Telomere shortening, atherosclerosis, and metabolic syndrome.
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Arteriosclerosis↗
Biomedical subjects
Nobuhiro Yamada
Publications and source records attributed to Nobuhiro Yamada.
Hepatic Akt activation induces marked hypoglycemia, hepatomegaly, and hypertriglyceridemia with sterol regulatory element binding protein involvement.
Akt is critical in insulin-induced metabolism of glucose and lipids. To investigate functions induced by hepatic Akt activation, a constitutively active Akt, NH(2)-terminally myristoylation signal-attached Akt (myr-Akt), was overexpressed in the liver by injecting its adenovirus into mice. Hepatic myr-Akt overexpression resulted in a markedly hypoglycemic, hypoinsulinemic, and hypertriglyceridemic phenotype with fatty liver and hepatomegaly. To elucidate the sterol regulatory element binding protein (SREBP)-1c contribution to these phenotypic features, myr-Akt adenovirus was injected into SREBP-1 knockout mice. myr-Akt overexpression induced hypoglycemia and hepatomegaly with triglyceride accumulation in SREBP-1 knockout mice to a degree similar to that in normal mice, whereas myr-Akt-induced hypertriglyceridemia in knockout mice was milder than that in normal mice. The myr-Akt-induced changes in glucokinase, phosphofructokinase, glucose-6-phosphatase, and PEPCK expressions were not affected by knocking out SREBP-1, whereas stearoyl-CoA desaturase 1 induction was completely inhibited in knockout mice. Constitutively active SREBP-1-overexpressing mice had fatty livers without hepatomegaly, hypoglycemia, or hypertriglyceridemia. Hepatic acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase 1, and glucose-6-phosphate dehydrogenase expressions were significantly increased by overexpressing SREBP-1, whereas glucokinase, phospho-fructokinase, glucose-6-phosphatase, and PEPCK expressions were not or only slightly affected. Thus, SREBP-1 is not absolutely necessary for the hepatic Akt-mediated hypoglycemic effect. In contrast, myr-Akt-induced hypertriglyceridemia and hepatic triglyceride accumulation are mediated by both Akt-induced SREBP-1 expression and a mechanism involving fatty acid synthesis independent of SREBP-1.
Animals↗
Preventing angiographic progression of coronary atherosclerosis with pravastatin.
We conducted a prospective study to investigate the relationship between the decrease of serum lipid levels during pravastatin therapy and changes of coronary angiography parameters in Japanese patients with coronary atherosclerosis. The patients were predominantly male, aged between 18 and 75 years (mean: 58 years), had at least 25% stenosis of one or more major coronary arteries, and had a serum total cholesterol ( TC) level > or = 200 mg/dl (5.18 mM/l). Treatment with pravastatin (10 mg/day) was continued for 3 years. Coronary angiography was performed before and 3 years after the start of pravastatin therapy to assess the relationship between the mean segment diameter (MSD), the minimal lumen diameter (MLD), and the annual changes of percent stenosis and TC levels. of 265 patients who were initially registered, 129 were followed for an average of 35 months. Consequently, second angiograms were only obtained in 68 patients for various reasons, so this group was used for analysis. During pravastatin therapy, the TC level significantly decreased from 239 mg/dl (6.19 mM/l) to 210 mg/dl (5.44 mM/l) (a 12% reduction; p<0.001). In addition, HDL-cholesterol increased by 5% (p=0.007), but the triglyceride level did not show a significant change. Both MSD and MLD were significantly improved on follow-up angiography, increasing from 2.67 mm to 2.76 mm and from 2.09 mm to 2.13 mm, respectively. However, no change of percent stenosis was observed. The mean TC level during treatment did not show any significant correlation with the changes of angiography parameters. However, a significant correlation was observed between the percent reduction of TC and the annual change of MSD (r=-0.272, p=0.027). A similar relationship was also found between the change of MLD and the percent reduction of TC (r=-0.260, p=0.035). In conclusion, the percent decrease of serum cholesterol may be a better indicator of clinical efficacy than the absolute cholesterol level during pravastatin therapy.
Coronary Angiography↗
[Diabetes mellitus and ischemic heart diseases].
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Arteriosclerosis↗
Resistin is regulated by C/EBPs, PPARs, and signal-transducing molecules.
Expression of the adipocyte-derived protein resistin, which is thought to play a key role in the development of insulin resistance in vivo, is regulated by a variety of hormones and mediators, including insulin and TNFalpha. Here we describe our use of adenovirus-mediated gene transfer to determine which transcription factors and signaling pathways affect resistin expression in 3T3-L1 adipocytes. We found that resistin expression was enhanced by overexpression of C/EBPalpha and suppressed by C/EBPzeta, a negative regulator of C/EBPalpha. Additionally, C/EBPalpha induced resistin even in L6 myocytes. Overexpression of PPARgamma markedly reduced resistin expression, whereas PPARalpha had no significant effect. Resistin expression was markedly suppressed by overexpression of the PI3-kinase p110alpha catalytic subunit and by Akt. Finally, overexpression of MEK1, MKK6, or MKK7 suppressed resistin expression. These findings indicate that resistin expression is regulated by C/EBPalpha and PPARgamma, partly via modulation of signal transduction in the PI3-kinase and MAP kinase pathways.
3T3 Cells↗
HMG-CoA reductase inhibitor decreases small dense low-density lipoprotein and remnant-like particle cholesterol in patients with type-2 diabetes.
Patients with type 2 diabetes are known to have abnormalities in their remnant metabolism and low density lipoprotein (LDL) subfraction pattern, with a preponderance of small dense LDL. The effects of pitavastatin, a newly synthesized 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, on lipoprotein profiles in patients with type 2 diabetes were determined. Thirty-three patients were treated with pitavastatin with a daily dose of 2 mg for 8 weeks. After treatment, triglyceride, total and LDL cholesterol were significantly reduced by 28.7 +/- 36.7%, 25.2 +/- 14.3% and 36.1 +/- 14.3%, respectively. Remnant-like particle cholesterol (RLP-C), an independent risk factor for CAD which is known to be elevated in diabetic patients, was also significantly reduced (-30.9 +/- 30.5%) by the treatment and this decrease correlated well with the decrease in triglyceride level. The proportion of small dense LDL, which is known for its atherogenisity, decreased from 29.9 +/- 26.2% to 19.7 +/- 22.7% and the mean LDL particle size significantly increased from 26.36 +/- 1.13 nm to 27.10 +/- 1.36 nm. Pitavastatin, which is known to improve triglyceride levels and cholesterol levels, also improves RLP-C level and LDL subfraction profiles, and this in turn may reduce the cardiovascular risk in patients with type 2 diabetes and dyslipidemia.
Adult↗
Vascular endothelial growth factor gene expression in a retinal pigmented cell is up-regulated by glucose deprivation through 3' UTR.
Diabetic retinopathy is known to be worsened when hypoglycemia occurs, however the pathogenic mechanisms are not defined. Vascular endothelial growth factor (VEGF) is increased in ocular fluid with diabetic retinopathy and linked with development of retinopathy. In this study, we examined whether glucose deficiency could up-regulate VEGF levels in retinal pigmented cells. Exposure to glucose deprived medium induced 30% up-regulation of VEGF mRNA. In hypoxia, as one of the most well-known inducer of VEGF, its up-regulation mechanism is mainly due to increase of transcription of VEGF gene via hypoxia response element in 5'-untranslated region (5'-UTR). We examined the role of 5'-UTR and 3'-UTR of VEGF gene in glucose deprived conditions using luciferase assay system. 5'-UTR containing reporter vector did not show increase of activity in glucose deprived conditions in contrast to the result in oxygen deprived condition. Both 5'-UTR and 3'-UTR containing vector demonstrated significant increase of activity in glucose deficient conditions compared with 5'-UTR containing vector. These findings suggest 3'-UTR of VEGF gene is important for increasing mRNA level in glucose deprived condition.
3' Untranslated Regions↗
A missense mutation in kynurenine aminotransferase-1 in spontaneously hypertensive rats.
Spontaneously hypertensive rats (SHR) are the most extensively used animal model for genetic hypertension, increased stroke damage, and insulin resistance syndromes; however, the identification of target genes has proved difficult. SHR show elevated sympathetic nerve activity, and stimulation of the central blood pressure control centers with glutamate or nicotine results in exaggerated blood pressure responses, effects that appear to be genetically determined. Kynurenic acid, a competitive glutamate antagonist and a non-competitive nicotinic antagonist, can be synthesized in the brain by the enzyme kynurenine aminotransferase-1 (KAT-1). We have previously shown that KAT-1 activity is significantly reduced in SHR compared with normotensive Wistar Kyoto rats (WKY). Here we show that KAT-1 contains a missense mutation, E61G, in all the strains of SHR examined but not in any of the WKY or outbred strains. Previous studies on F2 rats from a cross of stroke-prone SHR and WKY have shown a suggestive level of linkage between elevated blood pressure and the KAT-1 locus on chromosome 3. In addition, the mutant enzyme expressed in Escherichia coli displays altered kinetics. This mutation may explain the enhanced sensitivity to glutamate and nicotine seen in SHR that may be related to an underlying mechanism of hypertension and increased sensitivity to stroke.
Alleles↗
PPAR gamma ligands, troglitazone and pioglitazone, up-regulate expression of HMG-CoA synthase and HMG-CoA reductase gene in THP-1 macrophages.
Recently it has been reported that macrophages express a nuclear receptor, peroxisome proliferator-activated receptor gamma (PPAR gamma). Using a ligand of PPAR gamma, troglitazone or pioglitazone, we have shown that the expression of two genes involved in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase and HMG-CoA reductase, were increased by activation of PPAR gamma through a PPAR response element (PPRE) in THP-1 macrophages. In addition, treatment with troglitazone significantly increased the activity of HMG-CoA reductase and the amount of intracellular cholesterol. Thus, we conclude that PPAR gamma and its agonists increase the cholesterol content of macrophages by the increased expression of genes involved in cholesterol biosynthesis. These findings suggest that PPAR gamma may play a role in cholesterol metabolism in macrophages.
Cell Differentiation↗
Elimination of cholesterol ester from macrophage foam cells by adenovirus-mediated gene transfer of hormone-sensitive lipase.
Cholesterol ester (CE)-laden foam cells are a hallmark of atherosclerosis. To determine whether stimulation of the hydrolysis of cytosolic CE can be used as a novel therapeutic modality of atherosclerosis, we overexpressed hormone-sensitive lipase (HSL) in THP-1 macrophage-like cells by adenovirus-mediated gene delivery, and we examined its effects on the cellular cholesterol trafficking. We show here that the overexpression of HSL robustly increased neutral CE hydrolase activity and completely eliminated CE in the cells that had been preloaded with CE by incubation with acetylated low density lipoprotein. In these cells, cholesterol efflux was stimulated in the absence or presence of high density lipoproteins, which might be at least partially explained by the increase in the expression of ABCA1. Importantly, these effects were achieved without the addition of acyl-CoA:cholesterol acyltransferase inhibitor, cAMP, or even high density lipoproteins. Furthermore, the uptake and degradation of acetylated low density lipoprotein was significantly reduced probably by decreased expression of scavenger receptor A and CD36. Notably, the cells with stimulated CE hydrolysis did not exhibit either buildup of free cholesterol or cytotoxicity. In conclusion, increased hydrolysis of CE by the overexpression of HSL leads to complete elimination of CE from THP-1 foam cells not only by increasing efflux but also by decreasing influx of cholesterol.
Acetylation↗
[Recent studies on hyperlipidemia].
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Arteriosclerosis↗
Absence of sterol regulatory element-binding protein-1 (SREBP-1) ameliorates fatty livers but not obesity or insulin resistance in Lep(ob)/Lep(ob) mice.
Obesity is a common nutritional problem often associated with diabetes, insulin resistance, and fatty liver (excess fat deposition in liver). Leptin-deficient Lep(ob)/Lep(ob) mice develop obesity and those obesity-related syndromes. Increased lipogenesis in both liver and adipose tissue of these mice has been suggested. We have previously shown that the transcription factor sterol regulatory element-binding protein-1 (SREBP-1) plays a crucial role in the regulation of lipogenesis in vivo. To explore the possible involvement of SREBP-1 in the pathogenesis of obesity and its related syndromes, we generated mice deficient in both leptin and SREBP-1. In doubly mutant Lep(ob/ob) x Srebp-1(-/-) mice, fatty livers were markedly attenuated, but obesity and insulin resistance remained persistent. The mRNA levels of lipogenic enzymes such as fatty acid synthase were proportional to triglyceride accumulation in liver. In contrast, the mRNA abundance of SREBP-1 and lipogenic enzymes in the adipose tissue of Lep(ob)/Lep(ob) mice was profoundly decreased despite sustained fat, which could explain why the SREBP-1 disruption had little effect on obesity. In conclusion, SREBP-1 regulation of lipogenesis is highly involved in the development of fatty livers but does not seem to be a determinant of obesity in Lep(ob)/Lep(ob) mice.
Adipose Tissue↗
Insulin inhibits apoptosis of macrophage cell line, THP-1 cells, via phosphatidylinositol-3-kinase-dependent pathway.
Hyperinsulinemia has recently been reported as a risk factor for atherosclerotic diseases such as coronary heart disease; however, its precise mechanism is not well understood. To elucidate the role of insulin in the development of atherogenesis, we have investigated the effect of insulin on cell survival in macrophages, which are known to be important in the atherosclerotic process. Apoptosis was induced in macrophage cell lines derived from human monocytes or murine macrophages by serum starvation. Insulin administration retarded macrophage apoptosis by means of DNA laddering, dimethylthiazol diphenyltetrazolium bromide assay, and annexin V binding assay. Insulin also enhanced mRNA expression and protein production of the antiapoptotic Bcl-XL gene in a dose-dependent manner within the range of physiological concentrations. In the exploration of the signaling pathway involved in these antiapoptotic effects of insulin, pretreatment of cells with a specific inhibitor of phosphatidylinositol-3-kinase significantly suppressed insulin-mediated cell survival and insulin-induced Bcl-XL expression in macrophages. These data indicate that the survival effect of insulin on the apoptosis of macrophages is associated with the upregulation of Bcl-XL expression, and it may be mediated through the phosphatidylinositol-3-kinase signaling pathway. These mechanisms could be involved in the possible role of insulin in the development of atherosclerosis.
Androstadienes↗
A randomized, double-blind trial comparing the efficacy and safety of pitavastatin versus pravastatin in patients with primary hypercholesterolemia.
Pitavastatin (p-INN) is a novel and fully synthetic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, with a cholesterol-lowering action stronger than that of other statins currently in use. A 12-week, multi-center, randomized, double-blind, controlled study was conducted to confirm the efficacy and safety of pitavastatin compared with pravastatin, an agent for using to reduce low density lipoprotein cholesterol (LDL-C) in hypercholesterolemic patients. Patients were recruited at 43 institutes in Japan. Following more than 4 weeks run-in period, 240 patients were randomized to receive 2 mg of pitavastatin or 10 mg of pravastatin daily. At 12 weeks post-randomization, the pitavastatin group showed significantly lower LDL-C levels by -37.6% from baseline compared with -18.4% in the pravastatin group (P<0.05). Pitavastatin also significantly lowered total cholesterol (TC) by -28.2% compared with -14.0% of pravastatin (P<0.05). The LDL-C target level of <140 mg/dl was attained in 75% of the patients treated with pitavastatin, compared with 36% of those in the pravastatin group (P<0.05). Pitavastatin also significantly reduced triglycerides (TG), apo B, C-II and C-III, compared with pravastatin, and increased HDL-C, apo A-I and A-II, to the same extent of pravastatin. Safety was assessed by monitoring adverse events and measuring clinical laboratory parameters. The adverse event profile was similar for both treatment groups and neither treatment caused clinically relevant laboratory abnormalities. These results indicated that pitavastatin was more effective than pravastatin, and both drugs were well-tolerated in the treatment of hypercholesterolemia.
Adult↗
Secretion of macrophage migration inhibitory factor differs from interleukin-6 in hydrogen peroxide- and LPS-stimulated human fibroblasts.
To investigate the mechanism for secretion of macrophage migration inhibitory factor (MIF) in cultured human fibroblasts, we compared it with the secretion of interleukin-6 (IL-6) after stimulation with lipopolysaccharides (LPS) and H2O2. MIF content of the medium of 2.0 x 10(6) cells/20 ml after 20 h culture of nonstimulated fibroblasts was 0.30 +/- 0.06 ng/ml, whereas LPS-stimulation (10 microg/ml) only led to a 1.5-fold increase as compared with the nonstimulated cells. In contrast, a significant increase of IL-6 was induced by LPS-stimulation (6048 +/- 488 pg/ml in LPS-stimulated cells vs. 58 +/- 36 pg/ml in control cells). On the other hand, higher concentrations of H2O2 (0.6-1.2 mM) caused an increase of MIF secretion into the culture medium irrespective of LPS-stimulation; with 1.2 mM H2O2-stimulation for 20 h, it was increased to 40-fold as compared with the nonstimulated cells. However, lower concentrations (0.1-0.4 mM) did not cause this. Interestingly, H2O2-stimulation not only failed to increase IL-6 production from fibroblasts, but also repressed induction of IL-6 by LPS-stimulation in a dose-dependent manner. Genistein, a tyrosine kinase inhibitor, and H-7, a protein kinase C inhibitor, also inhibited IL-6 secretion but not MIF secretion in both LPS- and H2O2-stimulated fibroblasts. From analysis of trypan blue exclusion, formazan formation, morphological changes, and intracellular MIF content by Western blotting, we found that MIF secretion by H2O2 seemed to be mainly due to cell death and subsequent leakage of intracellular MIF. Taken together, these results suggest that MIF secretion differs from IL-6 via LPS-mediated signaling pathways.
Fibroblasts↗
Clinical efficacy of pitavastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, in patients with hyperlipidemia. Dose-finding study using the double-blind, three-group parallel comparison.
Pitavastatin (CAS 147526-32-7, NK-104), the first totally synthetic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor discovered in Japan, was examined. Pitavastatin significantly decreased the serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) at doses of 1 mg/day or more, and significant dose-dependence of the effect of this drug was observed within the dose range from 1 mg/day to 4 mg/day. It also significantly decreased the serum levels of triglycerides (TG) within this dose range. There was no dose-dependence of the incidence of adverse reactions to pitavastatin.
Adult↗
Acetyl-coenzyme A synthetase is a lipogenic enzyme controlled by SREBP-1 and energy status.
DNA microarray analysis on upregulated genes in the livers from transgenic mice overexpressing nuclear sterol regulatory element-binding protein (SREBP)-1a, identified an expressed sequence tag (EST) encoding a part of murine cytosolic acetyl-coenzyme A synthetase (ACAS). Northern blot analysis of the livers from transgenic mice demonstrated that this gene was highly induced by SREBP-1a, SREBP-1c, and SREBP-2. DNA sequencing of the 5' flanking region of the murine ACAS gene identified a sterol regulatory element with an adjacent Sp1 site. This region was shown to be responsible for SREBP binding and activation of the ACAS gene by gel shift and luciferase reporter gene assays. Hepatic and adipose tissue ACAS mRNA levels in normal mice were suppressed at fasting and markedly induced by refeeding, and this dietary regulation was nearly abolished in SREBP-1 knockout mice, suggesting that the nutritional regulation of the ACAS gene is controlled by SREBP-1. The ACAS gene was downregulated in streptozotocin-induced diabetic mice and was restored after insulin replacement, suggesting that diabetic status and insulin also regulate this gene. When acetate was administered, hepatic ACAS mRNA was negatively regulated. These data on dietary regulation and SREBP-1 control of ACAS gene expression demonstrate that ACAS is a novel hepatic lipogenic enzyme, providing further evidence that SREBP-1 and insulin control the supply of acetyl-CoA directly from cellular acetate for lipogenesis. However, its high conservation among different species and the wide range of its tissue distribution suggest that this enzyme might also play an important role in basic cellular energy metabolism.
Acetate-CoA Ligase↗
A kindred of familial acromegaly without evidence for linkage to MEN-1 locus.
Familial acromegaly (FA) is a rare inherited disease characterized by clustering of somatotrophic adenomas and acromegaly within a family without other manifestations of multiple endocrine neoplasia-type 1 (MEN-1). The genetic basis of this pituitary-specific phenotype is largely unknown, and its relationship to the MEN-1 locus on chromosome 11q13 also remains unclear. To test the hypothesis that FA results from a germline mutation of the MEN-1 locus, we performed a linkage analysis in a Japanese family with 2 members showing manifestations of acromegaly due to somatotroph adenomas. We also examined the adenoma of one patient for loss of heterozygosity (LOH) at 11q13 locus and for the presence of mutations of codon 201 and 227 in the gene for Gsalpha. Our results provided no evidence that either germline alterations of the MEN-1 locus, LOH at 11q13, or somatic mutation of Gsalpha plays a causative role in the development of somatotroph adenomas in our FA family. Together with the previous reports, these results suggest that there are at least two distinct subgroups of FA: one that results from a mutation in MEN-1 locus and the other whose causative gene is located outside the 11q13 locus.
Acromegaly↗