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)

Inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase have been approved for treatment of hypercholesterolemia in humans. This class of therapeutic agents, in addition to lowering plasma cholesterol, reduces plasma triglyceride levels. We have investigated the mechanism of triglyceride-lowering effect of lovastatin in the hypertriglyceridemic state by using a rodent model of hypertriglyceridemia and obesity, the Zucker obese (fa/fa) rat. Lovastatin treatment (4 mg/kg), as compared to placebo, caused a 338% reduction in plasma triglyceride (146 +/- 5 vs. 494 +/- 76 mg/dl), a 58% decrease in total cholesterol (99 +/- 13 vs. 156 +/- 18 mg/dl), and a 67% reduction in high density lipoprotein (HDL)-cholesterol (69 +/- 8 vs. 115 +/- 15 mg/dl). The fall seen in plasma triglyceride was due to a decrease in hepatic secretion of very low density lipoproteins (VLDL), determined after blocking the clearance of triglyceride-rich lipoproteins with Triton WR-1339. Lovastatin treatment did not affect either the activities of hepatic lipogenic enzymes, glucose-6-phosphate dehydrogenase, or malic enzyme, or the activities of the lipolytic enzymes of adipose tissue, lipoprotein lipase, or liver, hepatic triglyceride lipase. Supplementation of mevalonolactone in the diet partially reversed the changes in plasma triglyceride (265 +/- 37 vs. 146 +/- 5 mg/dl), but not in total or HDL-cholesterol. These data demonstrate that, in the hypertriglyceridemic Zucker rat model, HMG-CoA reductase inhibitors reduce the rate of secretion of VLDL and this effect can be partially reversed by administration of mevalonolactone.
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PMID:Mechanisms of triglyceride-lowering effect of an HMG-CoA reductase inhibitor in a hypertriglyceridemic animal model, the Zucker obese rat. 155 26

Studies of lipoproteins in this homogenous study population indicate clear and consistent associations between obesity and abnormalities in lipoproteins. These include both increases in VLDL and lower HDL, which were observed in both men and women. A high production of total body cholesterol in obese subjects, probably associated with increased flux of glucose and free fatty acids, leads to a greater production of VLDL. This, in turn, creates a greater flux of metabolic products of VLDL either back to the liver or through LDL. Obesity induces an increase in hepatic lipase, perhaps in women because of lower estrogen levels, which is associated with lower HDL concentrations, and altered HDL composition. Several of these observed changes, such as the greater proportion of VLDL remnants, the greater flux of particles through the LDL compartment, and the altered HDL composition, may be associated with increased atherosclerosis. However, preliminary data do not show a relationship between obesity and death from coronary heart disease in this population. More studies are needed to resolve this apparent conflict.
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PMID:Obesity, lipoproteins, and heart disease. 157 83

Silent myocardial ischemia (SI), an asymptomatic manifestation of coronary artery disease (CAD), was identified in 10% of apparently healthy nonsmoking, nondiabetic older (60 +/- 7 years, mean +/- SD) men with normal plasma cholesterol levels. We hypothesized that in the absence of other major risk factors for CAD, the men with SI would have reduced plasma levels of high density lipoprotein (HDL) and HDL2 subspecies due to an upper-body fat distribution (waist-to-hip ratio [WHR]), hyperinsulinemia, and abnormal postheparin plasma lipoprotein lipase (LPL) and hepatic lipase (HL) activities. Compared with 47 normal control subjects of similar age, obesity, and maximal aerobic capacity, the 18 men with SI had higher plasma triglyceride (TG) (162 +/- 71 versus 102 +/- 39 mg/dl, p less than 0.001) and lower HDL-C (33 +/- 6 versus 37 +/- 7 mg/dl, p less than 0.02) levels with no difference in low density lipoprotein cholesterol level. The HDL2b and HDL2a subspecies measured by gradient gel electrophoresis were also lower in the men with SI (p less than 0.01). The plasma glucose and insulin responses during an oral glucose tolerance test were the same in both groups. Postheparin plasma HL activity was significantly higher in 12 men with SI than in 41 control subjects (34 +/- 8 versus 27 +/- 10 mumol/ml.hr-1, p less than 0.03) and was correlated with log insulin area (r = 0.36, p less than 0.05) and WHR (r = 0.32, p less than 0.05) in the control subjects but not in the men with SI. In the control group, the percent HDL2b subspecies was correlated inversely with postheparin plasma HL activity (r = -0.46, p less than 0.01, n = 41) as well as WHR (r = -0.49, p less than 0.001, n = 47) and log insulin area (r = -0.37, p less than 0.05, n = 47) but not in the men with SI. Postheparin LPL activity was the same in both groups of men and did not correlate with HDL, WHR, insulin, or plasma TG levels. As the control subjects and men with SI had comparable degrees of abdominal obesity and hyperinsulinemia, these results suggest that the reduced HDL-C levels in men with SI may be related to elevations in HL activity. Thus, abdominal obesity, hyperinsulinemia, elevated TG levels, and low HDL-C and HDL2 subspecies levels may predispose these older men to atherosclerosis.
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PMID:Reduced HDL2 cholesterol subspecies and elevated postheparin hepatic lipase activity in older men with abdominal obesity and asymptomatic myocardial ischemia. 161 6

The diurnal changes in postheparin lipolytic activity (PHLA) were studied as on aspect of its physiological changes in eight healthy volunteers in a fasting state. Serum lipids and PHLA in obese males were measured to determine the etiology of obesity-associated hypertriglyceridemia with respect to triglyceride (TG) catabolism. In the healthy nonobese volunteers, the lipoprotein lipase (LPL) activity did not show any diurnal changes, but decreased with time during fasting. The hepatic triglyceride lipase (HTGL) activity underwent diurnal changes, and was high in the morning and low at night. Perceiving the metabolic difference between young obese individuals (obese since childhood) and middle-aged obese individuals (obese since adulthood), PHLA and serum lipids were simultaneously determined and examined from the aspect of TG catabolism in a young male group aged 17-27 and an older male group aged 35-62. The lower-age group consisted of 15 normal-weight men and 25 obese men with 11 years (mean) of a history of obesity. The higher-age group consisted of 15 normal-weight men and 25 obese men with 12 years of a history of obesity. No differences were found in total cholesterol and LDL-cholesterol between the normal-weight and obese individuals of both groups. However, HDL-cholesterol was significantly decreased, only in the obese individuals of the higher age group, compared to the normal-weight individuals of this group. Serum TG and insulin were significantly higher in the obese individuals than normal-weight individuals of both groups. In the obese individuals in both groups, a positive correlation was demonstrated between serum TG and insulin. This suggested the increased production of TG in association with hypertriglyceridemia. In addition, TG positively correlated with LPL and HTGL activities in young obese individuals, while a negative correlation was demonstrated only between TG and LPL activity in older obese individuals. These results indicated an age-related difference in TG catabolism in obese individuals with obesity-associated hypertriglyceridemia.
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PMID:[Diurnal changes in postheparin lipolytic activity (PHLA) and the role of PHLA in triglyceride catabolism in young and middle-aged obese individuals]. 175 27

The relative effects of obesity, alone or in combination with insulin resistance and hyperinsulinemia (with or without diabetes), on lipoprotein concentrations, blood pressure, and other risk factors for cardiovascular disease were investigated in 28 men (mean age, 63 years). Special attention was given to lipoprotein lipase (LPL) activity in tissues and to postheparin plasma LPL activity and hepatic lipase activity and their relation to insulin resistance. The 28 men fulfilled the entrance criteria of the study so that they could be allocated to one of the four groups (seven in each group): 1) normal body weight, normal fasting insulin level, and normal glucose tolerance (controls); 2) the same as in group 1 but with moderate obesity; 3) the same as in group 2 but with fasting hyperinsulinemia; 4) the same as in group 3 but with non-insulin-dependent diabetes mellitus. Glucose infusion rate for the control group was 8.1 +/- 2.1 mg/kg body wt/min (mean +/- SD) at an insulin infusion rate of 56 milliunits/m2/min. The average values in groups 2, 3, and 4 were 6.0 +/- 0.7, 3.2 +/- 0.5, and 1.9 +/- 1.0 mg/kg body wt/min, respectively. Concentrations of very low density lipoproteins as well as blood pressure and urate concentrations were highest and those of high density lipoproteins were lowest in the two hyperinsulinemic groups (groups 3 and 4). Skeletal muscle LPL activity was 46 +/- 23, 41 +/- 25, 23 +/- 6, and 31 +/- 13 milliunits/g wet wt (mean +/- SD) in the four groups, respectively. There was a positive correlation between glucose infusion rate and muscle LPL activity (r = 0.58, p less than 0.0001). The hepatic lipase activity was positively correlated with the insulin area under the curve of the intravenous glucose tolerance test (r = 0.35, p = 0.02). Furthermore, blood pressure, free fatty acid concentration, liver enzymes, and urate concentrations were significantly correlated with glucose infusion rate at the clamp test. These data give further support for insulin resistance as an important factor behind the observed lipoprotein abnormalities and blood pressure elevations as part of the insulin resistance syndrome characteristic for obese and diabetic patients.
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PMID:Lipoprotein lipase activity in skeletal muscle is related to insulin sensitivity. 191 6

Abnormalities of plasma lipid and lipoprotein concentrations are common in both insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetes mellitus. In general, individuals with IDDM who are untreated or inadequately treated have elevations in both postprandial and fasting triglyceride levels in association with reduced activity of lipoprotein lipase. Low-density lipoprotein (LDL) cholesterol levels can rise when insulin deficiency impacts on LDL-receptor function. When patients with IDDM are treated and plasma glucose levels well controlled, plasma very-low-density lipoprotein (VLDL) triglyceride and LDL cholesterol levels are usually normal. In addition, plasma high-density lipoprotein (HDL) cholesterol levels are normal or elevated in well-controlled IDDM subjects. In NIDDM, increased VLDL triglyceride and reduced HDL cholesterol concentrations are common and are only partially related to glycemic control. Overproduction of VLDL leads to hypertriglyceridemia, which can be exacerbated if lipoprotein lipase activity is also reduced. The regulation of LDL levels is complex; catabolism can be reduced if significant insulin deficiency exists or increased if significant hypertriglyceridemia is present. The reduced levels of HDL cholesterol in NIDDM appear to be related to increased exchange of HDL cholesteryl esters for VLDL triglycerides, although other mechanisms may exist. The roles of insulin resistance, obesity, and independently inherited abnormalities of lipoprotein metabolism in the etiology of dyslipidemia of NIDDM are complex and require further investigation. Finally, the effects of diabetes on glycosylation of apoproteins; on other lipid enzymes, particularly hepatic triglyceride lipase; on lipoprotein surface lipids; and on hepatic uptake of remnants have only just begun to be defined. In view of the marked increase in atherosclerotic cardiovascular disease in individuals with diabetes mellitus, prompt attention to and aggressive therapy for dyslipidemia should be a central component of care for these patients.
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PMID:Lipoprotein physiology in nondiabetic and diabetic states. Relationship to atherogenesis. 195 76

The effects of obesity, weight loss and weight maintenance on the serum lipid levels and lipoprotein lipase and hepatic triglyceride lipase were investigated in rats. Obesity induced by high-fat (HF) feeding was associated with decreased serum triglyceride levels (HF: 70.3 +/- 8.2, control (CON): 140.0 +/- 26.9 mg/dl, P less than 0.05), increased lipoprotein lipase (LPL, HF: 593.2 +/- 10.6 vs CON: 280 +/- 19.5 nmol FFA/min per mg tissue, P less than 0.05) and suppressed hepatic triglyceride lipase activities (HTGL, HF: 14.2 +/- 0.5 vs CON: 18.0 +/- 0.4 nmol FFA/min per mg tissue, P less than 0.01). After a weight loss to the level of control rats, weight maintenance was achieved either by high-protein (HP) or chow feedings (CH). Both high-protein (HFHP) and chow (HFHC) groups had similar weights but only high-protein feeding restored the normal body compositions. Both groups of rats had higher total (TC, HFHP: 146 +/- 10.7; HFCH: 104.8 +/- 5.1 mg/dl), and high density lipoprotein cholesterol levels (HDL-C, HFHP: 100.8 +/- 15.6; HFCH: 75.5 +/- 5.5 mg/dl) and lower lipoprotein lipase (HFHP: 238.2 +/- 15.8, HFCH: 354.8 +/- 34.9 nmol FFA/min per mg tissue) and hepatic triglyceride activities (HFHP: 16.3 +/- 1.1; HFCH: 14.5 +/- 0.6 nmol FFA/min per mg tissue) than control rats (TC: 70.1 +/- 4.7 mg/dl; HDL-C: 14.2 +/- 4.3 mg/dl; LPL: 742.4 +/- 82.3 nmol FFA/min per mg tissue; HTGL: 20.5 +/- 1.0 nmol FFA/min per mg tissue, P less than 0.05 to 0.005) or the rats who regained weight by resuming high-fat feeding (TC: 59.5 +/- 6.7 mg/dl; HDL-C: 10.2 +/- 6.7 mg/dl; LPL: 1284.3 +/- 90 nmol FFA/min per mg tissue; HTGL: 22.2 +/- 1.9 nmol FFA/min per mg tissue, P less than 0.05 to 0.005). The high protein-group had significantly higher total and high-density-lipoprotein cholesterol levels than the chow fed animals despite comparable body weights in both groups. The findings of this study suggest that weight maintenance induced by high protein feeding is more successful in restoring the normal body composition. However, high protein feeding is also associated with high serum cholesterol levels. The clinical applications of these findings need to be evaluated further.
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PMID:Effects of weight loss and weight maintenance on the serum lipids, lipoprotein lipase and hepatic triglyceride lipase activities in obese rats. 276 81

We measured serum lipids, lipoproteins and post-heparin plasma lipases, lipoprotein lipase and hepatic lipase, in 12 female patients with Type 1 (insulin-dependent) diabetes (postglucagon C-peptide undetectable), in 11 female insulin-treated patients with Type 2 (non-insulin-dependent) diabetes (postglucagon C-peptide greater than 0.60 nmol/l) and in 16 non-diabetic female control subjects. These three groups of subjects were similar with respect to age and obesity. Insulin dose was similar in patients with Type 1 and with Type 2 diabetes. HDL and HDL2 cholesterol were lower in patients with Type 2 diabetes than in non-diabetic control subjects (p less than 0.05) but did not differ between patients with Type 1 diabetes and non-diabetic control subjects. No difference in lipoprotein lipase activity was seen between the groups. The highest levels of lipoprotein lipase and hepatic lipase activities were observed in patients with Type 2 diabetes. Lipoprotein lipase activity correlated significantly with HDL cholesterol in patients with Type 1 diabetes (p less than 0.01) and in patients with Type 2 diabetes (p less than 0.001) but not in control subjects. Hepatic lipase activity did not correlate significantly with HDL cholesterol in any of the groups. In conclusion, postheparin plasma lipoprotein lipase and hepatic lipase activities do not seem to explain the difference in HDL cholesterol concentration between patients with Type 1 and Type 2 diabetes.
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PMID:Relationship between postheparin plasma lipases and high-density lipoprotein cholesterol in different types of diabetes. 342 2

To evaluate mechanisms of diabetes-induced changes in very-low-density lipoprotein (VLDL), VLDL triglyceride (TG) and VLDL apolipoprotein B (apoB) metabolism were studied in 12 obese Pima Indian control subjects and in 15 Pima Indian obese non-insulin-dependent diabetics. Eleven of the diabetics were restudied after reduction of hyperglycemia with oral sulfonylurea therapy. In addition, adipose, muscle, and postheparin lipoprotein lipase and postheparin hepatic lipase activities were measured in all subjects. Obese diabetics as compared with obese controls showed a trend toward increased production of VLDL TG (46 +/- 4 vs. 35 +/- 6 g/day, P = .10) but not of VLDL apoB (1595 +/- 106 vs. 1597 +/- 164 mg/day, NS); production of VLDL TG declined to control levels (33 +/- 4 g/day, P less than .05) during therapy, whereas there was no change in production of VLDL apoB. Diabetics had a clearance defect for VLDL, indicated by significantly lower fractional catabolic rates for both VLDL TG (10.6 +/- .9 vs. 13.1 +/- .9 pools/day, P less than .05) and VLDL apoB (5.6 +/- .4 vs. 7.5 +/- 0.7, P less than .05) as compared with controls; fractional catabolic rates increased after therapy (to 13.3 +/- 1.5, P less than .05, and 6.7 +/- .4, P less than .05, respectively). In the diabetics, this decrease in clearance was accompanied by a lower adipose lipoprotein lipase (.30 +/- .09 vs. .92 +/- .25 mumol X g-1 X h-1, P less than .01), which increased during therapy (to .61 +/- .17, P less than .05). Hepatic lipase also decreased significantly after therapy (27.4 +/- 3.6 to 26.4 +/- 3.2, P less than .01). Composition of VLDL in diabetics was also abnormal, indicated by a higher TG/apoB ratio (14.7 +/- .6 vs. 11.7 +/- .8, P less than .01); this ratio fell during therapy (to 12.5 +/- .8, P less than .05). The data indicate there are multiple abnormalities in structure and metabolism of VLDL in non-insulin-dependent diabetics. Control of hyperglycemia with sulfonylureas has the capability of reversing some of these abnormalities.
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PMID:Effects of NIDDM on very-low-density lipoprotein triglyceride and apolipoprotein B metabolism. Studies before and after sulfonylurea therapy. 353 Aug 55

To investigate the reasons for the lack of sex differences in high density lipoproteins (HDL) observed in population studies of the Pima Indians, we selected 18 lean (9 men, 9 women, body mass index (BMI) less than 27) and 22 obese (12 men, 10 women, BMI greater than 27) Pima Indians for an inpatient study of HDL composition. We measured lipase activities and steroid hormone concentrations, both of which have previously been implicated in the control of HDL. The lean women had higher concentrations of HDL and HDL2 than did either the obese women or the lean or obese men. Lean women had significantly lower hepatic lipase activities and significantly higher concentrations of estradiol compared to obese women. Lean women also had different HDL2 composition, as indicated by the molar ratio of HDL2 cholesterol/A-I. Significant negative correlations between HDL and obesity measured by either BMI or percent body fat were observed in both sexes, but the slope of the relationship was steeper in women. Significant negative associations were observed between HDL or HDL2 concentrations and hepatic lipase in both sexes, and there were significant positive associations between HDL2 and plasma estradiol in women. The data suggest that obesity in this population has a stronger negative influence on HDL concentrations in women, possibly through changes in estradiol and hepatic lipase activities. Since there are so few lean women in the Pima population, the net result is that HDL levels in women in the population as a whole do not differ from those of men.
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PMID:Lack of sex differences in high density lipoproteins in Pima Indians. Studies of obesity, lipase activities, and steroid hormones. 359 76


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