Publications (20)138.7 Total impact
- [Show abstract] [Hide abstract] ABSTRACT: Cardiovascular disease (CVD), the most common morbidity resulting from atherosclerosis, remains a frequent cause of death. Efforts to develop effective therapeutic strategies have focused on vascular inflammation as a critical pathology driving atherosclerosis progression. Nonetheless, molecular mechanisms underlying this activity remain unclear. Here, we ask whether angiopoietin-like protein 2 (Angptl2), a proinflammatory protein, contributes to vascular inflammation that promotes atherosclerosis progression. Histological analysis revealed abundant Angptl2 expression in endothelial cells and macrophages infiltrating atheromatous plaques in patients with cardiovascular disease. Angptl2 knockout in apolipoprotein E-deficient mice (ApoE(-/-)/Angptl2(-/-)) attenuated atherosclerosis progression by decreasing the number of macrophages infiltrating atheromatous plaques, reducing vascular inflammation. Bone marrow transplantation experiments showed that Angptl2 deficiency in endothelial cells attenuated atherosclerosis development. Conversely, ApoE(-/-) mice crossed with transgenic mice expressing Angptl2 driven by the Tie2 promoter (ApoE(-/-)/Tie2-Angptl2 Tg), which drives Angptl2 expression in endothelial cells but not monocytes/macrophages, showed accelerated plaque formation and vascular inflammation because of increased numbers of infiltrated macrophages in atheromatous plaques. Tie2-Angptl2 Tg mice alone did not develop plaques but exhibited endothelium-dependent vasodilatory dysfunction, likely because of decreased production of endothelial cell-derived nitric oxide. Conversely, Angptl2(-/-) mice exhibited less severe endothelial dysfunction than did wild-type mice when fed a high-fat diet. In vitro, Angptl2 activated proinflammatory nuclear factor-κB signaling in endothelial cells and increased monocyte/macrophage chemotaxis. Endothelial cell-derived Angptl2 accelerates vascular inflammation by activating proinflammatory signaling in endothelial cells and increasing macrophage infiltration, leading to endothelial dysfunction and atherosclerosis progression.
- [Show abstract] [Hide abstract] ABSTRACT: Objective: Overexpression of Angiopoietin-like protein 2 (Angptl2) in obese adipose tissues promotes adipose tissue inflammation and its-related metabolic abnormalities. In a comparative study with adiponectin, we investigated whether alterations in serum Angptl2 concentrations reflect the effect of lifestyle intervention on weight loss and improved metabolic parameters in overweight subjects. Methods: A total of 154 Japanese men (age, 40.9±5.1 years; body mass index, 26.9±3.6 kg m−2; abdominal circumference, 94.1±8.9 cm) underwent a 3-month lifestyle intervention and underwent follow-up for 3 months thereafter. Results: Decreased serum Angptl2 levels, but not increased serum adiponectin levels, were immediately apparent at the end of 3-month lifestyle intervention. Angptl2 levels continued to decrease for 3 months in parallel with body weight loss and improvement in metabolic indicators. In subjects showing ⩾6% weight reduction, markedly reduced Angptl2 levels were detected at the end of 3-month intervention, whereas increased adiponectin levels were detected 3 months after the end of intervention. Multivariate analysis revealed changes in serum Angptl2 levels associated with changes in triglycerides (TGs), aspartate aminotransferase and alanine aminotransferase. In contrast, changes in serum adiponectin levels were associated with altered high-density lipoprotein cholesterol (HDL-C) and fasting plasma glucose levels. Conclusion: A 3-month lifestyle intervention promoted weight reduction and improved glucose and lipid metabolism, an effect maintained 3 months later. Notably, our findings indicate that decreased Angptl2 levels are a good indicator of reduced visceral fat and metabolic improvement at early stages of lifestyle intervention. Thus, Angptl2 reflects adiposity and might be a key protein to regulate inflammation and TG metabolism, whereas adiponectin levels could reflect improved glucose and HDL-C metabolism.
- [Show abstract] [Hide abstract] ABSTRACT: Obesity is a life-threatening factor and is often associated with dysregulation of gene expression. Here, we show that the CNOT3 subunit of the CCR4-NOT deadenylase complex is critical to metabolic regulation. Cnot3(+/-) mice are lean with hepatic and adipose tissues containing reduced levels of lipids, and show increased metabolic rates and enhanced glucose tolerance. Cnot3(+/-) mice remain lean and sensitive to insulin even on a high-fat diet. Furthermore, introduction of Cnot3 haplodeficiency in ob/ob mice ameliorated the obese phenotype. Hepatic expression of most mRNAs is not altered in Cnot3(+/-) vis-à-vis wild-type mice. However, the levels of specific mRNAs, such as those coding for energy metabolism-related PDK4 and IGFBP1, are increased in Cnot3(+/-) hepatocytes, having poly(A) tails that are longer than those seen in control cells. We provide evidence that CNOT3 is involved in recruitment of the CCR4-NOT deadenylase to the 3' end of specific mRNAs. Finally, as CNOT3 levels in the liver and white adipose tissues decrease upon fasting, we propose that CNOT3 responds to feeding conditions to regulate deadenylation-specific mRNAs and energy metabolism.
- [Show abstract] [Hide abstract] ABSTRACT: Nifedipine, an L-type calcium (Ca) channel blocker, is one of the most widely used Ca channel-blocking medications for hypertension. Previous studies have reported an association of nifedipine hypertensive treatment with decreased body weight in obese hypertensive humans and rat models. However, the precise mechanism underlying how nifedipine functions metabolically has not been elucidated. Here, we investigated the long-term effect of a non-hypotensive nifedipine dose using a mildly obese, endothelial NO synthase-deficient mouse model. Treating these mice with nifedipine decreased their body weight gain ratio, and white adipose tissue weight compared with the untreated controls. Metabolic analyses indicated that nifedipine treatment upregulated whole-body energy expenditure through increasing oxygen consumption and reducing the respiratory exchange ratio, suggesting that nifedipine promotes lipid oxidation rather than carbohydrate utilization. Furthermore, nifedipine treatment upregulated the expression of the peroxisome proliferator-activated receptor-γ coactivator -1α (PGC-1α) in skeletal muscle. Overall, these results suggest that a non-hypotensive dose of nifedipine has pleiotropic effects on energy expenditure that could ameliorate obesity.
- [Show abstract] [Hide abstract] ABSTRACT: Obesity and related metabolic diseases, such as type 2 diabetes, hypertension and hyperlipidemia are an increasingly prevalent medical and social problem in developed and developing countries. These conditions are associated with increased risk of cardiovascular disease, the leading cause of death. Therefore, it is important to understand the molecular basis underlying obesity and related metabolic diseases in order to develop effective preventive and therapeutic approaches against these conditions. Recently, a family of proteins structurally similar to the angiogenic-regulating factors known as angiopoietins was identified and designated 'angiopoietin-like proteins' (ANGPTLs). Encoded by seven genes, ANGPTL1-7 all possess an N-terminal coiled-coil domain and a C-terminal fibrinogen-like domain, both characteristic of angiopoietins. ANGPTLs do not bind to either the angiopoietin receptor Tie2 or the related protein Tie1, indicating that these ligands function differently from angiopoietins. Like angiopoietins, some ANGPTLs potently regulate angiogenesis, but ANGPTL3, -4 and ANGPTL6/angiopoietin-related growth factor (AGF) directly regulate lipid, glucose and energy metabolism independent of angiogenic effects. Recently, we found that ANGPTL2 is a key adipocyte-derived inflammatory mediator that links obesity to systemic insulin resistance. In this minireview, we focus on the roles of ANGPTL2 and ANGPTL6/AGF in obesity and related metabolic diseases, and discuss the possibility that both could function as molecular targets for the prevention and treatment of obesity and metabolic diseases.
- [Show abstract] [Hide abstract] ABSTRACT: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by symmetrical polyarticular synovitis of the diarthrodial joints. Several proinflammatory cytokines derived from both infiltrating inflammatory cells and activated resident cells within the RA joint play a fundamental role in the processes that cause inflammation. However, anticytokine treatment is beneficial but not curative, the effects are only partial, and nonresponses are common. Therefore, an effort has been made to identify other key regulators of inflammation in articular structures to develop new therapies to suppress synovial inflammation and joint destruction in RA. Adipose tissue-derived angiopoietin-like protein 2 (Angptl2) activates an inflammatory cascade in endothelial cells and induces chemotaxis of monocytes/macrophages in obesity, resulting in initiation and propagation of inflammation within adipose tissues and obesity-related metabolic diseases. Angptl2 mRNA and protein are abundantly expressed in hyperplastic rheumatoid synovium of RA patients, especially in fibroblast-like and macrophage-like synoviocytes, but not in B and T lymphocytes. Angptl2 concentration in joints of RA patients was also significantly increased in comparison with patients with osteoarthritis, which in comparison with RA represents a significantly lower inflammatory grade form of arthritis. Notably, Angptl2 promoted increased chemotactic activities of CD14+CD16- monocytes from synovial fluid of RA patients. Therefore, Angptl2 acts as an important rheumatoid synovium-derived inflammatory mediator in RA pathogenesis.
- [Show abstract] [Hide abstract] ABSTRACT: Adiponectin is an anti-diabetic adipokine. Its receptors possess a seven-transmembrane topology with the amino terminus located intracellularly, which is the opposite of G-protein-coupled receptors. Here we provide evidence that adiponectin induces extracellular Ca(2+) influx by adiponectin receptor 1 (AdipoR1), which was necessary for subsequent activation of Ca(2+)/calmodulin-dependent protein kinase kinase beta (CaMKKbeta), AMPK and SIRT1, increased expression and decreased acetylation of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), and increased mitochondria in myocytes. Moreover, muscle-specific disruption of AdipoR1 suppressed the adiponectin-mediated increase in intracellular Ca(2+) concentration, and decreased the activation of CaMKK, AMPK and SIRT1 by adiponectin. Suppression of AdipoR1 also resulted in decreased PGC-1alpha expression and deacetylation, decreased mitochondrial content and enzymes, decreased oxidative type I myofibres, and decreased oxidative stress-detoxifying enzymes in skeletal muscle, which were associated with insulin resistance and decreased exercise endurance. Decreased levels of adiponectin and AdipoR1 in obesity may have causal roles in mitochondrial dysfunction and insulin resistance seen in diabetes.
- [Show abstract] [Hide abstract] ABSTRACT: Obesity has become a serious worldwide public health problem. Although neural degeneration in specific brain regions has been suggested to contribute to obesity phenotype in humans, a causal relationship between these two conditions has not been demonstrated experimentally. We now show that E4B (also known as UFD2a), a mammalian ubiquitin chain elongation factor (E4), induces the formation of intracellular aggregates positive for ubiquitin and the adaptor protein p62 when overexpressed in cultured cells or the brain. Mice transgenic for E4B manifested neural degeneration in association with aggregate formation, and they exhibited functional impairment specifically in a subset of hypothalamic neurons that regulate food intake and energy expenditure, resulting in development of hyperphagic obesity and related metabolic abnormalities. The neural pathology of E4B transgenic mice was similar to that of human neurodegenerative diseases associated with the formation of intracellular ubiquitin-positive deposits, indicating the existence of a link between such diseases and obesity and related metabolic disorders. Our findings thus provide experimental evidence for a role of hypothalamic neurodegeneration in obesity, and the E4B transgenic mouse should prove to be a useful animal model for studies of the relationship between neurodegenerative diseases and obesity.
- [Show abstract] [Hide abstract] ABSTRACT: Recent major increases in obesity and related metabolic diseases (known as the metabolic syndrome (MetS)) because of sedentary lifestyles and overnutrition in developed and developing countries, are an exploding medical and social problem. These conditions are associated with increased risk of cardiovascular disease (CVD), the leading cause of death. Thus, it is necessary to understand the molecular basis underlying MetS and develop effective preventive and therapeutic approaches against CVD. To date, 7 angiopoietin-like proteins (Angptls) that are structurally similar to angiopoietins have been identified. However, none binds to the angiopoietin receptor, Tie2, or to the closely related Tie1 receptor, suggesting that these ligands function differently from angiopoietins. Some Angptls potently regulate angiogenesis, similar to angiopoietins, whereas others have pleiotropic activity other than angiogenesis and function in lipid and energy metabolism. In this review, we focus on the roles of Angptl2 and Angptl6/angiopoietin-like growth factor (AGF) in the development of MetS and CVD, and discuss the potential for Angptl2 and Angptl6/AGF to function as molecular targets for the prevention and treatment of both conditions.
- [Show abstract] [Hide abstract] ABSTRACT: Recent studies of obesity have provided new insights into the mechanisms underlying insulin resistance and metabolic dysregulation. Numerous efforts have been made to identify key regulators of obesity-linked adipose tissue inflammation and insulin resistance. We found that angiopoietin-like protein 2 (Angptl2) was secreted by adipose tissue and that its circulating level was closely related to adiposity, systemic insulin resistance, and inflammation in both mice and humans. Angptl2 activated an inflammatory cascade in endothelial cells via integrin signaling and induced chemotaxis of monocytes/macrophages. Constitutive Angptl2 activation in vivo induced inflammation of the vasculature characterized by abundant attachment of leukocytes to the vessel walls and increased permeability. Angptl2 deletion ameliorated adipose tissue inflammation and systemic insulin resistance in diet-induced obese mice. Conversely, Angptl2 overexpression in adipose tissue caused local inflammation and systemic insulin resistance in nonobese mice. Thus, Angptl2 is a key adipocyte-derived inflammatory mediator that links obesity to systemic insulin resistance.
- [Show abstract] [Hide abstract] ABSTRACT: We investigated the efficacy of epalrestat, an aldose reductase inhibitor, for diabetic peripheral neuropathy in Japanese patients with type 2 diabetes. A total of 38 type 2 diabetic patients (22 men and 16 women; mean ± S.E.M. age 63.3 ± 1.0 years; duration of diabetes 9.6 ± 0.8 years) with diabetic neuropathy were newly administered 150 mg/day epalrestat (EP group). Motor nerve conduction velocity (MCV), sensory nerve conduction velocity (SCV), and minimum F-wave latency were evaluated before administration of epalrestat and after 1 and 2 years. Serum N(ɛ)-carboxymethyl lysine (CML) as a parameter of advanced glycation end products (AGEs), lipid peroxide, and soluble vascular cell adhesion molecule (sVCAM)-1 as a parameter of angiopathy were measured before administration and after 1 year. We compared the results with those of 36 duration of diabetes-matched type 2 diabetic patients (mean ± S.E.M. duration of diabetes 8.2 ± 0.7 years) as control (C group). The EP group showed significant suppression of deterioration of MCV (P<.01) and minimum F-wave latency (P<.01) in the tibial nerve and SCV (P<.05) in the sural nerve compared to those in the C group after 2 years. There was a significant difference in change in CML level between groups (-0.18 ± 0.13 mU/ml in the EP group vs. +0.22 ± 0.09 mU/ml in the C group, P<.05) after 1 year. Epalrestat suppressed the deterioration of diabetic peripheral neuropathy, especially in the lower extremity. Its effects might be mediated by improvement of the polyol pathway and suppression of production of AGEs.
- [Show abstract] [Hide abstract] ABSTRACT: Angiopoietin (Ang) signaling through the Tie2 receptor regulates vasculature. The role of Ang signaling in pulmonary hypertension is well investigated, but its role in lung development is not elucidated. Here, we show that the Tie2 agonist ligand, Ang1, was detected in lung tissue at birth and its expression gradually increased in mice, whereas its antagonist Ang2 was abundant at birth and decreased inversely with Ang1. Mice expressing the potent chimeric Ang1 protein COMP-Ang1 in surfactant protein C (SPC)-positive lung epithelial cells, showed 50% lethality at birth due to respiratory failure. Surviving mice displayed impaired adaptive responsive respiratory function. Histological analysis revealed that pulmonary artery and alveolar structure were significantly dilated, and alveolar density was decreased to approximately a third of controls. Thus, the precise regulation of Tie2 signaling through an Ang1/Ang2 expression switch is important to construct a mature lung vascular network system required for normal lung development.
- [Show abstract] [Hide abstract] ABSTRACT: Angiopoietin-like protein family 4 (Angptl 4) has been shown to regulate lipoprotein metabolism through the inhibition of lipoprotein lipase (LPL). We generated ApoE(-/-)Angptl 4(-/-) mice to study the effect of Angptl 4 deficiency on lipid metabolism and atherosclerosis. Fasting and postolive oil-loaded triglyceride (TG) levels were largely decreased in ApoE(-/-)Angptl 4(-/-) mice compared with and ApoE(-/-)Angptl 4(+/+) mice. There was a significant (75+/-12%) reduction in atherosclerotic lesion size in ApoE(-/-)Angptl 4(-/-) mice compared with ApoE(-/-) Angptl 4(+/+) mice. Peritoneal macrophages, isolated from Angptl 4(-/-) mice to investigate the foam cell formation, showed a significant decrease in newly synthesized cholesteryl ester (CE) accumulation induced by acetyl low-density lipoprotein (acLDL) compared with those from Angptl 4(+/+) mice. Thus, genetic knockout of Angptl 4 protects ApoE(-/-) mice against development and progression of atherosclerosis and strongly suppresses the ability of the macrophages to become foam cells in vitro.
Article: Angiopoietin-Like Proteins
- [Show abstract] [Hide abstract] ABSTRACT: Unlabelled: It is unclear how hepatic adiponectin resistance and sensitivity mediated by the adiponectin receptor, AdipoR2, contributes to the progression of nonalcoholic steatohepatitis (NASH). The aim of this study was to examine the roles of hepatic AdipoR2 in NASH, using an animal model. We fed C57BL/6 mice a methionine-deficient and choline-deficient (MCD) diet for up to 8 weeks and analyzed changes in liver pathology caused by either an AdipoR2 short hairpin RNA-expressing adenovirus or an AdipoR2-overexpressing adenovirus. Inhibition of hepatic AdipoR2 expression aggravated the pathological state of NASH at all stages: fatty changes, inflammation, and fibrosis. In contrast, enhancement of AdipoR2 expression in the liver improved NASH at every stage, from the early stage to the progression of fibrosis. Inhibition of AdipoR2 signaling in the liver diminished hepatic peroxisome proliferator activated receptor (PPAR)-alpha signaling, with decreased expression of acyl-CoA oxidase (ACO) and catalase, leading to an increase in lipid peroxidation. Hepatic AdipoR2 overexpression had the opposite effect. Reactive oxygen species (ROS) accumulation in liver increases hepatic production of transforming growth factor (TGF)-beta1 at all stages of NASH; adiponectin/AdipoR2 signaling ameliorated TGF-beta-induced ROS accumulation in primary cultured hepatocytes, by enhancing PPAR-alpha activity and catalase expression. Conclusion: The adiponectin resistance and sensitivity mediated by AdipoR2 in hepatocytes regulated steatohepatitis progression by changing PPAR-alpha activity and ROS accumulation, a process in which TGF-beta signaling is implicated. Thus, the liver AdipoR2 signaling pathway could be a promising target in treating NASH.
- [Show abstract] [Hide abstract] ABSTRACT: Transgenic mice overexpressing angiopoietin-related growth factor (AGF) exhibit enhanced angiogenesis, suggesting that AGF may be a useful drug target in ischemic disease. Our goal was to determine whether AGF enhances blood flow in a mouse hind-limb ischemia model and to define molecular mechanisms underlying AGF signaling in endothelial cells. Intramuscular injection of adenovirus harboring AGF into the ischemic limb increased AGF production, which increased blood flow through induction of angiogenesis and arteriogenesis, thereby reducing the necessity for limb amputation. In vitro analysis showed that exposing human umbilical venous endothelial cells to AGF increased nitric oxide (NO) production through activation of an ERK1/2-endothelial NO synthetase (eNOS) signaling pathway. AGF-stimulated eNOS phosphorylation, NO production, and endothelial cell migration were all abolished by specific MEK1/2 inhibitors. Moreover, AGF did not restore blood flow to ischemic hind-limbs of either mice receiving NOS inhibitor L-NAME or eNOS knockout mice. Activation of an ERK1/2-eNOS-NO pathway is a crucial signaling mechanism by which AGF increases blood flow through induction of angiogenesis and arteriogenesis. Further investigation of the regulation underlying AGF signaling pathway may contribute to develop a new clinical strategy for ischemic vascular diseases.
- [Show abstract] [Hide abstract] ABSTRACT: Recently, a family of proteins structurally similar to the angiogenic regulating factors angiopoietins was identified and designated "angiopoietin-like proteins" (Angptls). Encoded by seven genes, Angptls 1 to 7 all possess an N-terminal coiled-coil domain and a C-terminal fibrinogen-like domain, both characteristic of angiopoietins. However, Angptls do not bind to either the angiopoietin receptor Tie2 or the related protein Tie1 and remain orphan ligands. Nonetheless, Angptls 1, 2, 3, 4, and Angptl6/angiopoietin-related growth factor function to regulate angiogenesis. Angptls 3, 4, and Angptl6/angiopoietin-related growth factor also appear to directly regulate lipid, glucose, and energy metabolism independently of angiogenic effects. Recently, several lines of evidence reveal differential roles of Angptl structural domains in both angiogenesis and metabolism. Here, we briefly review what is currently known about Angptls function.
- [Show abstract] [Hide abstract] ABSTRACT: We investigated whether or not "low dose" metformin could prevent weight gain induced by pioglitazone. Sixty-nine patients with type 2 diabetes received 500-750 mg metformin a day for 12 weeks as an observation period before the start of the intervention. After an observation period, inadequately controlled patients (hemoglobin A1c >or=7.5%, n=34) received additional treatment with 15 mg pioglitazone (+P, M+P group). The other patients (n= 35) continued metformin monotherapy (Met group). In addition, another group consisting of 28 patients treated with 15 mg pioglitazone alone (Pio group) was observed. Body mass index (BMI), as well as several clinical parameters of glycemic control and lipid metabolism, was compared before and after 24 weeks of intervention. BMI increased significantly in the Pio group [24.0+/-3.8 vs. 24.8+/-4.3 kg/m(2), (mean +/- SD), p<0.001], but not in the M+P group (25.1+/-3.5 vs. 25.3+/-3.4 kg/m(2), NS) and Met group (24.0+/-3.3 vs. 24.0+/-3.5 kg/m(2), NS). In addition to improvement in glycemic control, a significant reduction in the atherogenic index of plasma (AIP), defined as log [TG x0.0112/HDL-C x0.02586], was observed in the Pio group (0.06+/-0.23 vs. -0.04+/-0.27, p<0.05) and M+P group (0.08+/-0.24 vs. -0.001+/-0.252, p<0.01), but not in the Met group. This study indicates potential benefits of the addition of pioglitazone to "low dose" metformin in terms of improvement of glucose and lipid metabolism without weight gain.