatty acids (FAs). We have shown previously that Elovl6 is a major target for sterol regulatory element binding proteins in the liver and that it plays a critical role in the development of obesity-induced insulin resistance by modifying FA composition. To further investigate the role of Elovl6 in the development of NASH and its underlying mechanism, we used three independent mouse models with loss or gain of function of Elovl6, and human liver samples isolated from patients with NASH. Our results demonstrate that (1) Elovl6 is a critical modulator for atherogenic high-fat diet-induced inflammation, oxidative stress, and fibrosis in the liver; (2) Elovl6 expression is positively correlated with severity of hepatosteatosis and liver injury in NASH patients; and (3) deletion of Elovl6 reduces palmitate-induced activation of the NLR family pyrin domain-containing 3 inflammasome; this could be at least one of the underlying mechanisms by which Elovl6 modulates the progress of NASH. Conclusion: Hepatic long-chain fatty acid composition is a novel determinant in NASH development, and Elovl6 could be a potential therapeutic target for the prevention and treatment of NASH. (HEPATOLOGY 2012;56:2199-2208)

DOI： 10.1002/hep.25932

Development of a new scoring system for predicting the 5 year incidence of type 2 diabetes in Japan: the Toranomon Hospital Health Management Center Study 6 (TOPICS 6) Reviewed

Y. Heianza, Y. Arase, S. D. Hsieh, K. Saito, H. Tsuji, S. Kodama, S. Tanaka, Y. Ohashi, H. Shimano, N. Yamada, S. Hara, H. Sone

Diabetologia 55 ( 12 ) 3213 - 3223 2012.12

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

Aims/hypothesis The aims of this study were to assess the clinical significance of introducing HbA1c into a risk score for diabetes and to develop a scoring system to predict the 5 year incidence of diabetes in Japanese individuals. Methods The study included 7,654 non-diabetic individuals aged 40-75 years. Incident diabetes was defined as fasting plasma glucose (FPG) ≤7.0 mmol/l, HbA1c ≤6.5% (48 mmol/mol) or self-reported clinician-diagnosed diabetes. We constructed a risk score using non-laboratory assessments (NLA) and evaluated improvements in risk prediction by adding elevated FPG, elevated HbA1c or both to NLA. Results The discriminative ability of the NLA score (age, sex, family history of diabetes, current smoking and BMI) was 0.708. The difference in discrimination between the NLA + FPG and NLA + HbA1c scores was non-significant (0.836 vs 0.837
p=0.898). A risk score including family history of diabetes, smoking, obesity and both FPG and HbA1c had the highest discrimination (0.887, 95% CI 0.871, 0.903). At an optimal cut-off point, sensitivity and specificity were high at 83.7% and 79.0%, respectively. After initial screening using NLA scores, subsequent information on either FPG or HbA1c resulted in a net reclassification improvement of 42.7% or 52.3%, respectively (p&lt
0.0001). When both were available, net reclassification improvement and integrated discrimination improvement were further improved at 56.7% (95% CI 47.3%, 66.1%) and 10.9% (9.7%, 12.1%), respectively. Conclusions/interpretation Information on HbA1c or FPG levels after initial screening by NLA can precisely refine diabetes risk reclassification. © Springer-Verlag 2012.

DOI： 10.1007/s00125-012-2712-0

Enhancement of antigen presenting ability in the leukemic plasmacytoid dendritic cell line (PMDC05) by lentiviral vector-mediated transduction of CD80 gene Reviewed

Akie Yamahira, Miwako Narita, Kayoko Ishii, R. M. Chamila Jayathilake, Minami Iwabuchi, Naoya Satoh, Takayoshi Uchiyama, Tomoyo Taniguchi, Shigeo Hashimoto, Noriyuki Kasahara, Emmanuelle Faure, Brooke Bogan, Jun Takizawa, Hirohito Sone, Masuhiro Takahashi

LEUKEMIA RESEARCH 36 ( 12 ) 1541 - 1546 2012.12

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

PMDC05, a leukemic plasmacytoid dendritic cell (pDC) line which was established in our laboratory, showed a capacity of generating antigen-specific cytotoxic T lymphocytes (CTLs). In order to enhance an antigen presenting ability of PMDC05, PMDC05 was transduced with CD80 gene by lentiviral vector, which was named as PMDC11. PMDC11 displayed a strong antigen presenting ability even without any stimulation, and by culturing with stimulators such as calcium ionophore PMDC11 gained a more potent antigen presenting ability. Our data suggested PMDC11 could be applied as antigen presenting cells more efficiently in adoptive cellular immunotherapy for tumors and severe infections in comparison with PMDC05. (C) 2012 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.leukres.2012.09.002

Cholesterol sulfate induces expression of the skin barrier protein filaggrin in normal human epidermal keratinocytes through induction of ROR alpha Reviewed

Osamu Hanyu, Hanako Nakae, Takashi Miida, Yuko Higashi, Hirotoshi Fuda, Motohiro Endo, Atsushi Kohjitani, Hirohito Sone, Charles A. Strott

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 428 ( 1 ) 99 - 104 2012.11

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Cholesterol sulfate is abundant in the human epidermis and is a putative natural ligand for retinoic acid receptor-related orphan receptor alpha (ROR alpha). Although direct binding of cholesterol sulfate is expected to activate ROR alpha, cholesterol sulfate can also induce ROR alpha expression and increase ROR alpha target gene expression. The purpose of this study was to determine whether cholesterol sulfate induces profilaggrin expression, a precursor of the barrier protein filaggrin in the epidermis, through activation of ROR alpha by directly binding to ROR alpha, or through increased ROR alpha expression. Immunohistochemical and polymerase chain reaction (PCR) analyses showed that ROR alpha was expressed in normal human epidermal keratinocytes (NHEKs) and that its expression increased during keratinocyte differentiation in parallel with that of profilaggrin and cholesterol sulfotransferase, which catalyzes the synthesis of cholesterol sulfate. Exogenous cholesterol sulfate significantly increased both ROR alpha and profilaggrin expression in NHEKs, whereas no effect on profilaggrin expression was observed in cells in which ROR alpha was knocked down with small interfering RNA (siRNA). Additionally, a luciferase reporter gene assay revealed that exogenous ROR alpha dose-dependently increased the activity of the profilaggrin gene promoter even in the absence of cholesterol sulfate, and that this response involves activator protein-1. In conclusion, the results of this study indicate that cholesterol sulfate induces filaggrin expression through increased ROR alpha expression. Further studies are required to fully elucidate the mechanisms involved. (C) 2012 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2012.10.013

Self-reported rate of eating is significantly associated with body mass index in Japanese patients with type 2 diabetes. Japan Diabetes Clinical Data Management Study Group (JDDM26) Reviewed

Aki Saito, Koichi Kawai, Morifumi Yanagisawa, Hiroki Yokoyama, Nobuichi Kuribayashi, Hidekatsu Sugimoto, Mariko Oishi, Takako Wada, Koichi Iwasaki, Azuma Kanatsuka, Noriharu Yagi, Fuminobu Okuguchi, Kazuhiro Miyazawa, Keiko Arai, Kazumi Saito, Hirohito Sone

APPETITE 59 ( 2 ) 252 - 255 2012.10

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD

We examined whether the rate of eating was associated with the body mass index and glycemic control status in Japanese patients with type 2 diabetes (50% women, mean +/- SD age 59.4 +/- 7.5 years). Rapid eating was significantly associated with body mass index (p = 0.047). The body mass index of those who reported eating quickly was 0.8 kg/m(2) higher than in individuals who reported eating at medium speed even after adjustment for known confounders. No significant association was observed between the rate of eating and HbA(1c). Our findings suggest an association between self-reported rapid eating and an elevated body mass index in patients with type 2 diabetes. (C) 2012 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.appet.2012.05.009

Development of Coronary Heart Disease and Cerebral Stroke in Japanese Elderly Patients with Nonalcoholic Fatty Liver Diseases

OGAWA Kyoko, OHMONTO SEKINE Yuki, HARA Shigeko, OKUDA Chikao, AMAKAWA Kazuhisa, ARIMOTO Satao, KATO Hisahito, HSIEH Shiun Dong, TANABE Maho, OGATA Chie, ISHIHARA Makiko, TSUJI Hiroshi, SAITO Kazumi, KODAMA Satoru, SONE Hirohito, ARASE Yasuji

Official Journal of the Japanese Society of Human Dry Dock 27 ( 3 ) 561 - 567 2012.9

Language：English Publisher：Japan Society of Ningen Dock

<b>Objective: </b>Metabolic syndrome enhances coronary heart disease and cerebral stroke. However, few longitudinal studies have been conducted on the incidence of coronary heart disease and cerebral stroke in Japanese patients with non-alcoholic fatty liver disease (NAFLD) and the risk factors for its development. <br><b>Methods: </b>A total of 1,798 NAFLD patients with an age of ≥60 years were enrolled. The primary event was the first onset of coronary heart disease or cerebral stroke. Independent factors associated with the incidence rate of such events were analyzed by the Kaplan-Meyer method and the Cox proportional hazard model. The mean observation period was 7.5 years.<br><b>Results: </b>The number of cases of coronary heart disease or cerebral stroke that developed was 137. The 10th year cumulative development rate was 11.7% in the NAFLD patients. Cox proportional hazards analysis revealed the following: 1) Coronary heart disease occurred with statistical significance when patients had poor control of blood pressure, smoking, low high density lipoprotein level, and high glucose level. 2) Ischemic stroke occurred with statistical significance when patients had poor control of blood pressure, an age of ≥70 years, and high glucose level. 3) Hemorrhagic stroke occurred with statistical significance when patients had poor control of blood pressure, age ≥70 years, low albumin level of <3.9 g/dL and high aspartate aminotransferase to platelet ratio index. <br><b>Conclusion: </b>Our study indicates that the risk factors for the development of vascular disease are different for coronary heart disease, ischemic stroke and hemorrhagic stroke in Japanese elderly patients with NAFLD.

DOI： 10.11320/ningendock.27.561

Other Link： https://jlc.jst.go.jp/DN/JALC/10009979603?from=CiNii

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