Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperlipidemia or dyslipidemia is one of the most important risk factors for coronary heart disease. The purpose of the present study was to identify gene polymorphisms for assessment of the genetic risk for myocardial infarction (MI) in individuals with low or high serum concentrations of high- density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, or triglyceride (TG), thereby contributing to the personalized prevention of MI in such individuals. The study population comprised 2682 unrelated Japanese individuals (1796 men, 886 women), including 1113 subjects (869 men, 244 women) with MI and 1569 controls (927 men, 642 women). The genotypes for 164 polymorphisms of 137 candidate genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Multivariable logistic regression analyses and stepwise forward selection procedures revealed that seven different polymorphisms were significantly (P<0.005) associated with MI in individuals with low or high serum concentrations of HDL- or LDL-cholesterol or of TG: the 190T --> C (Trp64Arg) polymorphism of ADRB3 in individuals with low HDL-cholesterol; the 1018C --> T (Thr145Met) polymorphism of GP1BA, the A --> G (Ile646Val) polymorphism of AKAP10, and the -55C --> T polymorphism of UCP3 in individuals with high HDL-cholesterol; the -603A --> G polymorphism of F3 and the -11377C --> G polymorphism of ADIPOQ in individuals with low LDL-cholesterol; the 1018C --> T polymorphism of GP1BA in individuals with low TG; and the 4G --> 5G polymorphism of PAI1 in individuals with high TG. No polymorphism was associated with MI in individuals with high LDL-cholesterol. These results suggest that polymorphisms associated with MI may differ among individuals with different lipid profiles. Stratification of subjects according to lipid profiles may thus be important for personalized prevention of MI based on genetic information.
Int J Mol Med 2007 Oct
PMID:Association of gene polymorphisms with myocardial infarction in individuals with different lipid profiles. 1778 91

There is increasing acknowledgment of the public health burden of metabolic syndrome. The metabolic syndrome is defined as emerging cardiovascular risk factors, or atherosclerosis, that are related to underlying insulin resistance. One of the adipokines, adiponectin, has antiatherogenic effects and augments the metabolic effects of insulin. To reduce mortality from cardiovascular disease, it is important to understand the pathophysiological properties of adiponectin and receptors in atherosclerotic regions. Recently, T-cadherin, which has been recognized as a unique cadherin molecule, has been characterized as a novel adiponectin receptor on vascular endothelial cells and smooth muscle. Notably, T-cadherin (also known as CDH13, cadherin 13, and H-cadherin) is abundantly expressed in injured vascular endothelial and smooth muscle cells in atherosclerotic regions. In the present review, we describe recent progress in research on adiponectin receptors, with emphasis on the unique vascular adiponectin receptor, T-cadherin, and its role in vascular disease.
Med Mol Morphol 2007 Sep
PMID:Adiponectin receptors, with special focus on the role of the third receptor, T-cadherin, in vascular disease. 1787 43

Adiponectin, a circulating adipocyte-derived secretory protein, reportedly plays an important role in liver fibrosis development, although the biological role of adiponectin in liver fibrogenesis is still controversial. Adiponectin is present in the serum as three oligometric complexes; namely, high-, middle-, and low-molecular weight (HMW, MMW, and LMW, respectively). Adiponectin exerts different biological activities in an oligomerization-dependent manner. The aim of our current study was to examine the alteration of each isoform of adiponectin and its receptors (AdipoR1, AdipoR2, and T-cadherin) during the choline-deficient L-amino acid-defined (CDAA) diet-induced rat liver fibrosis development. We also elucidated the methylation status of all receptors. The serum level of total adiponectin significantly increased during the liver fibrosis development. Among the three isoforms, only HMW adiponectin was significantly up-regulated whereas MMW and LMW were not. The expression of T-cadherin, which exclusively binds with HMW adiponectin, was significantly augmented as well. The AdipoR2 expression was markedly decreased and showed no marked difference from that of AdipoR1. No obvious methylation change was observed in all three receptors, suggesting that another mechanism is involved in the alteration of receptor gene expression. Collectively, since the specific ligand and receptor were augmented together, crosstalk between HMW adiponectin and T-cadherin may play an important role during liver fibrosis development in rats.
Int J Mol Med 2007 Nov
PMID:Crosstalk between high-molecular-weight adiponectin and T-cadherin during liver fibrosis development in rats. 1791 67

Type I Gaucher disease, a lysosomal storage disorder is associated with metabolic abnormalities such as high resting energy expenditure, low circulating adiponectin and peripheral insulin resistance. Treatment with enzyme replacement therapy (enzyme therapy) leads to a decrease in resting energy expenditure, but its influence on weight and risk of development of type II diabetes is unknown. We studied the BMI, prevalence of overweight, insulin resistance and type II diabetes in untreated and enzyme therapy treated Gaucher patients before and after several years of follow-up and compared this to data on healthy subjects from literature. We established that in untreated Gaucher patients the prevalence of overweight is lower than in the general population. Long-term treatment with enzyme therapy induces a larger than average weight gain leading to a similar prevalence of overweight in enzyme therapy treated patients and the general population. The prevalence of type II diabetes increases significantly during treatment with enzyme therapy, resulting in a comparable prevalence of type II diabetes in enzyme therapy treated patients and the general population.
Blood Cells Mol Dis
PMID:Overweight, insulin resistance and type II diabetes in type I Gaucher disease patients in relation to enzyme replacement therapy. 1795 7

Peroxisome proliferator-activated receptor gamma (PPARgamma) activity is regulated through association with ligands that include the thiazolidinedione class of antidiabetic drugs, as well as derivatives of polyunsaturated fatty acids. Induction of PPARgamma target gene expression involves ligand-dependent reconfiguration of the ligand-binding domain (LBD), followed by recruitment of specific transcriptional coactivators. In this study, we have identified an amino acid (F372) within helix 7 of the LBD that is required for the response of PPARgamma to endogenous ligands. Additionally, the data show that this amino acid is also required for expression of a novel subset of adipocyte genes (group 2), including fibroblast growth factor 21 (FGF21), and that the FGF21 gene is a direct target of PPARgamma. Expression of the group 2 genes is selectively repressed by the NAD-dependent deacetylase SIRT1 in mature 3T3-L1 adipocytes, since knockdown of SIRT1 through the constitutive expression of a corresponding RNA interference enhances their expression without affecting the expression of classic adipogenic genes, such as adiponectin and FABP4/aP2. It appears that many of the group 2 genes repressed by SIRT1 in mature adipocytes correspond to the same set of genes that are selectively activated by treatment of fat cells with the PPARgamma ligand, troglitazone. These data support a role for helix 7 of the LBD of PPARgamma in regulating adipocyte function and suggest that inhibition of SIRT1 in adipocytes induces the same insulin-sensitizing action as PPARgamma ligands.
Mol Cell Biol 2008 Jan
PMID:Identification of a domain within peroxisome proliferator-activated receptor gamma regulating expression of a group of genes containing fibroblast growth factor 21 that are selectively repressed by SIRT1 in adipocytes. 1795 59

Intensive blood glucose lowering can significantly reduce the risk of micro- and macrovascular complications in patients with diabetes mellitus. However, 30% of all treated patients do not achieve optimal blood glucose levels. Genetic factors may influence the response to glucose-lowering medication. A search of MEDLINE-indexed literature published between January 1966 and July 2007 revealed 37 studies reporting data on genetic polymorphisms and response to glucose-lowering drugs. Most studies involving cytochrome P450 (CYP) genes had small sample sizes (21 studies <50 subjects) and were among healthy volunteers. Multiple studies indicated that the CYP2C9 *3 allele (Ile359Leu polymorphism) was associated with decreased clearance of sulfonylurea drugs. Supporting this, one study reported an increased insulin secretion in CYP2C9*3 allele carriers when using the sulfonylurea agent glyburide. The CYP2C9*3 allele was also associated with a decreased clearance of meglitinides, whereas the CYP2C8*3 (Arg139Lys; Lys399Arg) variant increased the clearance of meglitinides. Polymorphisms in genes encoding the inwardly rectifying potassium channel Kir6.2 (KCNJ11) and the insulin receptor substrate-1 (IRS1) were reported to be associated with an increased risk of (secondary) failure to respond to sulfonylurea therapy. A significant decrease in fasting plasma glucose and hemoglobin A(1c) (HbA(1c)) in response to rosiglitazone was seen in subjects carrying the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma (PPARG) gene. Conversely, carriers of this polymorphism also had a higher conversion to diabetes mellitus when treated with acarbose; this effect was also seen in adiponectin (ADIPOQ) gene polymorphism carriers. Future studies with adequate sample sizes in which several SNPs in multiple candidate genes are genotyped in patients with diabetes should provide reliable information on genetic variants and response to glucose-lowering drugs.
Mol Diagn Ther 2007
PMID:Pharmacogenetics of glucose-lowering drug treatment: a systematic review. 1796 17

Metabolic dysregulation is associated with reproductive disorders, but the underlying mechanisms are not clearly understood. Adiponectin is an adipocyte-derived secretory factor that improves insulin sensitivity. Results from animal models indicate that overexpression of adiponectin impairs female fertility. We hypothesized that adiponectin regulates reproduction by altering the hypothalamic-pituitary axis. Mouse LbetaT2 immortalized gonadotrope cells express both adiponectin receptors 1 and 2. Adiponectin increases phosphorylation of AMP-activated protein kinase (AMPK), a downstream target of adiponectin receptors, and reduces basal and GnRH-stimulated LH secretion, acutely. The repression of LH secretion can be mimicked by 5-aminoimidazole-4-carboxamide-1-beta-riboside, an AMP analog, suggesting the involvement of AMPK. A dominant-negative AMPK mutant or compound C, a selective AMPK inhibitor, potentiates basal LH secretion and abolishes the inhibitory effect of adiponectin. Chronic activation of AMPK by 5-aminoimidazole-4-carboxamide-1-beta-riboside decreases cellular LH levels, and expression of dominant-negative AMPK increases cellular LH levels, suggesting a second effect of AMPK to regulate LH synthesis. Lastly, intravenous injection of an adenovirus expressing adiponectin into male mice reduces serum LH levels without changing FSH levels. In conclusion, our results suggest that adiponectin decreases LH secretion in pituitary gonadotropes in an AMPK-dependent manner.
Mol Endocrinol 2008 Mar
PMID:Adiponectin activates adenosine monophosphate-activated protein kinase and decreases luteinizing hormone secretion in LbetaT2 gonadotropes. 1800 41

Adipokines are secreted by adipose tissue and control various physiological systems. Low leptin levels during fasting stimulate feeding, reduce energy expenditure, and modulate neuroendocrine and immune function to conserve energy stores. On the other hand, rising leptin levels in the overfed state prevent weight gain by inhibiting food intake and increasing energy expenditure. These actions are mediated by neuronal circuits in the hypothalamus and brainstem. Leptin also controls glucose and lipid metabolism by targeting enzymes such as AMP-activated protein kinase and stearoyl-coenzyme A desaturase-1 in liver and muscle. Likewise, adiponectin and resistin control energy balance and insulin sensitivity via central and peripheral targets. As highlighted in this review, there are distinct as well as common signaling pathways for adipokines. Understanding adipokine signaling in the brain and other organs will provide insights into the pathogenesis and treatment of obesity, diabetes and various metabolic disorders.
Mol Endocrinol 2008 May
PMID:Adipokines and the peripheral and neural control of energy balance. 1820 44

Adiponectin is an adipokine that has been implicated in insulin resistance, a condition associated with polycystic ovarian syndrome in humans, but whether adiponectin can directly affect ovarian theca or granulosa cell function is unknown. Therefore, to determine the effects of adiponectin on proliferation, steroidogenesis and gene expression of large-follicle theca and granulosa cells, experiments were conducted using bovine ovarian cell cultures. RT-PCR was used to elucidate the effects of adiponectin on gene expression of CYP11A1 and LH receptor (LHR) in large-follicle theca and granulosa cells, as well as expression of CYP17A1 in theca cells and CYP19A1 in granulosa cells. Adiponectin decreased (P<0.05) insulin-induced progesterone and androstenedione production as well as attenuated IGF-I-induced LHR, CYP11A1, and CYP17A1 gene expression in theca cells. In contrast, adiponectin decreased (P<0.05) LHR mRNA abundance in granulosa cells but did not affect steroidogenic enzyme gene expression in granulosa cells. Adiponectin had no effect (P>0.10) on proliferation of large-follicle theca cells. RT-PCR also revealed that abundance of mRNA for the adiponectin receptor (ADIPOR2) was greater (P<0.05) in large-follicle than in small-follicle theca cells and did not significantly differ between small- and large-follicle granulosa cells. In cultured theca cells, LH increased (P<0.05) and IGF-I decreased (P<0.05) ADIPOR2 mRNA abundance. These results indicate that the inhibitory effects of adiponectin on steroidogenesis are primarily localized to theca cells and that the response of theca cells to adiponectin (i.e., ADIPOR2) may be regulated by LH and IGF-I.
Mol Cell Endocrinol 2008 Mar 12
PMID:Role of adiponectin in regulating ovarian theca and granulosa cell function. 1828 73

Adipose tissue-derived cytokines (adipokines) are associated with the development of inflammation and insulin resistance. However, which adipokine(s) mediate this linkage and the mechanisms involved during obesity is poorly understood. Through proteomics and microarray screening, we recently identified lipocalin 2 (LCN 2) as an adipokine that potentially connects obesity and its related adipose inflammation. Herein we show that the levels of LCN2 mRNA are dramatically increased in adipose tissue and liver of ob/ob mice and primary adipose cells isolated from Zucker obese rats, and thiazolidinedione administration reduces LCN2 expression. Interestingly, addition of LCN2 induces mRNA levels of peroxisome proliferator-activated receptor-gamma (PPARgamma) and adiponectin. Reducing LCN2 gene expression causes decreased expression of PPARgamma and adiponectin, slightly reducing insulin-stimulated Akt2 phosphorylation at Serine 473 in 3T3-L1 adipocytes. LCN2 administration to 3T3-L1 cells attenuated TNFalpha-effect on glucose uptake, expression of PPARgamma, insulin receptor substrate-1, and glucose transporter 4, and secretion of adiponectin and leptin. When added to macrophages, LCN2 suppressed lipopolysaccharide-induced cytokine production. Our data suggest that LCN2, as a novel autocrine and paracrine adipokine, acts as an antagonist to the effect of inflammatory molecules on inflammation and secretion of adipokines.
Mol Endocrinol 2008 Jun
PMID:The role of lipocalin 2 in the regulation of inflammation in adipocytes and macrophages. 1829 40


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