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)

The aim of this study was to investigate whether the EcoRI restriction fragment length polymorphism (RFLP) of the apolipoprotein (apo) B-100 gene influences the associations described among obesity, regional adipose tissue distribution, and plasma lipoprotein levels. For this purpose, blood samples were collected from 56 healthy men for whom we had extensive measurements of regional adipose tissue distribution (both anthropometric and computed tomography-derived measurements) and data on the plasma lipoprotein-lipid profile. DNA was extracted from white blood cells, and RFLP analysis was performed. Subjects were classified into two groups on the basis of their apoB-100 EcoRI genotype: subjects homozygous for the major 11-kb allele, the 11/11 group (n = 40), and subjects carrying the minor 13-kb allele, the 13/11 group (n = 16). Subjects carrying the 13-kb allele had lower percent body fat and abdominal adipose tissue accumulation than subjects homozygous for the 11-kb allele (P < .05). Although leaner, the 13/11 group did not show a more favorable plasma lipoprotein-lipid profile than the group homozygous for the 11-kb allele. In fact, after statistical control for the difference in percent body fat between the two genotype groups, the 13/11 group showed significantly higher plasma cholesterol levels (P < .05) and nearly significantly higher apoB levels than the 11/11 group (P = .06). The association patterns between indices of regional adiposity and plasma cholesterol and apoB levels were also different between the two EcoRI genotype groups. Only in the 13/11 group was the abdominal visceral adipose tissue area significantly associated with these plasma variables.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:ApoB-100 gene EcoRI polymorphism. Relations to plasma lipoprotein changes associated with abdominal visceral obesity. 790 36

Dyslipidemia secondary to obesity is commonly observed in both animals and humans. As it has been hypothesized that obesity can result in overproduction of VLDL, leading to the subsequent dyslipidemia, we have examined the triglyceride and apoB secretion rates in vivo in obese C57BI/ KsJ db/db and C57BI/6J ob/ob mice and their lean littermates. In ob/ob animals, obesity resulted in significantly lower, not higher, triglyceride secretion rates in both males (3.94 +/- 0.49 mg/h per g liver vs. 5.45 +/- 0.29 mg/h per g liver in lean littermates, P < 0.001) and females (4.29 +/- 0.81 mg/h per g liver vs. 5.25 +/- 0.59 mg/h/g liver, P < 0.001). For db/db, the obese females did not show a statistically significant triglyceride secretion rate compared to their lean littermates. Only the male db/db animals showed a significantly higher triglyceride secretion rate compared with lean littermates (5.50 +/- 1.1 mg/h per g liver vs. 3.37 +/- 0.36 mg/h/g liver, P < 0.001). Examination of the apolipoprotein B (apoB) secretion rates showed that for ob/ob animals and db/db obese females, apoB48 secretion was significantly decreased compared to that of normal littermates, with a small increase in apoB-100 secretion. Total apoB secreted, however, was not increased. Our data further suggest that the predominant cause of the dyslipidemia under these conditions is a defect in removal of VLDL from the circulation.
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PMID:Obesity in db and ob animals leads to impaired hepatic very low density lipoprotein secretion and differential secretion of apolipoprotein B-48 and B-100. 925 55

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 (&epsi;4) and decrease (&epsi;2) 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 know that upper body obesity is associated with metabolic complications, but we don't know how regional body fat distribution influences postprandial lipemia in obese adults. Thus, this study explored the respective effects of android or gynoid types of obesity and fasting triglyceridemia on postprandial lipid metabolism and especially triglyceride-rich lipoproteins. Twenty-four obese and 6 lean normotriglyceridemic women (control), age 24-57 yr, were enrolled. Among obese women with an android phenotype, 9 exhibited normal plasma triglyceride levels (mean: 1.38 mmol/L) (NTAO), and 7 displayed a frank hypertriglyceridemia (mean: 2.40 mmol/L) (HTAO). The 8 patients with a gynoid phenotype had normal triglyceride levels (mean: 1.00 mmol/L) (GO). All were given a mixed test meal providing 40 g triglycerides. Serum and incremental chylomicron triglycerides 0-7 h areas under the curve (AUCs) as well as triglyceride levels in apoB-48-containing triglyceride-rich lipoprotein (TRLs) or chylomicrons were significantly higher in HTAOs and NTAOs than in GOs and controls postprandially. The size of chylomicron particles was bigger in controls and GOs than in HTAOs and NTAOs postprandially. Android obese subjects showed abnormally elevated fasting apoB-48 and apoB-100 triglyceride-rich lipoprotein (TRL) levels. Most abnormalities that were found correlated to plasma levels of insulin and apoC-III. In conclusion, an abnormal postprandial lipid pattern is a trait of abdominal obesity even without fasting hypertriglyceridemia.
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PMID:Influence of obesity and body fat distribution on postprandial lipemia and triglyceride-rich lipoproteins in adult women. 992 81

The purpose of this study was to determine the relationship between insulin resistance and apoB100 metabolism in African American males. Fifteen subjects, 33 +/- 7.6 years old, were divided into two groups, insulin-resistant (IR) or insulin-sensitive (IS), based on the sum of the plasma insulin concentrations during an oral glucose tolerance test. The IR group (n = 8) differed significantly from the IS group (n = 7) with respect to body mass index (BMI) (30.1 vs 23.1 kg/m2; P = 0.0003), fasting triglycerides, (118 vs 54 mg/dl, P = 0. 013), and total plasma apolipoprotein B100 (80 vs 59 mg/dl, P = 0.014). Significantly elevated apoB100 levels in the IR group were seen in very low density lipoprotein (VLDL) (5.1 vs 3.4 mg/dl, P = 0.045) and intermediate density lipoprotein (IDL) (18 vs 12 mg/dl, P = 0.017) but not in low density lipoprotein (LDL) (57 vs 46 mg/dl, P = 0.19). Total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apolipoprotein A-I, and blood pressure were not significantly different between the two groups. There was a high correlation between the sum of insulins during the oral glucose tolerance test and the BMI (rho = 0.88, P = 0.0001). In five IR and five IS subjects, apoB100 kinetics were determined in the fasting state using a bolus dose of deuteroleucine and multicompartmental modeling. IR subjects had significantly lower fractional catabolic rates (FCR) in the larger VLDL1 (-70%), the smaller VLDL2 (-71%), and the IDL (-53%) fractions. No significant differences in production rates were observed for any lipoprotein class. There was a significant correlation between the sum of insulins and the FCR of the apoB100 of VLDL1 (rho = -0.65, P = 0.05) and of IDL (rho = -0.85, P = 0.004). The correlation coefficient of the sum of insulins and the FCR of VLDL2 was -0.61 with P = 0.067. We conclude that in this population of African American males, IR is correlated with a decreased FCR of apoB100 in VLDL and IDL and elevated plasma levels of apoB and triglycerides (TG). These changes might be explained by decreased clearance of the TG-rich lipoproteins. We postulate that this may reflect decreased lipoprotein and/or hepatic lipase activity related to insulin resistance and its association with obesity.
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PMID:A study of the metabolism of apolipoprotein B100 in relation to insulin resistance in African American males. 1046 Jun 97

Intestinal cells synthesize and secrete chylomicrons in the postprandial state. Synthesis of these particles is defective in abetalipoproteinemia and chylomicron retention disease. Chylomicrons are very large, heterogeneous, lipid-rich particles ranging in diameters from 75 to 450 nm and function to transport dietary fat and fat-soluble vitamins to blood. The size heterogeneity of the secreted particles depends on the rate of fat absorption, type and amount of fat absorbed. The fatty acid composition of triglycerides present in chylomicrons reflects the composition of dietary fat, whereas the fatty acid composition of chylomicron phospholipids does not. The differences in the fatty acid compositions are also observed when lipids are labeled with glycerol. Thus, the differences are not due to differential incorporation of dietary fatty acids into different lipids but are mainly due to different pools of lipids used for chylomicron assembly. It has been suggested that preformed phospholipids and nascent triglycerides are preferentially used for intestinal lipoprotein assembly. Biosynthesis of chylomicrons requires apoB48. ApoB48 is translated from apoB mRNA that is post-transcriptionally edited in the intestinal cells to incorporate a stop codon. Nascent apoB48 may be cotranslationally lipidated and this process is critically dependent on the presence of microsomal triglyceride transfer protein. Two different models have been proposed for the assembly of chylomicrons. In the independent model, intestinal cells are hypothesized to synthesize VLDL and chylomicron by two independent pathways. The chylomicron assembly pathway is hypothesized to be sensitive to a surfactant, Pluronic L81, but that of VLDL assembly is not. In the sequential assembly model, synthesis of all lipoproteins is hypothesized to begin with the assembly of apoB-containing primordial lipoprotein particles. The primordial particles are suggested to fuse with triglyceride-rich lipid droplets that are synthesized independently of apoB. This process results in the core expansion of primordial particles and the synthesis of nascent lipoproteins. Differences in the size of secreted lipoproteins may be due to differences in the size of triglyceride-rich lipid droplets. Pluronic L81 is hypothesized to inhibit the formation of large triglyceride-rich droplets that serve as precursors for chylomicron assembly. In this review, we have discussed some signposts that might be unique to different steps in the assembly of chylomicrons. First, it is proposed that the association of preformed phospholipids with nascent apoB in the endoplasmic reticulum may serve as a signpost for the very early steps in the assembly of chylomicrons. Second, association of large amounts of newly synthesized triglycerides compared to preformed triglycerides may serve as a signpost for the assembly of larger lipoproteins. Third, the incorporation of retinyl esters may serve as markers for the final stages of chylomicron assembly. These signposts may be helpful in the identification and characterization of various intermediates in the assembly of chylomicrons. The knowledge about the molecular assembly of chylomicrons may lead to better therapeutic agents for controlling various hyperlipidemias, obesity, and atherosclerosis.
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PMID:Signposts in the assembly of chylomicrons. 1122 73

Nonalcoholic steatohepatitis (NASH) is a syndrome frequently associated with obesity, diabetes mellitus, and dyslipidemia. Increased fasting insulinemia and blood glucose levels may trigger a reduced catabolism of lipoproteins rich in triglycerides by lipoprotein lipase (LPL) and an increase in their fasting and postprandial levels. An association between postprandial lipemia and coronary heart disease has been observed, and many studies now support this concept. The most important result of our study is the increase in triglyceride-rich lipoproteins response after a fat load in NASH patients, the increase of incremental area under the postprandial curve, and the duration of the hypertriglyceridemic peaks. The persisting postprandial plasma triglyceride elevation in NASH patients was mostly due to the elevated plasma level of large triglyceride-rich particles. These data are coupled with lower plasma HDL2-cholesterol levels. As for lipoprotein analyses, the number of apolipoprotein B100 (ApoB100) particles is not significantly different between the two groups, and the higher content of triglycerides in NASH very low density lipoproteins (VLDL) increases the triglyceride-to-ApoB ratio and the particle size. A decreased enzymatic activity of LPL or a defective assembly and secretion of VLDL from hepatocytes due to a moderate reduction in microsomal triglyceride transfer protein could be involved in the overloading of VLDL. Moreover, the undetectable levels of ApoB48 in triglyceride-rich lipoproteins fraction A could be related to the synthesis of smaller and denser chylomicrons. NASH patients not only are insulin resistant but also tend to present alterations in fatty meal delivery, suggesting that an increase in fasting plasma insulin and glucose, with insulin resistance, joins with depressed metabolism of triglyceride-rich lipoproteins. An increase in postprandial triglyceride levels with production of large VLDL suggests an atherogenic behavior of lipid metabolism, in accordance with the high prevalence of the metabolic syndrome in NASH patients. This paper suggests that a fat load may be useful in early detection of atherogenic risk in the presence of otherwise normal fasting plasma lipids.
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PMID:Postprandial triglyceride-rich lipoprotein metabolism and insulin sensitivity in nonalcoholic steatohepatitis patients. 1176 56

The dysmetabolic syndrome of insulin resistance and visceral obesity is characterized by elevated plasma concentration of triacylglycerol-rich lipoprotein (TRL) remnants that may be related to increased cardiovascular risk. Perturbed hepato-intestinal cholesterol metabolism may play a contributory role in this abnormality. We therefore investigated the association between plasma markers of cholesterol absorption and synthesis with TRL remnant metabolism in 35 men with the metabolic syndrome (MS). Plasma campesterol:cholesterol and lathosterol:cholesterol ratios were measured as estimates of cholesterol absorption and synthesis respectively. Remnant metabolism was assessed by measuring remnant-like particle-cholesterol (RLP-C), apolipoprotein (apo)B-48 and the fractional catabolic rate (FCR) of a labelled remnant-like emulsion. Compared with controls, subjects with the MS had significantly lower plasma campesterol:cholesterol ratio, but higher lathosterol:cholesterol ratio ( P <0.05). Plasma RLP-C and apoB-48 concentrations were also higher ( P <0.01) and the remnant-like emulsion FCR was lower ( P <0.05). The plasma campesterol:cholesterol ratio was inversely correlated ( P <0.05) with plasma triacylglycerols ( r =-0.346), RLP-C ( r =-0.443), apoB-48 ( r =-0.427) and plasma lathosterol:cholesterol ratio ( r =-0.366); the campesterol:cholesterol ratio was also positively correlated with the remnant-like emulsion FCR ( r =0.398, P <0.05). In multiple regression analysis, the significant correlations between plasma campesterol:cholesterol ratio and plasma triacylglycerols, RLP-C, apoB-48 and FCR of the remnant-like emulsion were independent of age, dietary energy and plasma lathosterol. Our findings suggest that in subjects with the MS alterations in cholesterol absorption and synthesis may be closely linked with the kinetic defects in TRL metabolism.
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PMID:Relationships between cholesterol homoeostasis and triacylglycerol-rich lipoprotein remnant metabolism in the metabolic syndrome. 1265 82

Visceral obesity is frequently associated with high plasma triglycerides and low plasma high density lipoprotein-cholesterol (HDL-C), and with high plasma concentrations of apolipoprotein B (apoB)-containing lipoproteins. Atherogenic dyslipidemia in these patients may be caused by a combination of overproduction of very low density lipoprotein (VLDL) apoB-100, decreased catabolism of apoB-containing particles, and increased catabolism of HDL-apoA-I particles. These abnormalities may be consequent on a global metabolic effect of insulin resistance. Weight reduction, increased physical activity, and moderate alcohol intake are first-line therapies to improve lipid abnormalities in visceral obesity. These lifestyle changes can effectively reduce plasma triglycerides and low density lipoprotein-cholesterol (LDL-C), and raise HDL-C. Kinetic studies show that in visceral obesity, weight loss reduces VLDL-apoB secretion and reciprocally upregulates LDL-apoB catabolism, probably owing to reduced visceral fat mass, enhanced insulin sensitivity and decreased hepatic lipogenesis. Adjunctive pharmacologic treatments, such as HMG-CoA reductase inhibitors, fibric acid derivatives, niacin (nicotinic acid), or fish oils, may often be required to further correct the dyslipidemia. Therapeutic improvements in lipid and lipoprotein profiles in visceral obesity can be achieved by several mechanisms of action, including decreased secretion and increased catabolism of apoB, as well as increased secretion and decreased catabolism of apoA-I. Clinical trials have provided evidence supporting the use of HMG-CoA reductase inhibitors and fibric acid derivatives to treat dyslipidemia in patients with visceral obesity, insulin resistance and type 2 diabetes mellitus. Since drug monotherapy may not adequately optimize dyslipoproteinemia, dual pharmacotherapy may be required, such as HMG-CoA reductase inhibitor/fibric acid derivative, HMG-CoA reductase inhibitor/niacin and HMG-CoA reductase inhibitor/fish oils combinations. Newer therapies, such as cholesterol absorption inhibitors, cholesteryl ester transfer protein antagonists and insulin sensitizers, could also be employed alone or in combination with other agents to optimize treatment. The basis for a multiple approach to correcting dyslipoproteinemia in visceral obesity and the metabolic syndrome relies on understanding the mechanisms of action of the individual therapeutic components.
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PMID:Dyslipidemia in visceral obesity: mechanisms, implications, and therapy. 1528 98

The metabolism of apolipoproteins (apo)B-48, B-100, and A-I was studied with a primed constant infusion of deuterium-labeled leucine in the fed state in 3 male individuals with chronic kidney disease (CKD), a glomerular filtration rate (GFR) of 28 to 57 mL/min/1.73 m2, obesity (body mass index [BMI] 33.1), and the metabolic syndrome. Compared to 5 obese controls (BMI 30.1) and 13 non-obese controls (BMI 25.2), these CKD subjects had high plasma levels of triglycerides (TG) (343 +/- 27.5 mg/dL v 144 +/- 34.4 in the obese controls, P < .001) and low apoA-I (86.7 +/- 3.9 mg/dL). An abnormal high-density lipoprotein (HDL) particle subpopulation pattern was found, with low levels of pre beta-1 and alpha1. Compared to the obese controls, very-low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) apoB-100 levels were elevated 2- to 3-fold, while LDL apoB-100 levels were slightly lower (-7 %) and apoB-48 levels were comparable. The high TG levels were not associated with statistically significant changes in VLDL apoB-100 kinetics, although the production rate (PR) was higher and the fractional catabolic rate (FCR) was lower. The slightly lower LDL apoB-100 levels were accompanied by a significant 3-fold increase in the FCR and a 2.7-fold increase in the PR. The lower apoA-I levels were accompanied by a 1.6-fold increase in the FCR. Compared to the non-obese controls, the PR of apoA-I was increased by 61% and 38%, respectively (P < .001) in CKD and in obese control subjects. In the control subjects, the PR of apoA-I was significantly correlated with the BMI (r = 0.81, P < .0001). The kinetic results are consistent with these hypotheses: (1) CKD is associated with decreased clearance of the TG-rich lipoproteins (TRLs) and increased catabolism of LDL; (2) obesity increases apoB-100 and apoA-I production; and (3) in CKD, TG transfer to HDL, making HDL more susceptible to catabolism, accounts for the low apoA-I levels.
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PMID:Apolipoprotein A-I, B-100, and B-48 metabolism in subjects with chronic kidney disease, obesity, and the metabolic syndrome. 1537 79


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