Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0028754 (obesity)
124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was designed to examine whether n-3 and n-6 polyunsaturated fatty acids at a very low dietary level (about 0.2%) would alter liver activities in respect to fatty acid oxidation. Obese Zucker rats were used because of their low level of fatty acid oxidation, which would make increases easier to detect. Zucker rats were fed diets containing different oil mixtures (5%, w/w) with the same ratio of n-6/n-3 fatty acids supplied either as fish oil or arachidonic acid concentrate. Decreased hepatic triacylglycerol levels were observed only with the diet containing fish oil. In mitochondrial outer membranes, which support carnitine palmitoyltransferase I activity, cholesterol content was similar for all diets, while the percentage of 22:6n-3 and 20:4n-6 in phospholipids was enhanced about by 6 and 3% with the diets containing fish oil and arachidonic acid, respectively. With the fish oil diet, the only difference found in activities related to fatty acid oxidation was the lower sensitivity of carnitine palmitoyltransferase I to malonyl-CoA inhibition. With the diet containing arachidonic acid, peroxisomal fatty acid oxidation and carnitine palmitoyltransferase I activity were markedly depressed. Compared with the control diet, the diets enriched in fish oil and in arachidonic acid gave rise to a higher specific activity of aryl-ester hydrolase in microsomal fractions. We suggest that slight changes in composition of n-3 or n-6 polyunsaturated fatty acids in mitochondrial outer membranes may alter carnitine palmitoyltransferase I activity.
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PMID:Effect of dietary n-3 and n-6 polyunsaturated fatty acids on lipid-metabolizing enzymes in obese rat liver. 796 69

This paper provides a broad overview of the epidemiological and genetical aspects of common multifactorial diseases in man with focus on three well-studied ones, namely, coronary heart disease (CHD), essential hypertension (EHYT) and diabetes mellitus (DM). In contrast to mendelian diseases, for which a mutant gene either in the heterozygous or homozygous condition is generally sufficient to cause disease, for most multifactorial diseases, the concepts of genetic susceptibility' and risk factors' are more appropriate. For these diseases, genetic susceptibility is heterogeneous. The well-studied diseases such as CHD permit one to conceptualize the complex relationships between genotype and phenotype for chronic multifactorial diseases in general, namely that allelic variations in genes, through their products interacting with environmental factors, contribute to the quantitative variability of biological risk factor traits and thus ultimately to disease outcome. Two types of such allelic variations can be distinguished, namely those in genes whose mutant alleles have (i) small to moderate effects on the risk factor trait, are common in the population (polymorphic alleles) and therefore contribute substantially to the variability of biological risk factor traits and (ii) profound effects, are rare in the population and therefore contribute far less to the variability of biological risk factor traits. For all the three diseases considered in this review, a positive family history is a strong risk factor. CHD is one of the major contributors to mortality in most industrialized countries. Evidence from epidemiological studies, clinical correlations, genetic hyperlipidaemias etc., indicate that lipids play a key role in the pathogenesis of CHD. The known lipid-related risk factors include: high levels of low density lipoprotein cholesterol, low levels of high density lipoprotein cholesterol, high apoB levels (the major protein fraction of the low density lipoprotein particles) and elevated levels of Lp(a) lipoprotein. Among the risk factors which are not related to lipids are: high levels of homocysteine, low activity of paraoxonase and possibly also elevated plasma fibrinogen levels. In addition to the above, hypertension, diabetes and obesity (which themselves have genetic determinants) are important risk factors for CHD. Among the environmental risk factors are: high dietary fat intake, smoking, stress, lack of exercise etc. About 60% of the variability of the plasma cholesterol is genetic in origin. While a few genes have been identified whose mutant alleles have large effects on this trait (e.g., LDLR, familial defective apoB-100), variability in cholesterol levels among individuals in most families is influenced by allelic variation in many genes (polymorphisms) as well as environmental exposures. A proportion of this variation can be accounted for by two alleles of the apoE locus that increase (ε4) and decrease (ε2) cholesterol levels, respectively. A polymorphism at the apoB gene (XbaI) also has similar effects, but is probably not mediated through lipids. High density lipoprotein cholesterol levels are genetically influenced and are related to apoA1 and hepatic lipase (LIPC) gene functions. Mutations in the apoA1 gene are rare and there are data which suggest a role of allelic variation at or linked LIPC gene in high density lipoprotein cholesterol levels. Polymorphism at the apoA1--C3 loci is often associated with hypertriglyceridemia. The apo(a) gene which codes for Lp(a) is highly polymorphic, each allele determining a specific number of multiple tandem repeats of a unique coding sequence known as Kringle 4. The size of the gene correlates with the size of the Lp(a) protein. The smaller the size of the Lp(a) protein, the higher are the Lp(a) levels. (ABSTRACT TRUNCATED)
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PMID:Ionizing radiation and genetic risks. VI. Chronic multifactorial diseases: a review of epidemiological and genetical aspects of coronary heart disease, essential hypertension and diabetes mellitus. 987 81

We have evaluated the possible association of polycystic ovary syndrome (PCOS) with 15 genomic variants previously described to influence insulin resistance, obesity, and/or type 2 diabetes mellitus. Seventy-two PCOS patients and 42 healthy controls were genotyped for 15 variants in the genes encoding for paraoxonase (three variants), plasma cell differentiation antigen glycoprotein, human sorbin and SH3 domain containing 1, plasminogen activator inhibitor-1, peroxisome proliferator-activated receptor-gamma2, protein tyrosine phosphatase 1B (two variants), adiponectin (two variants), IGF1, IGF2, IGF1 receptor, and IGF2 receptor. Compared with controls, PCOS patients were more frequently homozygous for the -108T variant in paraoxonase (36.6% vs. 9.5%; P = 0.002) and homozygous for G alleles of the ApaI variant in IGF2 (62.9% vs. 38.1%; P = 0.018). Paraoxonase is a serum antioxidant enzyme and, because -108T alleles result in decreased paraoxonase expression, this increase in oxidative stress might result in insulin resistance. G alleles of the ApaI variant in IGF2 may increase IGF2 expression, and IGF2 stimulates adrenal and ovarian androgen secretion. In conclusion, the paraoxonase -108 C-->T variant and the ApaI polymorphism in the IGF2 gene are associated with PCOS and might contribute to increased oxidative stress, insulin resistance, and hyperandrogenism in this prevalent disorder.
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PMID:Association of the polycystic ovary syndrome with genomic variants related to insulin resistance, type 2 diabetes mellitus, and obesity. 1518 Oct 35

Paraoxonase, an enzyme associated with high-density lipoprotein (HDL-PON), exerts a protective effect against oxidative damage of circulating cells and lipoproteins, modulates the susceptibility of HDL to atherogenic modifications such as glycation and homocysteinylation, and even exerts an antiinflammatory role. The aim of the present study was to investigate the relationship between lipoprotein oxidative stress and the activity of HDL-PON in healthy and obese subjects. Therefore, the activity of HDL-PON and the levels of lipid hydroperoxides in HDL and low-density lipoprotein (LDL) isolated from plasma of obese females (n = 12) and age-sex-matched controls (n = 31) were compared. Our results demonstrated for the first time that the activity of HDL-PON in obese subjects was significantly lower compared with that in controls (P < 0.001). Moreover, our results showed a significant increase in the levels of lipid hydroperoxides in HDL and LDL isolated from obese subjects (P < 0.001). The negative correlations established between HDL-PON activity and the levels of lipid hydroperoxides associated with HDL and LDL confirm the relationship between paraoxonase activity and lipid peroxidation of lipoproteins. Plasma levels of leptin correlated negatively with HDL-PON activity and positively with levels of lipid hydroperoxides in HDL and LDL of obese subjects, suggesting a relationship between leptin and oxidative damage of lipoproteins. In conclusion, our study demonstrated that the increase in oxidative stress in LDL and HDL of obese subjects is associated with a decrease in HDL-PON activity. The lower paraoxonase activity and the compositional changes in HDL and LDL could contribute to the greater risk of cardiovascular disease associated with obesity.
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PMID:Paraoxonase activity in high-density lipoproteins: a comparison between healthy and obese females. 1561 29

Leptin, a 167-amino acid peptide hormone produced by white adipose tissue, is primarily involved in the regulation of food intake and energy expenditure. Leptin receptors are expressed in many tissues including the cardiovascular system. Plasma leptin concentration is proportional to body adiposity and is markedly increased in obese individuals. Recent studies suggest that hyperleptinemia may play an important role in obesity-associated cardiovascular diseases including atherosclerosis. Leptin exerts many potentially atherogenic effects such as induction of endothelial dysfunction, stimulation of inflammatory reaction, oxidative stress, decrease in paraoxonase activity, platelet aggregation, migration, hypertrophy and proliferation of vascular smooth muscle cells. Leptin-deficient and leptin receptor-deficient mice are protected from arterial thrombosis and neointimal hyperplasia in response to arterial wall injury. Several clinical studies have demonstrated that high leptin level predicts acute cardiovascular events, restenosis after coronary angioplasty, and cerebral stroke independently of traditional risk factors. In addition, plasma leptin correlates with markers of subclinical atherosclerosis such as carotid artery intima-media thickness and coronary artery calcifications. Inhibition of leptin signaling may be a promising strategy to slow the progression of atherosclerosis in hyperleptinemic obese subjects.
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PMID:Leptin and atherosclerosis. 1658 Jun 76

Obesity and insulin resistance (IR) increase the risk for coronary heart disease; however, much of this risk is not attributable to traditional risk factors. We sought to determine whether weight loss associated with supervised aerobic exercise beneficially alters biomarkers of oxidative stress and whether these alterations are associated with improvements in measures of insulin resistance. Twenty-five sedentary and overweight to obese [body mass index (BMI) = 33.0 +/- 0.8 kg/m(2)] individuals, with characteristics of the metabolic syndrome, participated in a 4- to 7-mo weight loss program that consisted of energy restriction (reduced by approximately 500 kcal/day) and supervised aerobic exercise (5 days/wk, 45 min/day at 60% Vo(2 max); approximately 375 kcal/day). IR and insulin sensitivity were assessed by the calculation of the homeostasis model assessment (HOMA) and quantitative insulin sensitivity check index (QUICKI), respectively. Oxidative stress was assessed by oxidized LDL (oxLDL), myeloperoxidase (MPO), and low- and high- density lipoprotein (LDL and HDL) lipid hydroperoxide concentrations in serum. Indexes for antioxidative status included apolipoprotein A1 (apoA1) concentrations and paraoxonase-1 (PON1) activity and protein concentrations. Exercise- and diet-induced weight loss ( approximately 10%) significantly (P < 0.05) increased insulin sensitivity and reduced IR, oxLDL, and LDL lipid hydroperoxides but did not alter HDL lipid hydroperoxides or MPO concentrations. Lifestyle modification impacted systemic antioxidative status by increasing apoA1 concentrations and reducing serum PON1 protein and activity. Changes in oxidative stress were not associated with alterations in HOMA or QUICKI. Diet- and exercise-induced weight loss ( approximately 10%) improves measures of insulin sensitivity and beneficially alters biomarkers of oxidative status.
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PMID:Exercise and diet induced weight loss improves measures of oxidative stress and insulin sensitivity in adults with characteristics of the metabolic syndrome. 1747 52

The metabolic syndrome is a common and complex disorder combining obesity, dyslipidemia, hypertension, and insulin resistance. It is a primary risk factor for diabetes and cardiovascular disease. We showed for the first time that the metabolic syndrome is associated with a higher fraction of oxidized LDL and thus with higher levels of circulating oxidized LDL. Hyperinsulinemia and impaired glycaemic control, independent of lipid levels, were associated with increased in vivo LDL oxidation, as reflected by the higher prevalence of high oxidized LDL. High levels of oxidized LDL were associated with increased risk of future myocardial infarction, even after adjustment for LDL-cholesterol and other established cardiovascular risk factors. This association is in agreement with the finding that accumulation of oxidized LDL, which activates/induces subsets of smooth muscle cells and macrophages to gelatinase production, was associated with upstream localization of a vulnerable plaque phenotype. Dyslipidemia and insulin resistance in obese LDL receptor-deficient mice were associated with increased oxidative stress and impaired HDL-associated antioxidant defence associated with accelerated atherosclerosis due to increased macrophage infiltration and accumulation of oxidized LDL in the aorta. The accumulation of oxidized LDL was partly due to an impaired HDL-associated antioxidant defence due to a decrease in PON. Our data in this experimental model are thus the more relevant because a decrease in PON activity was found to be associated with a defective metabolism of oxidized phospholipids by HDL from patients with type 2 diabetes. Weight loss in leptin-deficient, obese, and insulin-resistant mice was associated with expressional changes of key genes regulating adipocyte differentiation, glucose transport and insulin sensitivity, lipid metabolism, oxidative stress and inflammation, most of which are under the transcriptional control of PPARs. We established an important relationship between PPAR-gamma and SOD1 for the prevention of the oxidation of LDL in the arterial wall. For example we showed that rosuvastatin decreased the oxidized LDL accumulation by increasing the expression of PPAR-gamma and SOD1. In addition, we established a relation between increased PPAR-alpha expression in the adipose tissue and a change in the gene expression pattern, which explains the decrease of free fatty acids, triglycerides and the increase in insulin sensitivity. We demonstrated that plaque oxidized LDL correlated with coronary plaque complexity in a swine atherosclerosis model. Oxidized LDL correlated positively with the expression of IRF1 and TLR2 suggesting a relation between oxidative stress and inflammation in coronary atherosclerotic plaques. Oxidized LDL induced further the expression of TLR2 and IRF1 in macrophages in vitro suggesting a causative link. As in the mouse model described above, plaque oxidized LDL correlated negatively with SOD1 expression and ox-LDL inhibited the expression of SOD1 in macrophages in vitro. We showed that TLR2, CXCR4 and MYC are overexpressed in monocytes of obese women at high cardiovascular risk and that weight loss was associated with a concomitant decrease of their expression. This suggests that the transcription factor cMYC has an atherogenic effect by inducing pro-inflammatory genes. The increased expression of TLR2 and CXCR4 were observed in the absence of an increase in ox-LDL but in the presence of an increase in SOD1. Interestingly, the expression of SOD1 correlated also with that of MYC, suggesting that it has an atherogenic effect by inducing the expression of an anti-oxidant enzyme. How ox-LDL prevents this increase remains to be determined. How we plan to do this is explained in the next part. In aggregate, our studies contributed to a better understanding of the relationships between metabolic syndrome, insulin signalling, oxidative stress and inflammation and atherosclerosis. We identified paraoxonase, interferon regulatory factor-1, toll-like receptors, CXCR4 and SOD1 as possible targets for intervention.
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PMID:Relations between metabolic syndrome, oxidative stress and inflammation and cardiovascular disease. 1866 60

Research into the paraoxonase (PON) gene family has flourished over the past few years. In the 1970s and 1980s, only PON1 was known, and the investigations were conducted, essentially, by toxicologists focusing on protection against organophosphate poisoning. Since then, two new members of the family, PON2 and PON3, have been identified, both being shown to play antioxidant and anti-inflammatory roles. Evidence exists indicating that the PON family is central to a wide variety of human illnesses such as cardiovascular disease, diabetes mellitus, metabolic syndrome, obesity, non-alcoholic steatohepatitis, and several mental disorders. However, research is hampered considerably by the methods currently available to measure the activity of these enzymes. In this review, we summarize the state of knowledge on PON biochemistry and function, the influence of genetic variations, and the involvement of PON in several diseases. The problems associated with PON measurement, such as sample acquisition, lack of reference methods, and variety of substrates, will be presented. Also, we cover some of the present lines of research and propose some others for future progress in this field.
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PMID:The paraoxonases: role in human diseases and methodological difficulties in measurement. 1925 16

The paraoxonase (PON) gene family has 3 members, PON1, PON2 and PON3, which are known to be involved in oxidative stress-associated processes such as dyslipidemia, diabetes and coronary heart disease. Although PON3 is the least studied paraoxonase, recent findings have shown that it can significantly reduce atherosclerotic lesion formation and obesity in PON3 transgenic mice. Here, we describe the isolation and molecular characterization of the cDNA encoding the porcine PON3 gene. We also report the cloning of three porcine PON3 transcript variants resulting from alternate splicing of exons. Our results show that PON3 mRNA and protein are ubiquitously expressed in pig tissues. Moreover, the relative abundance of PON3 mRNA, measured in perirenal and subcutaneous fat tissues, is higher in obese Upton Meishan gilts compared with the leaner Large White and Ham Line gilts. PON3 mRNA levels measured in fat tissues positively correlate with subcutaneous, visceral and total body fat weights. Four single nucleotide polymorphisms (SNP) were identified in the PON3 coding sequence, and among these, an association was found between the c.449G>A polymorphism and the longissimus dorsi depth estimated breeding value (EBV) trait. Knowledge of the structure, distribution and expression profile of the porcine PON3 gene provides insights into its physiological function. Our results provide further support for involvement of PON3 in obesity-related disorders.
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PMID:Molecular characterization and expression analysis of the porcine paraoxonase 3 (PON3) gene. 1942 87

Whether frail elderly subjects are more insulin resistant (IR) than non-frail is unclear. How obesity, muscle mass, inflammation, hormonal and lipid status, oxidative stress, antioxidant capacity and physical activity influences insulin sensitivity (IS) in frail elderly subjects remains uncertain. We determined (1) whether frail elderly persons are more IR than non-frail elderly and (2) the influence of abdominal fat mass (AFM), muscle mass index (MMI), inflammation (CRP), hormonal (cortisol, free IGF-1, DHEA) and lipid (FFA, triglyceride (TG)) status, oxidative stress (paraoxonase-1 (PON-1), malondialdehyde (MDA)), antioxidant capacity (vitamin C, E) and physical activity (PASE questionnaire) on IS (QUICKI) in 16 frail obese (FO), 17 frail lean (FL) and 21 healthy, non-obese (HN) elderly subjects. IS was lower in FO than FL, but there was no significant difference between HN and FO or FL. There were no significant differences among groups for CRP, cortisol, IGF-1, DHEA, FFA, TG, PON-1, MDA, vitamin C and E and PASE. Age, AFM and MMI significantly correlated with IS. Only AFM and MMI were significant predictors explaining, respectively, 18.5% and 8.5% of the variance in IS. Increased abdominal obesity is associated with IR in frail elderly. Non-obese frail persons are not more IR than their healthy counterparts.
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PMID:Frailty in the elderly is associated with insulin resistance of glucose metabolism in the postabsorptive state only in the presence of increased abdominal fat. 1972 76


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