Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to characterize the lipoprotein profile and cholesterol metabolism in Yoshida rats, a strain of inbred genetically hyperlipemic animals. For comparison, Brown Norway rats were used as control animals. Plasma cholesterol and triglycerides were higher in Yoshida as compared to Brown Norway, the elevation of cholesterol being due to a rise in HDL fraction. Triglyceride distribution among lipoproteins showed an increase in VLDL fraction. Hyperlipemia was not related to diabetes, hypothyroidism or nephropathy. Plasma triglycerides production was increased in Yoshida rats, while lipoprotein and hepatic lipases were similar in the two groups. Hypercholesterolemia was associated with a defect of lipoprotein receptor activity and with elevated HMG-CoA reductase and cholesterol 7 alpha - hydroxylase; conversely ACAT activity was lower in Yoshida as compared to Brown Norway rats. Sterol fecal excretion was comparable in the two groups and hypercholesterolemia in Yoshida rats was not associated to an increase of cholesterol saturation of the bile. We suggest that lipoprotein overproduction is the main cause for hyperlipidemia in this strain of rats.
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PMID:Plasma lipoproteins and cholesterol metabolism in Yoshida rats: an animal model of spontaneous hyperlipemia. 159 76

We investigated plasma lipoprotein profiles and the activities of tissue cholesterol regulating enzymes in Wistar fatty rats, an animal model for non-insulin-dependent diabetes mellitus (NIDDM). Wistar fatty rats were made by transfer of the fa gene to the Wistar Kyoto rats by backcross-breeding. Wistar fatty and control non-diabetic littermates were given a laboratory chow or an atherogenic diet containing 1 percent (weight percent) cholesterol, 0.5 percent cholic acid, and 5 percent lard. Under the chow diet, plasma fasting glucose and immunoreactive insulin concentrations in Wistar fatty rats were 1.5- and 6-fold higher than controls, respectively. Plasma cholesterol was significantly increased in Wistar fatty rats compared with controls. Elevated plasma cholesterol levels in Wistar fatties was accounted for by the increases of cholesterol content in the d less than 1.006 g/ml lipoprotein and high-density lipoproteins. Under the atherogenic diet, plasma cholesterol levels in Wistar fatties were further increased by 129 percent compared with controls. The diet-induced increase of cholesterol contents was shown in all lipoprotein classes for Wistar fatty rats. The activities of regulatory enzymes for cholesterol biosynthesis or absorption were measured in Wistar fatty rats. Both hepatic and intestinal 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase activities were significantly higher in Wistar fatty rats than those in controls (P less than 0.05 and P less than 0.01, respectively). ACAT activities in Wistar fatties were significantly increased in the intestine (P less than 0.05) and decreased in the liver in comparison with controls (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Abnormalities of plasma lipoproteins in a new genetically obese rat with non-insulin-dependent diabetes mellitus (Wistar fatty rat). 189 25

The effect of diabetes control on the activities of hydroxymethylglutaryl-CoA reductase (HMG-CoA reductase), cholesterol acyltransferase (ACAT), and phenol 2-monooxygenase, the major enzymes regulating cholesterol metabolism, was determined in alloxan-induced diabetic rabbits, and the results obtained were correlated with lipid and lipoprotein levels. Although intestinal HMG-CoA reductase activity was significantly increased (P less than 0.001) in poorly controlled compared with moderately controlled diabetic rabbits, there was a significant reduction in the activities of intestinal ACAT (P less than 0.01), hepatic HMG-CoA reductase (P less than 0.05) and ACAT (P less than 0.001), and phenol 2-monooxygenase (P less than 0.01). The poorly controlled animals were hypercholesterolemic (P less than 0.01), and this was reflected in the very-low-density and high-density lipoprotein fractions. Serum cholesterol levels in the nondiabetic and moderately controlled diabetic groups were similar. This increase in intestinal HMG-CoA reductase activity in the poorly controlled diabetic animals occurred in the absence of hyperphagia. Although abnormalities in cellular cholesterol metabolism could be partly responsible for the alterations in serum cholesterol levels in diabetes, the precise mechanisms underlying these enzymatic changes have yet to be elucidated.
Diabetes 1990 May
PMID:Cholesterol metabolism in alloxan-induced diabetic rabbits. 233 20

1. Hyperlipidaemia is associated with diabetes mellitus. 2. A comparison of cholesterol synthesis and utilization in alloxan-induced diabetic rats and rabbits revealed that interspecies differences existed only in the response of the key enzymes regulating cholesterol utilization, namely cholesterol 7 alpha-hydroxylase and ACAT in the liver and intestine respectively. 3. The activity of cholesterol 7 alpha-hydroxylase was enhanced in diabetic rats but was markedly reduced in diabetic rabbits. 4. Intestinal ACAT activity, though unchanged in diabetic rats was reduced in diabetic rabbits. 5. Such species differences in cholesterol utilization may underlie the different degree of susceptibility to hypercholesterolaemia that exists between these two species.
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PMID:A comparative study of the rate-limiting enzymes of cholesterol synthesis, esterification and catabolism in the alloxan-induced diabetic rat and rabbit. 342 2

Atherosclerosis is well recognized as an inflammatory disease and circulating markers of inflammation such as C-reactive protein and soluble adhesion molecules are strong predictors of atherosclerotic lesion development and future cardiovascular events. Several cells (endothelial, smooth muscle and macrophages) and proteins (inflammatory cytokines and adhesion molecules) contribute to this inflammatory process and lesion development. Although lipid management with statins does reduce levels of circulating inflammatory markers, this appears to be unrelated LDL-lowering. Thus, the recent focus has been shifted to develop molecules that directly affect the atherosclerotic process without effects on plasma lipids. Much of this research was initially focused on cytokine antagonists and adhesion molecule expression inhibitors, which are now at different stages pre-clinical and clinical development. Additional targets have begun gaining prominence in the past few years -- modulation of proteins involved in reverse cholesterol transport and lipid metabolism in the vessel wall such as ApoA1/apoE/ABCA1, ACAT, and LpPLA2 and regulation of molecules involved in matrix remodeling and cell proliferation such as matrix metalloproteinases and heparan sulfate proteoglycans. The current approaches for the treatment of atherosclerosis are 1) reduction of risk factors for the disease -- e.g., lipids, hypertension and diabetes and 2) direct disease modifiers. The purpose of this review is to examine key scientific advances and the prospect of these approaches in the prevention of cardiovascular disease.
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PMID:Atherosclerosis -- new targets and therapeutics. 1532 Jul 83

High-density lipoprotein (HDL) cholesterol is a heterogeneous group of lipoproteins exhibiting a variety of properties like prostacyclin production stimulation, decrease in platelet aggregation, endothelial cell apoptosis inhibition, and low-density lipoprotein oxidation blockade. Epidemiologic studies have shown an inverse relation between HDL cholesterol levels and cardiovascular risk. Low HDL cholesterol is associated with increased risk for myocardial infarction, stroke, sudden death, peripheral artery disease, and postangioplasty restenosis. In contrast, high HDL levels are associated with longevity and protection against atherosclerotic disease development. Given the evolving epidemic of obesity, diabetes mellitus, and metabolic syndrome, the prevalence of low HDL will continue to rise. In the United States, low HDL is present in 35% of men, 15% of women, and approximately 63% of patients with coronary artery disease. Data extracted from the Framingham study highlight that 1-mg increase in HDL levels decreases by 2% to 3% the risk of cardiovascular disease. There is no doubt regarding clinical importance about isolated low HDL, but relatively few clinicians consider a direct therapeutic intervention of this dyslipidemia. In this sense, lifestyle measures should be the first-line strategy to manage low HDL levels. On the other hand, pharmacologic options include niacin, fibrates, and statins. Fibrates appear to reduce risk preferentially in patients with low HDL with metabolic syndrome, whereas statins reduce risk across all levels of HDL. Torcetrapib, a cholesteryl esters transfer protein inhibitor, represented a hope to raise this lipoprotein; however, all clinical trials on this drug had ceased after ILLUMINATE, RADIANCE and ERASE trials had recorded an increase in mortality, rates of myocardial infarction, angina, and heart failure. In the near future, drugs as beta-glucans, Apo-A1 mimetic peptides, and ACAT inhibitors, are the new promises to treat this condition.
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PMID:Pharmacologic management of isolated low high-density lipoprotein syndrome. 1864 43

Growing evidence suggests that the small intestine may contribute to excessive postprandial lipemia, which is highly prevalent in insulin-resistant/Type 2 diabetic individuals and substantially increases the risk of cardiovascular disease. The aim of the present study was to determine the role of high glucose levels on intestinal cholesterol absorption, cholesterol transporter expression, enzymes controlling cholesterol homeostasis, and the status of transcription factors. To this end, we employed highly differentiated and polarized cells (20 days of culture), plated on permeable polycarbonate filters. In the presence of [(14)C]cholesterol, glucose at 25 mM stimulated cholesterol uptake compared with Caco-2/15 cells supplemented with 5 mM glucose (P < 0.04). Because combination of 5 mM glucose with 20 mM of the structurally related mannitol or sorbitol did not change cholesterol uptake, we conclude that extracellular glucose concentration is uniquely involved in the regulation of intestinal cholesterol transport. The high concentration of glucose enhanced the protein expression of the critical cholesterol transporter NPC1L1 and that of CD36 (P < 0.02) and concomitantly decreased SR-BI protein mass (P < 0.02). No significant changes were observed in the protein expression of ABCA1 and ABCG8, which act as efflux pumps favoring cholesterol export out of absorptive cells. At the same time, 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity was decreased (P < 0.007), whereas ACAT activity remained unchanged. Finally, increases were noted in the transcription factors LXR-alpha, LXR-beta, PPAR-beta, and PPAR-gamma along with a drop in the protein expression of SREBP-2. Collectively, our data indicate that glucose at high concentrations may regulate intestinal cholesterol transport and metabolism in Caco-2/15 cells, thus suggesting a potential influence on the cholesterol absorption process in Type 2 diabetes.
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PMID:Modulation of intestinal cholesterol absorption by high glucose levels: impact on cholesterol transporters, regulatory enzymes, and transcription factors. 1877 61

Cholesterol is essential to the growth and viability of cells. The metabolites of cholesterol include: steroids, oxysterols, and bile acids, all of which play important physiological functions. Cholesterol and its metabolites have been implicated in the pathogenesis of multiple human diseases, including: atherosclerosis, cancer, neurodegenerative diseases, and diabetes. Thus, understanding how cells maintain the homeostasis of cholesterol and its metabolites is an important area of study. Acyl-coenzyme A:cholesterol acyltransferases (ACATs, also abbreviated as SOATs) converts cholesterol to cholesteryl esters and play key roles in the regulation of cellular cholesterol homeostasis. ACATs are most unusual enzymes because (i) they metabolize diverse substrates including both sterols and certain steroids; (ii) they contain two different binding sites for steroidal molecules. In mammals, there are two ACAT genes that encode two different enzymes, ACAT1 and ACAT2. Both are allosteric enzymes that can be activated by a variety of sterols. In addition to cholesterol, other sterols that possess the 3-beta OH at C-3, including PREG, oxysterols (such as 24(S)-hydroxycholesterol and 27-hydroxycholesterol, etc.), and various plant sterols, could all be ACAT substrates. All sterols that possess the iso-octyl side chain including cholesterol, oxysterols, various plant sterols could all be activators of ACAT. PREG can only be an ACAT substrate because it lacks the iso-octyl side chain required to be an ACAT activator. The unnatural cholesterol analogs epi-cholesterol (with 3-alpha OH in steroid ring B) and ent-cholesterol (the mirror image of cholesterol) contain the iso-octyl side chain but do not have the 3-beta OH at C-3. Thus, they can only serve as activators and cannot serve as substrates. Thus, within the ACAT holoenzyme, there are site(s) that bind sterol as substrate and site(s) that bind sterol as activator; these sites are distinct from each other. These features form the basis to further pursue ACAT structure-function analysis, and can be explored to develop novel allosteric ACAT inhibitors for therapeutic purposes. This article is part of a Special Issue entitled 'Steroid/Sterol signaling'.
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PMID:Acyl-CoA:cholesterol acyltransferases (ACATs/SOATs): Enzymes with multiple sterols as substrates and as activators. 2521 43