Papers - FURUHASHI Masato

Addition of ROCK Inhibitors Alleviates Prostaglandin-Induced Inhibition of Adipogenesis in 3T3L-1 Spheroids.

Yosuke Ida, Tatsuya Sato, Araya Umetsu, Megumi Watanabe, Masato Furuhashi, Fumihito Hikage, Hiroshi Ohguro

Bioengineering (Basel, Switzerland)   9 ( 11 )  2022.11  [International journal]

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To elucidate the additive effects of the ROCK inhibitors (ROCK-i), ripasudil (Rip) and Y27632 on bimatoprost acid (BIM-A), a prostaglandin analog (PG), on adipose tissue, two- and three-dimensional (2D or 3D) cultures of 3T3-L1 cells, the most well characterized cells in the field of lipid research, were used. The cells were subjected to a variety of analyses including lipid staining, real-time cellular metabolic analysis, the mRNA expressions of genes related to adipogenesis and extracellular matrices (ECMs) as well as the sizes and physical properties of the 3D spheroids by a micro-squeezer. BIM-A induced strong inhibitory effects on most of the adipogenesis-related changes in the 2D and 3D cultured 3T3-L1 cells, including (1) the enlargement and softening of the 3D spheroids, (2) a dramatic enhancement in lipid staining and the expression of adipogenesis-related genes, and (3) a decrease in mitochondrial and glycolytic metabolic function. By adding ROCK-i to the BIM-A, most of these BIM-A-induced effects were cancelled. The collective findings reported herein suggest that ROCK-i eliminated the PG-induced suppression of adipogenesis in the 3T3-L1 cells, accompanied by the formation of enlarged 3D spheroids. Such effects of adding ROCK-i to a PG in preadipocytes on cellular properties appear to be associated with the suppression of PG-induced adverse effects, and provide additional insight into our understanding of lipid-related research.

DOI PubMed

The Selective α1 Antagonist Tamsulosin Alters ECM Distributions and Cellular Metabolic Functions of ARPE 19 Cells in a Concentration-Dependent Manner.

Yosuke Ida, Tatsuya Sato, Megumi Watanabe, Araya Umetsu, Yuri Tsugeno, Masato Furuhashi, Fumihito Hikage, Hiroshi Ohguro

Bioengineering (Basel, Switzerland)   9 ( 10 )  2022.10  [International journal]

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The purpose of the present study was to examine the effect of the selective α1 antagonist tamsulosin (TAM) on human retinal pigment epithelium cells, ARPE 19. Two-dimension (2D) and three-dimension (3D) cultured ARPE 19 cells were used in the following characterizations: (1) ultrastructure by scanning electron microscopy (SEM) (2D); (2) barrier functions by transepithelial electrical resistance (TEER) measurements, and FITC-dextran permeability (2D); (3) real time cellular metabolisms by Seahorse Bioanalyzer (2D); (4) physical properties, size and stiffness measurements (3D); and (5) expression of extracellular matrix (ECM) proteins, including collagen1 (COL1), COL4, COL6 and fibronectin (FN) by qPCR and immunohistochemistry (2D and 3D). TAM induced significant effects including: (1) alteration of the localization of the ECM deposits; (2) increase and decrease of the TEER values and FITC-dextran permeability, respectively; (3) energy shift from glycolysis into mitochondrial oxidative phosphorylation (OXPHOS); (4) large and stiffened 3D spheroids; and (5) down-regulations of the mRNA expressions and immune labeling of most ECM proteins in a concentration-dependent manner. However, in some ECM proteins, COL1 and COL6, their immunolabeling intensities were increased at the lowest concentration (1 μM) of TAM. Such a discrepancy between the gene expressions and immunolabeling of ECM proteins may support alterations of ECM localizations as observed by SEM. The findings reported herein indicate that the selective α1 antagonist, TAM, significantly influenced ECM production and distribution as well as cellular metabolism levels in a concentration-dependent manner.

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Fatty liver index(FLI)の高値は虚血性心疾患の独立した予測因子である

森 和真, 田中 希尚, 東浦 幸村, 塙 なぎさ, 大西 浩文, 古橋 眞人

日本高血圧学会総会プログラム・抄録集 ( (NPO)日本高血圧学会 )  44回   60 - 60  2022.10

Fatty liver index(FLI)の高値は虚血性心疾患の独立した予測因子である

森 和真, 田中 希尚, 東浦 幸村, 塙 なぎさ, 大西 浩文, 古橋 眞人

日本高血圧学会総会プログラム・抄録集 ( (NPO)日本高血圧学会 )  44回   60 - 60  2022.10

FGF-2 enhances fibrogenetic changes in TGF-β2 treated human conjunctival fibroblasts.

Yuri Tsugeno, Masato Furuhashi, Tatsuya Sato, Megumi Watanabe, Araya Umetsu, Soma Suzuki, Yosuke Ida, Fumihito Hikage, Hiroshi Ohguro

Scientific reports   12 ( 1 ) 16006 - 16006  2022.09  [International journal]

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The objective of the current study was to examine the effects of fibroblast growth factor-2 (FGF-2) on conjunctival fibrogenesis that was induced by the presence of transforming growth factor-β2 (TGF-β2). Two-dimension (2D) and three-dimension (3D) cultured human conjunctival fibroblasts (HconF) were used for this purpose. The 2D and 3D cultured HconF were characterized by transendothelial electrical resistance (TEER) and FITC dextran permeability measurements (2D), real-time metabolic analyses (2D), size and stiffness measurements (3D), and the mRNA expression of extracellular matrix molecules, their modulators, Tissue inhibitor of metalloproteinases and matrix metalloproteinases and ER-stress related genes (2D and 3D). FGF-2 significantly increased planar proliferation, as evidenced by TEER values and FITC dextran permeability, and shifted glucose metabolism to the energetic phenotype of 2D HconF cells, and the stiffness of the 3D spheroids, and these effects were further enhanced in the presence of TGF-β2. Analyses of the expression of possible candidate molecules involved in cell architecture and stress indicated that some additive effects caused by both factors were also recognized in some of these molecules. The findings reported herein indicate that the FGF-2, either along or additively with TGF- β2 increased the fibrogenetic changes on the plane as well as in the spatial space of HconF cells.

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All Trans-Retinoic Acids Facilitate the Remodeling of 2D and 3D Cultured Human Conjunctival Fibroblasts.

Yuri Tsugeno, Tatsuya Sato, Megumi Watanabe, Megumi Higashide, Masato Furuhashi, Araya Umetsu, Soma Suzuki, Yosuke Ida, Fumihito Hikage, Hiroshi Ohguro

Bioengineering (Basel, Switzerland)   9 ( 9 )  2022.09  [International journal]

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Vitamin A derivative, all-trans-retinoic acid (ATRA), is known to be a potent regulator of the growth and differentiation of various types of cells. In the present study, the unidentified effects of ATRA on superficial and vertical spreading conjunctival scarring were examined. The study involved the use of two-dimensional (2D) and three-dimensional (3D) cultures of human conjunctival fibroblast (HconF) cells in the presence or absence of TGF-β2. The effects of ATRA (1 μM) on superficial or vertical spreading conjunctival scarring were evaluated by the barrier function by trans-endothelial electrical resistance (TEER) and FITC dextran permeability measurements and real-time metabolic analysis, as well as the physical properties, namely, the size and stiffness, of 3D spheroids, respectively. In addition, the expressions of several related molecules, including extracellular matrix (ECM) molecules, ECM modulators including a tissue inhibitor of metalloproteinases (TIMPs), matrix metalloproteinases (MMPs), and ER stress-related factors, were examined. ATRA significantly induced (1) an increase in TEER values and a decrease in FITC dextran permeability, respectively, in the 2D monolayers, and (2) relatively and substantially increased the size and stiffness, respectively, of the 3D spheroids. These ATRA-induced effects were further enhanced in the TGF-β2-treated cells, whereas the TGF-β2-induced enhancement in glycolytic capacity was canceled by the presence of ATRA. Consistent with these physical and morphological effects, the mRNA expressions of several molecules were significantly but differently induced between 2D and 3D cultures by ATRA, although the presence of TGF-β2 did not substantially affect these gene expression levels. The findings reported in this study indicate that ATRA may exacerbate both superficial and vertical conjunctival fibrosis spreading independently of TGF-β2-induced changes.

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All-trans Retinoic Acids Synergistically and Beneficially Affect In Vitro Glaucomatous Trabecular Meshwork (TM) Models Using 2D and 3D Cell Cultures of Human TM Cells.

Megumi Watanabe, Tatsuya Sato, Yuri Tsugeno, Megumi Higashide, Masato Furuhashi, Araya Umetsu, Soma Suzuki, Yosuke Ida, Fumihito Hikage, Hiroshi Ohguro

International journal of molecular sciences   23 ( 17 )  2022.08  [International journal]

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We report herein on the effects of all-trans retinoic acid (ATRA) on two-dimensional (2D) and three-dimensional (3D) cultures of human trabecular meshwork (HTM) cells that were treated with transforming growth factor β2 (TGF-β2). In the presence of 5 ng/mL TGF-β2, the effects of ATRA on the following were observed: (1) the barrier function of the 2D HTM monolayers, as determined by trans-endothelial electrical resistance (TEER) and fluorescein isothiocyanate (FITC) dextran permeability measurements; (2) a Seahorse cellular bio-metabolism analysis; (3) physical properties, including the size and stiffness, of 3D spheroids; (4) the gene expression of extracellular matrix (ECM) molecules, ECM modulators including tissue inhibitor of metalloproteinases (TIMPs), matrix metalloproteinases (MMPs), tight junction (TJ)-related molecules, and endoplasmic reticulum (ER)-stress-related factors. ATRA significantly inhibited the TGF-β2-induced increase in the TEER values and FITC dextran permeability of the 2D monolayers, while an ATRA monotreatment induced similar effects as TGF-β2. A real-time metabolic analysis revealed that ATRA significantly inhibited the TGF-β2-induced shift in metabolic reserve from mitochondrial oxidative phosphorylation to glycolysis in 2D HTM cells, whereas ATRA alone did not induce significant metabolic changes. In contrast, ATRA induced the formation of substantially downsized and softer 3D spheroids in the absence and presence of TGF-β2. The different effects induced by ATRA toward 2D and 3D HTM cells were also supported by the qPCR analysis of several proteins as above. The findings reported here indicate that ATRA may induce synergistic and beneficial effects on TGF-β2-treated 2D- and 3D-cultured HTM cells; those effects varied significantly between the 2D and 3D cultures.

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Brimonidine Modulates the ROCK1 Signaling Effects on Adipogenic Differentiation in 2D and 3D 3T3-L1 Cells

Araya Umetsu, Yosuke Ida, Tatsuya Sato, Megumi Watanabe, Yuri Tsugeno, Masato Furuhashi, Fumihito Hikage, Hiroshi Ohguro

Bioengineering    2022.07  [Refereed]

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An α2-Adrenergic Agonist, Brimonidine, Beneficially Affects the TGF-β2-Treated Cellular Properties in an In Vitro Culture Model

Megumi Watanabe, Tatsuya Sato, Yuri Tsugeno, Megumi Higashide, Masato Furuhashi, Araya Umetsu, Soma Suzuki, Yosuke Ida, Fumihito Hikage, Hiroshi Ohguro

Bioengineering ( {MDPI} {AG} )  9 ( 7 ) 310 - 310  2022.07  [Refereed]

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Human Trabecular Meshwork (HTM) Cells Treated with TGF-β2 or Dexamethasone Respond to Compression Stress in Different Manners.

Megumi Watanabe, Tatsuya Sato, Yuri Tsugeno, Araya Umetsu, Soma Suzuki, Masato Furuhashi, Yosuke Ida, Fumihito Hikage, Hiroshi Ohguro

Biomedicines   10 ( 6 )  2022.06  [International journal]

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To characterize our recently established in vitro glaucomatous human trabecular meshwork (HTM) models using dexamethasone (DEX)- or TGF-β2-treated HTM cells, (1) two-dimensional (2D) cultured HTM cells were characterized by means of the real-time cellular metabolism analysis using a Seahorse analyzer, and (2) the effects of mechanical compression stresses toward the three-dimensional (3D) HTM spheroids were evaluated by analyzing the gene expression of several ECM proteins, inflammatory cytokines, and ER stress-related factors of those 3D HTM spheroid models. The results indicated that (1) the real-time cellular metabolism analysis indicated that TGF-β2 significantly induced an energy shift from mitochondrial oxidative phosphorylation (OXPHOS) into glycolysis, and DEX induced similar but lesser effects. In contrast, ROCK2 inhibition by KD025 caused a substantial reverse energy shift from glycolysis into OXPHOS. (2) Upon direct compression stresses toward the untreated control 3D HTM spheroids, a bimodal fluctuation of the mRNA expressions of ECM proteins was observed for 60 min, that is, initial significant upregulation (0-10 min) and subsequent downregulation (10-30 min) followed by another upregulation (30-60 min); those of inflammatory cytokines and ER stress-related factors were also bimodally changed. However, such compression stresses for 30 min toward TGF-β2- or DEX-treated 3D HTM spheroids induced downregulation of most of those of inflammatory cytokines and ER stress-related factors in addition to upregulation of COL1 and downregulation of FN. The findings presented herein indicate that (1) OXPHOS of the HTM cells was decreased or increased by TGF-β2 or DEX stimulation or ROCK2 inhibition, and (2) mechanical compression stresses toward 3D HTM spheroids may replicate acute, subacute, and chronic HTM models affected by elevated intraocular pressures.

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Metabolic dysfunction-associated fatty liver disease predicts new onset of chronic kidney disease better than does fatty liver or nonalcoholic fatty liver disease.

Marenao Tanaka, Kazuma Mori, Satoko Takahashi, Yukimura Higashiura, Hirofumi Ohnishi, Nagisa Hanawa, Masato Furuhashi

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association    2022.05  [International journal]

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BACKGROUND: Possible associations of chronic kidney disease (CKD) with fatty liver (FL) and nonalcoholic fatty liver disease (NAFLD) have recently been focused on. Metabolic dysfunction-associated fatty liver disease (MAFLD), defined as FL with overweight/obesity, type 2 diabetes mellitus or metabolic abnormalities, has been proposed as a new feature of chronic liver disease. However, the relationship between MAFLD and new onset of CKD has not been fully addressed. METHODS: We investigated the associations of FL, NAFLD and MAFLD with the development of CKD, defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2 or positive for urinary protein, over a 10-year period in 28 890 Japanese subjects who received annual health examinations. After exclusion of subjects with no data for abdominal ultrasonography and subjects with CKD at baseline, a total of 13 159 subjects (men/women: 8581/4578, mean age: 48 years) were recruited. RESULTS: The prevalences of FL, NAFLD and MAFLD were 34.6% (men/women: 45.1%/15.1%), 32.8% (men/women: 42.7%/14.5%) and 32.3% (men/women: 42.4%/13.4%), respectively. During the 10-year follow-up period, 2163 subjects (men/women: 1475/688) had new onset of CKD. Multivariable Cox proportional hazard model analyses showed that MAFLD (hazard ratio [95% confidence interval]: 1.12 [1.02-1.26], p = 0.027), but not FL or NAFLD, was an independent risk factor for new onset of CKD after adjustment of age, sex, eGFR, current smoking habit, ischemic heart disease, diabetes mellitus, overweight/obesity, hypertension and dyslipidemia. The addition of MAFLD (continuous net reclassification improvement [NRI]: 0.154, integrated discrimination improvement [IDI]: 0.0024) to traditional risk factors without metabolic abnormalities significantly improved the discriminatory capacity better than did the addition of FL (NRI: 0.138, IDI: 0.0018) or NAFLD (NRI: 0.132, IDI: 0.0017). CONCLUSIONS: MAFLD is modestly and independently associated with new onset of CKD and predicts the risk for development of CKD better than does FL or NAFLD.

DOI PubMed

High fatty liver index is an independent predictor of ischemic heart disease during a 10-year period in a Japanese population.

Kazuma Mori, Marenao Tanaka, Yukimura Higashiura, Nagisa Hanawa, Hirofumi Ohnishi, Masato Furuhashi

Hepatology research : the official journal of the Japan Society of Hepatology   52 ( 8 ) 687 - 698  2022.05  [International journal]

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AIM: Fatty liver index (FLI), which is calculated by using body mass index, waist circumference and levels of γ-glutamyl transferase and triglycerides, is a validated surrogate marker of nonalcoholic fatty liver disease. We retrospectively investigated the relationship between FLI and the development of ischemic heart disease (IHD) during a 10-year period. METHODS: Among subjects who received annual health checkups (n = 28 990), a total of 18 851 subjects (men/women: 11 659/7192) were enrolled after exclusion of subjects with missing data and those with IHD at baseline. RESULTS: FLI at baseline was significantly higher in men than in women. During the 10-year period, 450 men (3.9%) and 123 women (1.7%) had new onset of IHD determined by a self-reported questionnaire survey. Multivariable Cox proportional hazard models with a restricted cubic spline showed that hazard risk (HR) for the development of IHD increased with a higher FLI at baseline after adjustment of age, sex, current smoking habit, family history of IHD and diagnosis of diabetes mellitus, hypertension, dyslipidemia and chronic kidney disease at baseline. There was no significant interaction between FLI and sex for the adjusted HR. When divided by tertiles of FLI at baseline (T1∼T3), the adjusted risk for development of IHD in the T3 group (HR [95% confidence interval]: 1.34 [1.05-1.71]) was significantly higher than that in the T1 group as the reference. The addition of FLI into traditional risk factors for IHD significantly improved the discriminatory capability. CONCLUSIONS: A high level of FLI is an independent predictor of new onset of IHD during a 10-year period.

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Hypoxia Differently Affects TGF-β2-Induced Epithelial Mesenchymal Transitions in the 2D and 3D Culture of the Human Retinal Pigment Epithelium Cells.

Soma Suzuki, Tatsuya Sato, Megumi Watanabe, Megumi Higashide, Yuri Tsugeno, Araya Umetsu, Masato Furuhashi, Yosuke Ida, Fumihito Hikage, Hiroshi Ohguro

International journal of molecular sciences   23 ( 10 )  2022.05  [International journal]

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The hypoxia associated with the transforming growth factor-β2 (TGF-β2)-induced epithelial mesenchymal transition (EMT) of human retinal pigment epithelium (HRPE) cells is well recognized as the essential underlying mechanism responsible for the development of proliferative retinal diseases. In vitro, three-dimensional (3D) models associated with spontaneous O2 gradients can be used to recapitulate the pathological levels of hypoxia to study the effect of hypoxia on the TGF-β2-induced EMT of HRPE cells in detail, we used two-dimensional-(2D) and 3D-cultured HRPE cells. TGF-β2 and hypoxia significantly and synergistically increased the barrier function of the 2D HRPE monolayers, as evidenced by TEER measurements, the downsizing and stiffening of the 3D HRPE spheroids and the mRNA expression of most of the ECM proteins. A real-time metabolic analysis indicated that TGF-β2 caused a decrease in the maximal capacity of mitochondrial oxidative phosphorylation in the 2D HRPE cells, whereas, in the case of 3D HRPE spheroids, TGF-β2 increased proton leakage. The findings reported herein indicate that the TGF-β2-induced EMT of both the 2D and 3D cultured HRPE cells were greatly modified by hypoxia, but during these EMT processes, the metabolic plasticity was different between 2D and 3D HRPE cells, suggesting that the mechanisms responsible for the EMT of the HRPE cells may be variable during their spatial spreading.

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Reply to the comments of Naharci <i>et al</i> . on “Circulating level of fatty acid‐binding protein 4 is an independent predictor of metabolic dysfunction‐associated fatty liver disease in middle‐aged and elderly individuals”

Marenao Tanaka, Masato Furuhashi

Journal of Diabetes Investigation ( Wiley )  13 ( 5 ) 928 - 929  2022.05

DOI

代謝異常関連脂肪肝疾患(MAFLD)とCKD発症リスクの関連についての検討

田中 希尚, 高橋 聖子, 森 和真, 東浦 幸村, 大西 浩文, 塙 なぎさ, 古橋 眞人

日本腎臓学会誌 ( (一社)日本腎臓学会 )  64 ( 3 ) 223 - 223  2022.05

代謝異常関連脂肪肝疾患(MAFLD)とCKD発症リスクの関連についての検討

田中 希尚, 高橋 聖子, 森 和真, 東浦 幸村, 大西 浩文, 塙 なぎさ, 古橋 眞人

日本腎臓学会誌 ( (一社)日本腎臓学会 )  64 ( 3 ) 223 - 223  2022.05

Increased LDL cholesterol level is associated with deterioration of renal function in males

Arata Osanami, Marenao Tanaka, Masato Furuhashi, Hirofumi Ohnishi, Nagisa Hanawa, Tomohisa Yamashita, Norihito Moniwa, Tetsuji Miura

Clinical Kidney Journal ( Oxford University Press (OUP) )   2022.04

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Abstract Background Relationships between levels of serum lipid fractions and the time course of renal function are discrepant in the literature. Here we examined this issue by analyses of healthy subjects in a cohort. Methods Of all subjects who received health examinations at Keijinkai Maruyama Clinic, Sapporo in 2006, subjects with hypertension, diabetes mellitus or chronic kidney disease (CKD) and those taking medication for dyslipidemia were excluded, and a total of 5,586 subjects (male/female: 3,563/2,023, mean age: 43 ± 8 years) were followed for 10 years. Results Linear mixed effect models showed that baseline low-density lipoprotein (LDL)-cholesterol level was negatively associated with estimated glomerular filtration rate (eGFR) during the 10-year follow-up period after adjustment of confounders. Interactions between the follow-up year and baseline level of LDL-cholesterol or high-density lipoprotein (HDL)-cholesterol for eGFR values during the follow-up period were significant in males but not in females. There were no significant interactions for eGFR between the follow-up year and baseline levels of total cholesterol, triglycerides, or HDL-cholesterol/triglycerides ratio. During the follow-up period, 346 males and 223 females developed CKD. When male subjects were divided into subgroups according to tertiles of baseline levels of LDL-cholesterol, the adjusted risk for CKD in the third tertial group was significantly higher than that in the first tertile group as a reference (hazard ratio [95% confidence interval]: 1.39 [1.02-1.90], p = 0.035). Such a difference was not observed for LDL-cholesterol tertiles in females or HDL-cholesterol tertiles in both sexes. Conclusions A high LDL-cholesterol level may be a risk factor of new-onset CKD in apparently healthy males.

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High fibrosis-4 (FIB-4) index predicts new onset of ischemic heart disease during a 10-year period in a general population

Yukimura Higashiura, Marenao Tanaka, Kazuma Mori, Takuma Mikami, Itaru Hosaka, Hirofumi Ohnishi, Nagisa Hanawa, Masato Furuhashi

European Heart Journal Open ( Oxford University Press (OUP) )   2022.04

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Abstract Aims The fibrosis-4 (FIB-4) index, calculated by using age, platelet count and levels of aspartate aminotransferase and alanine aminotransferase, is a noninvasive indicator for detection of liver fibrosis. Advanced hepatic fibrosis is associated with morbidity and mortality in patients with nonalcoholic fatty liver disease. However, the relationship between liver fibrosis and the development of ischemic heart disease (IHD) has not fully been addressed. Methods and Results We investigated the association between FIB-4 index and new onset of IHD during a 10-year period in a general population of subjects who received annual health examinations (n = 28,990). After exclusion of subjects with missing data and those with a history of IHD at baseline, a total of 13,448 subjects (men/women: 8,774/4,674, mean age: 48 years) were included. During the 10-year period, 378 men (4.3%) and 77 women (1.6%) had new onset of IHD. Multivariable Cox proportional hazard models with a restricted cubic spline showed that hazard risk for the development of IHD increased with a higher FIB-4 index at baseline after adjustment of age, sex, fatty liver (FL) determined by ultrasonography, estimated glomerular filtration rate, habits of current smoking and alcohol drinking, family history of IHD, and diagnosis of hypertension, diabetes mellitus and dyslipidemia. When divided by FL, FIB-4 index was an independent predictor for the development of IHD in subjects with FL but not in those without FL. The addition of FIB-4 index to traditional risk factors for IHD significantly improved the discriminatory capability. Conclusion A high level of FIB-4 index predicts new onset of IHD during a 10-year period.

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Fibrosis-4(FIB-4)Indexは新規の虚血性心疾患発症の独立した予測因子である

東浦 幸村, 古橋 眞人, 田中 希尚, 森 和真, 高橋 聖子, 大西 浩文, 塙 なぎさ

糖尿病 ( (一社)日本糖尿病学会 )  65 ( Suppl.1 ) S - 187  2022.04

Plasma Tsukushi Concentration Is Associated with High Levels of Insulin and FGF21 and Low Level of Total Cholesterol in a General Population without Medication.

Masato Furuhashi, Yukimura Higashiura, Akiko Sakai, Masayuki Koyama, Marenao Tanaka, Shigeyuki Saitoh, Kazuaki Shimamoto, Hirofumi Ohnishi

Metabolites   12 ( 3 )  2022.03  [International journal]

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Tsukushi (TSK) is a member of the small leucine-rich proteoglycan family that controls developmental processes and organogenesis. TSK was also identified as a new hepatokine, which is mainly expressed in the liver, and is secreted by hepatocytes, to regulate energy and glycolipid metabolism in response to nonalcoholic fatty liver disease. However, the role of plasma TSK, especially its role in the general population, has not been fully addressed. We investigated the associations between plasma TSK concentration and several metabolic markers, including fibroblast growth factor 21 (FGF21), a hepatokine, and adiponectin, an adipokine, in 253 subjects (men/women: 114/139) with no medication in the Tanno-Sobetsu Study, which employed a population-based cohort. There was no significant sex difference in plasma TSK concentration, and the level was positively correlated with the fatty liver index (FLI) (r = 0.131, p = 0.038), levels of insulin (r = 0.295, p < 0.001) and levels of FGF21 (r = 0.290, p < 0.001), and was negatively correlated with the total cholesterol level (r = -0.124, p = 0.049). There was no significant correlation between the TSK level and body mass index, waist circumference, adiponectin, high-density lipoprotein cholesterol or total bile acids. The multivariable regression analysis showed that high levels of insulin and FGF21 and a low level of total cholesterol were independent determinants of plasma TSK concentration, after adjustment for age, sex and FLI. In conclusion, plasma TSK concentration is independently associated with high levels of insulin and FGF21, a hepatokine, and a low level of total cholesterol, but not with adiposity and adiponectin, in a general population of subjects who have not taken any medications.

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