Papers by Hitoshi Shimano
Hepatology, Feb 7, 2020
Dysfunctional hepatic lipid metabolism is a cause of non-alcoholic fatty liver disease (NAFLD), t... more Dysfunctional hepatic lipid metabolism is a cause of non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide, and is closely associated with insulin resistance and type 2 diabetes (T2D). ELOVL fatty acid elongase (Elovl6) is responsible for converting C16 saturated and monounsaturated fatty acids (FAs) into C18 species. We have previously shown that Elovl6 contributes to obesity-induced insulin resistance by modifying hepatic C16/C18-related FA composition. To define the precise molecular mechanism by which hepatic Elovl6 affects energy homeostasis and metabolic disease, we generated liver-specific Elovl6 knockout (LKO) mice. Unexpectedly, LKO mice were not protected from high-fat diet-induced insulin resistance. Instead, LKO mice exhibited higher insulin sensitivity than controls when consuming a high-sucrose diet (HSD), which induces lipogenesis. Hepatic patatin-like phospholipase domain-containing protein 3 (Pnpla3) expression was downregulated in LKO mice, and adenoviral Pnpla3 restoration reversed the enhancement in insulin sensitivity in HSD-fed LKO mice. Lipidomic analyzes showed that the hepatic ceramide(d18:1/18:0) content was lower in LKO mice, which may explain the effect on insulin sensitivity. Ceramide(d18:1/18:0) enhances protein
Nature Medicine, Dec 4, 2005
Using an expression cloning strategy, we have identified TFE3, a basic helix-loop-helix protein, ... more Using an expression cloning strategy, we have identified TFE3, a basic helix-loop-helix protein, as a transactivator of metabolic genes that are regulated through an E-box in their promoters. Adenovirus-mediated expression of TFE3 in hepatocytes in culture and in vivo strongly activated expression of IRS-2 and Akt and enhanced phosphorylation of insulin-signaling kinases such as Akt, glycogen synthase kinase 3b and p70S6 kinase. TFE3 also induced hexokinase II (HK2) and insulin-induced gene 1 (INSIG1). These changes led to metabolic consequences, such as activation of glycogen and protein synthesis, but not lipogenesis, in liver. Collectively, plasma glucose levels were markedly reduced both in normal mice and in different mouse models of diabetes, including streptozotocin-treated, db/db and KK mice. Promoter analyses showed that IRS2, HK2 and INSIG1 are direct targets of TFE3. Activation of insulin signals in both insulin depletion and resistance suggests that TFE3 could be a therapeutic target for diabetes.
Journal of Lipid Research, Jun 1, 2002
The mammalian enzyme involved in the final elongation of de novo fatty acid biosynthesis followin... more The mammalian enzyme involved in the final elongation of de novo fatty acid biosynthesis following the building of fatty acids to 16 carbons by fatty acid synthase has yet to be identified. In the process of searching for genes activated by sterol regulatory element-binding protein 1 (SREBP-1) by using DNA microarray, we identified and characterized a murine cDNA clone that is highly similar to a fatty acyl-CoA elongase gene family such as Cig30, Sscs, and yeast ELOs. Studies on the cells overexpressing the fulllength cDNA indicate that the encoded protein, designated fatty acyl-CoA elongase (FACE), has a FACE activity specific for long-chains; C12-C16 saturated-and monosaturated-fatty acids. Hepatic expression of this identified gene was consistently activated in the livers of transgenic mice overexpressing nuclear SREBP-1a,-1c, or-2. FACE mRNA levels are markedly induced in a refed state after fasting in the liver and adipose tissue. This refeeding response is significantly reduced in SREBP-1 deficient mice. Dietary PUFAs caused a profound suppression of this gene expression, which could be restored by SREBP-1c overexpression. Hepatic FACE expression was also highly up-regulated in leptin-deficient ob/ ob mice. Hepatic FACE mRNA was markedly increased by administration of a pharmacological agonist of liver X-activated receptor (LXR), a dominant activator for SREBP-1c expression. These data indicated that this elongase is a new member of mammalian lipogenic enzymes regulated by SREBP-1, playing an important role in de novo synthesis of long-chain saturated and monosaturated fatty acids in conjunction with fatty acid synthase and stearoyl-CoA desaturase.
Molecular Endocrinology, Jul 1, 2003
As one of the four major families of pattern recognition receptors (PRRs), toll like receptors (T... more As one of the four major families of pattern recognition receptors (PRRs), toll like receptors (TLRs) are crucial and important components of the innate immune system. Peroxisome proliferatoractivated receptors (PPARs) with three isoforms are transcription factors classified as a subfamily of nuclear receptor proteins, and are of significant regulatory activity in cellular differentiation, development, metabolism, and tumorigenesis. It is well established that PPARs agonists display anti-inflammatory effects through inhibition of the nuclear factor-kappa B (NF-κB) pathway, a key regulator of immune and inflammatory responses, in a sense that TLRs signaling pathways are mainly toward activation of NF-κB. Through a systematic review of previous studies, we aimed to address and clarify the reciprocal interaction between TLRs and PPARs in hope to find alternative therapeutic approaches for inflammatory diseases. Among the available scientific database, 31 articles were selected for this review. A comprehensive review of this database confirms the presence of a cross-talk between PPARs and TLRs, indicating that not only PPARs stimulation may affect the expression level of TLRs via several mechanisms leading to modulating TLRs activities, but also TLRs have the potential to moderate the expression of PPARs. We, therefore, conclude that, as a key regulator of the innate immune system, the interaction between PPARs and TLRs is a potential therapeutic target in disease treatment.
Journal of Lipid Research, 2002
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Biochemical and Biophysical Research Communications, 2013
Transcription factor E3 (TFE3) belongs to a basic helix-loop-helix family, and is involved in the... more 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 suggested 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.
Journal of Diabetes Investigation, Apr 25, 2017
Aims/Introduction: Peroxisome proliferator-activated receptor-a (PPARa) is a therapeutic target f... more Aims/Introduction: Peroxisome proliferator-activated receptor-a (PPARa) is a therapeutic target for hyperlipidemia. K-877 is a new selective PPARa modulator (SPPARMa) that activates PPARa transcriptional activity. The aim of the present study was to assess the effects of K-877 on lipid metabolism in vitro and in vivo compared with those of classical PPARa agonists. Materials and Methods: To compare the effects of K-877 on PPARa transcriptional activity with those of the classical PPARa agonists Wy14643 (Wy) and fenofibrate (Feno), the cell-based PPARa transactivation luciferase assay was carried out. WT and Ppara-/mice were fed with a moderate-fat (MF) diet for 6 days, and methionine-choline-deficient (MCD) diet for 4 weeks containing Feno or K-877. Results: In luciferase assays, K-877 activated PPARa transcriptional activity more efficiently than the classical PPARa agonists Feno and Wy. After being fed MF diet containing 0.001% K-877 or 0.2% Feno for 6 days, mice in the K-877 group showed significant increases in the expression of Ppara and its target genes, leading to marked reductions in plasma triglyceride levels compared with those observed in Feno-treated animals. These K-877 effects were blunted in Ppara-/mice, confirming that K-877 activates PPARa. In further experiments, K-877 (0.00025%) and Feno (0.1%) equally improved the pathology of MCD diet-induced non-alcoholic fatty liver disease, with increased expression of hepatic fatty acid oxidation genes. Conclusions: The present data show that K-877 is an attractive PPARa-modulating drug and can efficiently reduce plasma triglyceride levels, thereby alleviating the dysregulation of lipid metabolism.
Endocrine Abstracts, May 3, 2017
Journal of Atherosclerosis and Thrombosis, 2012
The post-challenge glucose (PCG) level has been suggested to be superior to the fasting blood glu... more The post-challenge glucose (PCG) level has been suggested to be superior to the fasting blood glucose (FG) level for predicting the risk of future cardiovascular disease (CVD); however, the extent of its superiority has not been consistently shown among previous cohort studies. Therefore, we conducted a meta-analysis to summarize the quantitative association of FG and PCG with CVD risk and compared the strengths of the two associations. Method: Electronic literature searches using MEDLINE and EMBASE with an additional manual search were conducted for prospective observational studies of the association of FG and PCG with CVD risk. Studies were included if they were prospective studies in which the relative risk (RR) of CVD per 1 standard deviation increase in both FG and PCG could be estimated. Pooled relative risks for the incremental increase were calculated as RRFG and RRPCG using a bivariate random-effects model. Result: Data were obtained from 14 eligible studies that included 70,889 participants and 2,927 cases. The pooled RRFG and RRPCG (95% confidence interval) were, respectively, 1.15 (1.06 to 1.26) and 1.24 (1.12 to 1.36); the difference was significant (P 0.001). The association of PCG with CVD risk was stronger in studies that targeted participants with a baseline mean FG 100 mg/dl (P 0.001) or mean age ≥ 55 years (P 0.004). Conclusions: Overall, the association of PCG with CVD risk was stronger than that of FG by approximately 50% on a log scale. Measuring PCG is especially important in populations with relatively low FG levels or in the elderly, although it is often burdensome in routine clinical practice.
Diabetes Research and Clinical Practice, Oct 1, 2014
Helicobacter pylori (HP) has been a major risk factor for a number of important upper gastrointes... more Helicobacter pylori (HP) has been a major risk factor for a number of important upper gastrointestinal conditions such as chronic gastritis, peptic ulcer disease, and gastric mucosa associated lymphoid tissue lymphoma [1]. Previous metaanalyses for cohort studies reported that HP eradication treatment itself decreased the risk of gastric cancer by 35% [2] and improved the proportion of successful healing of peptic ulcer by 48% [3].
Journal of Biological Chemistry, Jul 1, 2008
2 The abbreviations used are: CDK, cyclin-dependent kinase; RNAi, RNA-mediated interference; MEF,... more 2 The abbreviations used are: CDK, cyclin-dependent kinase; RNAi, RNA-mediated interference; MEF, mouse embryonic fibroblast; HFHS, high fat high sucrose; PPAR, peroxisome proliferator-activated receptor; DEXA, dual energy x-ray absorptiometry; TUNEL, terminal dUTP nick-end labeling; C/EBP, CCAAT/enhancer-binding protein.
Diabetes-metabolism Research and Reviews, Nov 1, 2013
BackgroundUsing high‐normal levels of haemoglobin A1C (Abnormal‐A1C) or fasting plasma glucose (F... more BackgroundUsing high‐normal levels of haemoglobin A1C (Abnormal‐A1C) or fasting plasma glucose (FPG) (Abnormal‐FPG) for diabetes screening are expected to improve the ability to detect persons with or at high risk of diabetes. We assessed the diagnostic and predictive capacity for diabetes of Abnormal‐A1C and Abnormal‐FPG. We compared these to the combined use of the two measures to the single use of either measurement.MethodsWe analysed 31 eligible cross‐sectional or cohort studies that assessed diagnostic or predictive ability, respectively, by using lower A1C and FPG cutoff values than recommended by current diabetes criteria. Positive and negative likelihood ratios (LR+ and LR−) were calculated to assess the ability to confirm or exclude diabetes, respectively, on the basis of a bivariate random‐effects model.ResultsWith both Abnormal‐A1C and Abnormal‐FPG, the pooled LR+ was above 4 for diagnosing diabetes and above 3 for predicting diabetes. However, the pooled LR− for predicting diabetes was higher with Abnormal‐A1C (0.48) and Abnormal‐FPG (0.49) in comparison with that for diagnosing diabetes (0.27, Abnormal‐A1C; 0.28, Abnormal‐FPG). In eight studies that assessed the predictive ability of the combination of A1C and FPG, using either Abnormal‐A1C or Abnormal‐FPG could lower LR− to 0.17 from 0.43 for only Abnormal‐A1C and from 0.38 for only Abnormal‐FPG. Accordingly, LR+ was also lowered to 2.37 from 3.36 for only Abnormal‐A1C and from 3.84 for only‐Abnormal‐FPG.ConclusionThe use of the two blood glucose tests had insufficient capacity to identify subjects at high risk for diabetes but had considerable capacity to identify undiagnosed diabetes. Copyright © 2013 John Wiley & Sons, Ltd.
Medicine, Feb 1, 2017
Comparison of baseline characteristics and clinical course in Japanese patients with type 2 diabe... more Comparison of baseline characteristics and clinical course in Japanese patients with type 2 diabetes among whom different types of oral hypoglycemic agents were chosen by diabetes specialists as initial monotherapy (JDDM 42
The Journal of Clinical Endocrinology and Metabolism, Mar 1, 2013
The objective of the study was to develop a screening score for undiagnosed diabetes by eliciting... more The objective of the study was to develop a screening score for undiagnosed diabetes by eliciting information on noninvasive clinical markers and to assess its effectiveness for identifying the presence of diabetes and predicting future diabetes. Design, Setting, and Participants: A screening score was cross-sectionally developed for 33 335 Japanese individuals aged 18-88 years without known diabetes who underwent a health examination. We validated its utility and compared it with existing screening tools in an independent population (n ϭ 7477). After initial assessment of the instrument, 7332 nondiabetic individuals were followed up for a mean 4.0 years. Results: Prevalence of undiagnosed diabetes (fasting plasma glucose Ն 7.0 mmol/L or glycated hemoglobin Ն 6.5%) was 2.9% (n ϭ 965). Diabetes score included age, sex, family history of diabetes, current smoking habit, body mass index, and hypertension with an area under the receiver-operating characteristics curve of 0.771. Screening with 8 or more points yielded a sensitivity of 72.7% and a specificity of 68.1%. In the validation cohort, the area under the receiver-operating characteristics curve was 0.806. The developed score with 8 or more points had better positive predictive value (9.6%) and positive likelihood ratio (2.52) compared with existing tools (positive predictive value, from 6.9% to 9.4%; positive likelihood ratio, from 1.77 to 2.46) in which each tool's highest combination of sensitivity and specificity was observed. The 4-year cumulative risk of developing diabetes gradually escalated in association with higher screening scores at the initial examination. Conclusions: Our algorism could serve as a self-assessment tool for undiagnosed diabetic patients needing timely medical care and as a prognostic tool for individuals without present diabetes who must be closely followed up to prevent future diabetes.
Diabetologia, Sep 7, 2012
Aims/hypothesis The aims of this study were to assess the clinical significance of introducing Hb... more Aims/hypothesis The aims of this study were to assess the clinical significance of introducing HbA 1c 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, HbA 1c ≥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 HbA 1c 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 + HbA 1c scores was non-significant (0.836 vs 0.837; p00.898). A risk score including family history of diabetes, smoking, obesity and both FPG and HbA 1c had the highest discrimination (0.887, 95% CI 0.871, 0.903). At an optimal cutoff 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 HbA 1c resulted in a net reclassification improvement of 42.7% or 52.3%, respectively (p<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.
Diabetes Care, Apr 11, 2012
ON BEHALF OF THE JAPAN DIABETES COMPLICATIONS STUDY GROUP* OBJECTIVEdTo determine the best lipid ... more ON BEHALF OF THE JAPAN DIABETES COMPLICATIONS STUDY GROUP* OBJECTIVEdTo determine the best lipid variable to predict coronary heart disease (CHD) in Japanese patients with type 2 diabetes. RESEARCH DESIGN AND METHODSdEligible Japanese men and women (1,771) aged 40-70 years with type 2 diabetes from 59 institutes nationwide were followed for a planned 8-year period. The performance of eight conventional lipid variables, i.e., total cholesterol (TC), LDL-cholesterol (LDLC), HDL-cholesterol (HDLC), triglycerides (TGs), non-HDLC, TC/HDLC ratio, LDLC/HDLC ratio, and TG/HDLC ratio, as predictors of incident CHD were evaluated by four methods: hazard ratio (HR) per one SD increment by multivariate Cox analysis, x 2 likelihood ratio test, area under the receiver operating characteristic curve (AUC), and tertile analysis. RESULTSdAlthough all variables significantly predicted CHD events in men, non-HDLC (HR per one SD 1.78 [95% CI 1.43-2.21]; AUC 0.726) and TC/HDLC (HR 1.63 [1.36-1.95]; AUC 0.718) had the better predictive performances among the variables, including LDLC. In women, TGs (log-transformed; HR 1.72 [1.21-2.43]; AUC 0.708) were the best predictor according to results of tertile analysis (HR of the top tertile versus the bottom tertile 4.31 [1.53-12.16]). The associations with incident CHD were linear and continuous. CONCLUSIONSdFor Japanese diabetic men, non-HDLC and TC/HDLC were the best predictors, whereas TGs were most predictive for women. These findings, which included prominent sex differences, should be considered among clinical approaches to risk reduction among East Asians with diabetes.
2 The abbreviations used are: CDK, cyclin-dependent kinase; RNAi, RNA-mediated interference; MEF,... more 2 The abbreviations used are: CDK, cyclin-dependent kinase; RNAi, RNA-mediated interference; MEF, mouse embryonic fibroblast; HFHS, high fat high sucrose; PPAR, peroxisome proliferator-activated receptor; DEXA, dual energy x-ray absorptiometry; TUNEL, terminal dUTP nick-end labeling; C/EBP, CCAAT/enhancer-binding protein.
Atherosclerosis Supplements, 2003
after a 3-day therapy with both simvastatin (from 5.19 to 3.02 µg/L; p=0.08) and fenofibrate (fro... more after a 3-day therapy with both simvastatin (from 5.19 to 3.02 µg/L; p=0.08) and fenofibrate (from 4.18 to 2.37 µg/L; p=0.02). At the site of microvascular injury, a nonsignificant tendency towards the suppressed thrombin formation was also found in response to both hypolipemic drugs (p=0.08 and p=0.1). A significant decrease in serum CRP levels was observed after 3 doses of simvastatin, from mean, 2.11 to 1.18 mg/L (p=0.008) and fenofibrate: 2.19 to 1.46 mg/L (p=0.03). IL-6 was also lower after a 3-day treatment with simvastatin or fenofibrate, compared with the initial values, from 3.1 to 1.73 (p=0.05) and from 2.2 to 1.6 ng/mL (p=0.03), respectively. Our preliminary results indicate that in CAD patients with the elevated cholesterol levels both agents appear to show nonlipid antithrombotic and anti-inflammatory effects as early as after a 3-day treatment.
Nutrients, Sep 21, 2022
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
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Papers by Hitoshi Shimano