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)

We tested the hypothesis that hypercorticosteronemia causes the hypercholesterolemia in young developing "fatty" rats. Obesity induced increases in corticosterone. Insulin, glucose, body weight, average daily food intake, plasma triglyceride, plasma phospholipids, liver weight, liver triglyceride, various adipose tissue parameters, and liver hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase activity were all ameliorated by adrenalectomy. Adrenalectomy exacerbated the hypercholesterolemia in obese animals and induced it in lean rats. Changes or lack of change in hepatic microsomal cholesterol, HMG-CoA reductase, and 7 alpha-hydroxylase, combined with the adrenalectomy-induced curtailment of tissue storage of cholesterol in adipose tissue, all contribute to the hypercholesterolemia caused by adrenalectomy. We suggest a mechanism whereby this may be related to elevated hepatic very low-density lipoprotein secretion rates. The elevated HMG-CoA reductase activity in obese rats results from the lower liver microsomal free cholesterol content. We conclude that the absence of glucocorticoids does not directly reduce plasma cholesterol in obese Zucker rats. The surprising elevation of cholesterol by adrenalectomy is due to other prevailing mechanisms in liver and adipose tissue, which curtail their capacity to store cholesterol.
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PMID:Is there a role for the adrenals in the development of hypercholesterolemia in Zucker fatty rats? 151 9

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

Coronary heart disease is the leading cause of death among patients with non-insulin-dependent diabetes mellitus (NIDDM). NIDDM patients have a high frequency of dyslipidemia, which along with obesity, hypertension, and hyperglycemia may contribute significantly to accelerated coronary atherosclerosis. Because risk factors for coronary heart disease are additive and perhaps multiplicative, even mild degrees of dyslipidemia may enhance coronary heart disease risk. Therefore, therapeutic strategies for management of NIDDM should give equal emphasis to controlling hyperglycemia and dyslipidemia. The National Cholesterol Education Program recently issued guidelines for treatment of hyperlipidemia in adults including diabetic patients. Because of the unique features of diabetic dyslipidemia, however, we suggest that certain modifications in these guidelines be made to meet specific needs of diabetic patients. For example, therapeutic goals for serum cholesterol reduction should be lower in diabetic patients than in nondiabetic subjects. Particular emphasis should be given to weight reduction in NIDDM patients. In some diabetic patients, monounsaturated fatty acids may be a better replacement for saturated fatty acids than carbohydrates. The target for cholesterol lowering should include both very-low-density lipoprotein and low-density lipoprotein (LDL) (non-high-density lipoprotein) rather than LDL alone. To obtain a substantial reduction of cholesterol levels, drug therapy may be required in many patients. However, first-line drugs for nondiabetic patients (nicotinic acid and bile acid sequestrants) may be less desirable in NIDDM patients than hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors and even fibric acids. In fact, HMG CoA reductase inhibitors may be the drugs of choice for NIDDM patients with elevated LDL cholesterol and borderline hypertriglyceridemia, whereas gemfibrozil appears preferable for NIDDM patients with severe hypertriglyceridemia.
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PMID:Management of dyslipidemia in NIDDM. 219 Jul 70

Coronary artery disease (CAD) is the leading cause of death among whites with non-insulin-dependent diabetes mellitus (NIDDM). Several risk factors--dyslipidemia induced by NIDDM, obesity, hypertension and hyperglycemia--likely contribute to accelerated atherosclerosis. The dyslipidemia in NIDDM is characterized by abnormalities in composition and metabolism of very low density lipoproteins, low-density lipoproteins (LDL) and high-density lipoproteins (HDL). However, because of the lack of long-term prospective epidemiologic studies, the relative importance of lipoprotein risk factors in the causation of CAD in diabetic patients is not clear. The World Health Organization Multinational Study of vascular disease in diabetics observed increased prevalence of CAD in diabetic populations with relatively high levels of plasma cholesterol and supports the concept that lowering cholesterol levels may significantly reduce coronary risk in NIDDM. To determine the effectiveness of lovastatin, an inhibitor of HMG CoA reductase, for lowering cholesterol levels, 16 patients with NIDDM and mild to moderate increases in plasma cholesterol were given lovastatin (20 mg twice daily) in a randomized, double-blind, placebo-controlled manner for 4 weeks. Compared with the placebo, lovastatin reduced concentrations of total cholesterol (233 +/- 10 vs 172 +/- 7 mg/dl [standard error of the mean], p less than 0.001), LDL cholesterol (140 +/- 9 vs 101 +/- 6 mg/dl, p less than 0.001), and LDL apolipoprotein-B (108 +/- 16 vs 80 +/- 16 mg/dl, p less than 0.001). Plasma triglycerides and very low density lipoprotein cholesterol levels also decreased by 31 and 42%, respectively. Although HDL cholesterol levels did not increase, the total cholesterol/HDL cholesterol ratio decreased significantly with lovastatin therapy. No adverse effects were noted and glycemic control was well-maintained.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Treatment of dyslipidemia in non-insulin-dependent diabetes mellitus with lovastatin. 305 23

Serum cholesterol concentrations, lecithin-cholesterol acyltransferase (LCAT), and hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activities of lean and obese Zucker rats were compared. The excess serum cholesterol of the female obese rat is found to be mainly free cholesterol associated with very low-density lipoproteins, whereas that of the male obese rat is carried as cholesterol esters associated with high-density lipoproteins. The high level of serum free cholesterol in the female obese rat is not due to a deficiency in lecithin-cholesterol acyltransferase activity. This enzyme activity is found to be elevated in the male obese rat. Hepatic HMG-CoA reductase activity declines as rats mature; this observation is most apparent in obese male rats. Lean rats exhibit the normal diurnal rhythm, but mature obese rats show little diurnal variation in HMG-CoA reductase activity. Obese female rats maintain high reductase activities, but the activities of obese male rats remain low at all times. Starvation suppresses liver HMG-CoA reductase and serum cholesterol in both lean and obese female rats. Thus, an increase in hepatic cholesterol synthesis may contribute to hypercholesterolemia in the obese female Zucker rat. On the other hand, factors such as nonhepatic synthesis or a decreased cholesterol catabolism may play more important roles in maintaining high serum cholesterol in the obese male Zucker rat.
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PMID:Serum cholesterol, lecithin-cholesterol acyltransferase, and hepatic hydroxymethylglutaryl coenzyme A reductase activities of lean and obese Zucker rats. 396 58

In the past history of the pharmaceutical industry, secondary metabolites have been screened almost exclusively for antimicrobial activities. This biased and narrow view has severely limited the potential application of microbial metabolites. Fortunately, this situation is changing and we are now entering into a new era in which microbial metabolites are being applied to diseases heretofore only subjected to synthetic compounds. This new approach is the application of microbial secondary metabolites to diseases that are not caused by other bacteria or fungi. For years, major drugs such as hypotensive and anti-inflammatory agents that are used for non-infectious diseases have been strictly synthetic products. Similarly, major therapeutics for parasitic diseases in animals (for example, coccidiostats and anthelminthics) resulted strictly from screens of chemically synthesized compounds followed by molecular modification. However, today fermentation products such as monensin and lasalocid dominate the coccidiostat market. The avermectins, another group of streptomycete products, have high activity against helminths and arthropods. Indeed, their activity appears to be an order of magnitude greater than previously discovered anthelminthic agents, the vast majority of which are synthetic compounds. Umezawa's group in Japan has isolated many microbial products with important pharmacological activities by screening with simple enzymic assays. There is much interest in a natural inhibitor of intestinal glucosidase, which is produced by an actinomycete of the genus Actinoplanes. The aim is to decrease hyperglycaemia and triacylglycerol synthesis in adipose tissue, liver and the intestinal wall of patients with diabetes, obesity and type IV hyperlipidaemia. Another natural compound of interest is mevinolin, a fungal product which acts as a cholesterol-lowering agent in animals. Mevinolin is produced by Aspergillus terreus. In its hydroxyacid form (mevinolinic acid), mevinolin is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase from liver. It is clear that, although the microbe has contributed greatly to the benefit of mankind, we have merely scratched the surface of the potential of microbial activity.
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PMID:A new era of exploitation of microbial metabolites. 640 Apr 79

Obesity is often associated with an elevated total body cholesterol synthesis. In order to evaluate the role of hepatic cholesterogenesis in this phenomenon, we assayed the rate-limiting step in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in the microsomal fraction of liver biopsies obtained operatively from ten morbidly obese (relative body weight greater than 155%) subjects. Eighteen normal-weight patients (relative body weight less than 120%) with cholesterol gallstones served as controls. Hepatic HMG CoA reductase activity, expressed as pmol X min-1 X mg protein-1, was 60% higher in the obese subjects compared to the gallstone patients (P less than 0.05). Microsomal protein concentration was lower in the obese patients, so that enzyme activity calculated per gram liver was not significantly different between the two groups. However, mevalonate formation, expressed in terms of total organ activity, was higher in the obese than in the nonobese group. The results suggest that the liver is a major contributor to the increased cholesterol production seen in obesity.
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PMID:Hepatic cholesterol metabolism in obesity: activity of microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase. 711 74

Atherosclerosis is the principal cause of diabetic morbidity and mortality. Diabetic dyslipidemia, obesity, and hypertension are significant contributing factors in the acceleration of the atherosclerotic process. Regardless of the type of diabetes, increased levels of very-low-density lipoprotein triglyceride, modified levels of low-density lipoprotein cholesterol, and decreased levels of high-density lipoprotein (HDL) cholesterol are the main lipoprotein abnormalities in diabetic patients. These abnormalities can be improved in part by glycemic control, but additional intervention may be needed. Diet and exercise are important elements in the management of dyslipidemia, but lipid-lowering drugs (especially fibrates and HMG-CoA reductase inhibitors) also may be necessary for the control of diabetic dyslipidemia. Based on these findings, the American Diabetes Association Consensus Panel and the revised treatment guidelines of the National Cholesterol Education Program recommend treatment of hypertriglyceridemia/low HDL cholesterol as a risk factor of coronary heart disease in diabetic and nondiabetic individuals alike. Aggressive treatment is recommended, therefore, particularly in diabetic patients and in all patients with existing vascular disease.
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PMID:Prevention of atherosclerosis in diabetes: emphasis on treatment for the abnormal lipoprotein metabolism of diabetes. 826 43

S-allyl cysteine sulfoxide, isolated from garlic, A. sativum, is more or less as active as gugulipid in controlling hypercholestermia, obesity and derangement of enzyme activities in cholesterol diet fed rats. The beneficial effects of the drugs are partly due to their inhibitory effects on transaminases, alkaline phosphatase, lipogenic enzymes and HMG CoA reductase and partly due to their stimulatory effects on plasma lecithin-cholesterol acyl transferase lipolytic enzymes and fecal excretion of sterols and bile acids.
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PMID:Effects of S-allyl cysteine sulfoxide isolated from Allium sativum Linn and gugulipid on some enzymes and fecal excretions of bile acids and sterols in cholesterol fed rats. 857 6

Obese persons are at risk for cholesterol gallstones because their bile is saturated with cholesterol. The risk increases during rapid weight loss by means of certain very-low-calorie diets or gastric bypass surgery. Gallstone risk factors during rapid weight loss include increased bile cholesterol saturation index and gallbladder stasis. Obese subjects were randomized to one of two low-calorie liquid diets for rapid weight loss: a 520-kcal diet with less than 2 g fat/d, and a 900-kcal diet with 30 g fat/d (including one 10-g fat meal to stimulate maximal gallbladder emptying). Bile and blood lipids, saturation index, leukocyte 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity, and ultrasonographic gallbladder emptying were measured repeatedly during dietary treatment. Both diets produced comparable weight loss of 22%. Bile cholesterol saturation index increased during both diets (26%), but fell to 15% below prediet level after weight loss. Compared with subjects' maximal gallbladder emptying fraction of 66%, the 520-kcal diet provided poor gallbladder emptying (35%), whereas the 10-g fat meal of the 900-kcal diet provided maximal emptying. Gallstones developed in four of six 520-kcal subjects and none of seven 900-kcal subjects (P = .021), an unanticipated difference that resulted in premature study termination for ethical reasons. Blood lipids and HMG CoA reductase activity in mononuclear leukocytes fell at week 8 during both diets, but recovered while weight was still being lost. The findings suggest that gallstone risk during rapid weight loss may be reduced by maintenance of gallbladder emptying with a small amount of dietary fat. Ultimately, weight loss reduced bile cholesterol saturation and improved highdensity lipoprotein (HDL) levels.
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PMID:The role of gallbladder emptying in gallstone formation during diet-induced rapid weight loss. 878 21


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