Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In mutant analbuminaemic rats (NAR), females demonstrate a more marked hypertriglyceridaemia than males. Ovariectomy decreases triglyceride levels in female NAR. We measured triglyceride secretion rates in vivo as well as the activity of acetyl CoA carboxylase (ACC) and fatty acid synthase (FAS) in hepatic cytosol obtained from female control Sprague-Dawley (SD) rats and NAR with or without ovariectomy. NAR were severely hyperlipidaemic, and triglyceride, cholesterol, apolipoprotein A-I and plasma protein concentrations levels were decreased (all P < 0.01) by ovariectomy. Only triglyceride levels were decreased by ovariectomy in the SD rats (P < 0.05). Oestradiol treatment in ovariectomized NAR restored plasma protein and triglyceride concentrations to levels similar to those observed in intact female NAR and caused a marked increase in plasma cholesterol. Ovariectomy in NAR reduced lipoprotein triglycerides and cholesterol in VLDL, IDL and LDL1, but had little effect on the triglyceride-cholesterol ratio of these particles. Both ACC and FAS activities were markedly increased in NAR vs. SD rats (P < 0.01). This increase was partially corrected by ovariectomy. There was no significant effect of ovariectomy on ACC or FAS activity in the SD rats. Triglyceride secretion rates were significantly increased in NAR vs. SD rats (135 +/- 10 vs. 103 +/- 12 nmol/min per 100 g body weight; P < 0.05). Ovariectomy markedly decreased triglyceride secretion rate in NAR to 69 +/- 6 (P < 0.01), but not in SD rats (92 +/- 8 nmol/min per 100 g body weight, NS). Oestradiol treatment in ovariectomized SD rats restored triglyceride levels but had no significant effect on triglyceride secretion rate (106 +/- 23 nmol/min per 100 g).(ABSTRACT TRUNCATED AT 250 WORDS)
Atherosclerosis 1995 Sep
PMID:Ovariectomy decreases plasma triglyceride levels in analbuminaemic rats by lowering hepatic triglyceride secretion. 854 55

The fatty liver dystrophy (fld) mutant mouse is characterized by neonatal fatty liver and hypertriglyceridemia that resolve at weaning, and neuropathy affecting peripheral nerve in adulthood. We now report additional significant manifestations of this single gene mutation, which include adipose tissue deficiency, glucose intolerance, and increased susceptibility to atherosclerosis. In adult fld/fld mice, both white and brown fat pads exhibit an 80% reduction in mass compared with wild-type controls, and consist of immature adipocytes as assessed by morphological and molecular criteria. The lack of lipid accumulation in fld/fld adipose tissue could be attributed, in part, to a failure to induce expression of lipoprotein lipase and enzymes involved in fatty acid synthesis, such as fatty acid synthase and acetyl-CoA carboxylase. Related to the deficiency of adipose tissue, fld/fld mice were also found to exhibit profound glucose intolerance, modest hyperinsulinemia, and reduced tissue response to insulin. As insulin resistance is a important risk factor in vascular disease, we examined susceptibility of fld/fld mice to diet-induced atherosclerosis. Mutant mice fed an atherogenic diet developed 2-fold greater aortic lesions than their wild-type counterparts, despite having a less atherogenic lipoprotein cholesterol profile. The fld adipose-deficient phenotype has both similarities to and distinctions from the group of rare human diseases known as lipodystrophies.
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PMID:Adipose tissue deficiency, glucose intolerance, and increased atherosclerosis result from mutation in the mouse fatty liver dystrophy (fld) gene. 1088 87

Fenofibrate is a potent hypolipidemic agent that lowers plasma lipid levels and may thus decrease the incidence of atherosclerosis. Here we investigated the molecular mechanism of fenofibrate's hypolipidemic action by characterizing its in vivo effects on the expression of mRNAs and the activities of pivotal enzymes in cholesterol and triglyceride metabolism in the hamster. Treatment of hamsters with fenofibrate led to a dose-dependent reduction in serum cholesterol concentrations. Studies on the incorporation of [(14)C]acetate and [(14)C]mevalonate into cholesterol suggested that this effect occurs primarily through inhibition of cholesterol biosynthesis at steps prior to mevalonate. Fenofibrate decreased levels of hepatic enzyme activities and mRNAs for 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) synthase and HMG CoA reductase. A potential mechanism for transcriptional regulation of these enzymes is via SREBP-2 that we found to be suppressed 2-fold by fenofibrate. Fenofibrate also lowered circulatory triglyceride levels. In keeping with the effect, we observed strong suppression of fatty acid synthase, acetyl-CoA carboxylase and apolipoprotein C-III mRNA and stimulation of lipoprotein lipase and acyl-CoA oxidase mRNA in the liver of fenofibrate-treated hamsters. These observations suggest that the effect of fenofibrate on triglyceride metabolism is likely to be a result of both decreased fatty acid synthesis and increased lipoprotein lipase and acyl-CoA oxidase gene expression in the liver. Surprisingly, alterations in lipoprotein lipase, acyl-CoA oxidase, acetyl-CoA carboxylase, and apolipoprotein C-III could not be observed in hamster hepatocytes incubated with fenofibric acid in vitro. These observations raise the possibility that changes in these genes may be secondary to the metabolic alterations occurring in animals but not in cultured cells and thus that the effect of fenofibrate on these genes may be indirect.
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PMID:Regulation of lipid metabolism and gene expression by fenofibrate in hamsters. 1173 32

Chronic intraperitoneal or subcutaneous insulin administration increases triglyceride secretion rate (TGSR) in normal rats. We wished to determine the effect of this treatment on TGSR and the hepatic lipogenic enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) in diabetic rats. Streptozotocin-diabetic rats, untreated (D), diabetic rats treated with insulin (3 U/day for 21 days) intraperitoneally (IP) or subcutaneously (SC) and non-diabetic rats (N) were studied. TGSR was determined using Triton WR-1339. Fasting glucose and triglyceride levels, high in D, were normalized by insulin treatment regardless of route. Peripheral insulin levels were lowest in D and highest in SC, portal insulin levels were lowest in D and highest in IP. Non-esterified fatty acid levels were not elevated in D, presumably due to adipose tissue depletion. TGSR was reduced in D (P<0.05) and was normalized following insulin administration, regardless of route. ACC activity was normal, but FAS was decreased in D (P<0.05). ACC and FAS were normal in both IP and SC. Thus, in streptozotocin-diabetic rats, chronic intraperitoneal or subcutaneous insulin treatment increases TGSR and FAS activity from their low levels in insulin-deficient rats to levels equal to but not higher than those in normal rats.
Atherosclerosis 2002 Apr
PMID:The effect of chronic insulin delivery via the intraperitoneal versus the subcutaneous route on hepatic triglyceride secretion rate in streptozotocin diabetic rats. 1188 17

The purpose of this study was to discover the effects of soybean beta-conglycinin (7S-globulin) and glycinin (11S-globulin) on serum lipid levels and metabolism in the livers of normal and genetically obese mice. Male normal (ICR) and obese (KK-Ay) mice were fed ad libitum high fat diets for two weeks, followed by a 2-week restriction of diet (2 g diet/mouse/day) containing 20% casein, soybean beta-conglycinin, or soybean glycinin, and then sacrificed immediately. Serum triglyceride (TG), glucose, and insulin levels of beta-conglycinin-fed mice were lower than in casein- and glycinin-fed mice of both strains. In order to analyze the related events to these effects, enzyme activities and relative mRNA levels of lipid metabolism-related proteins were measured. The activities of two enzymes related to fatty acid beta-oxidation were higher while that of fatty acid synthase was lower in livers of beta-conglycinin-fed mice than of casein-fed both mice. Messenger RNA levels of acyl-CoA oxidase (fatty acid beta-oxidation related enzyme) were significantly higher in livers of beta-conglycinin-fed mice than of both casein-fed mice. On the contrary, mRNA levels of SREBP-1 and 2 tended to be lowered in livers of soy protein-fed mice than of both casein-fed mice. Fecal excretion of TG was higher in beta-conglycinin-fed mice than in casein-fed mice. Our results demonstrated that the soy beta-conglycinin diet reduced serum TG levels by acceleration of beta-oxidation, suppression of fatty acid synthase and/or increased TG fecal excretion, and also diminished serum glucose and insulin levels. Some of these events might be caused at the transcriptional levels, judged from the result that relative messenger RNA levels of lipid metabolism-related proteins were altered. These results suggest that soy beta-conglycinin could be a potentially useful dietary protein source for the prevention of hypertriglyceridemia, hyperinsulinemia, and hyperglycemia, which are recognized as risk factors for atherosclerosis.
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PMID:Soybean beta-conglycinin diet suppresses serum triglyceride levels in normal and genetically obese mice by induction of beta-oxidation, downregulation of fatty acid synthase, and inhibition of triglyceride absorption. 1498 Dec 98

Polycyclic aromatic hydrocarbons (PAHs), aryl hydrocarbon receptor (AHR) ligands, induce atherogenesis. Liver X receptor (LXR) alpha is known to be involved in the control of cholesterol homeostasis. Thus, the purpose of this study was to investigate the effects of 3-methlycholanthrene (MC), one of the PAHs, on LXRalpha-mediated signal transductions. We found that expression of mRNAs for ATP binding cassette A1, sterol regulatory element binding protein 1c (SREBP-1c), fatty acid synthase, and stearoyl-CoA desaturase was suppressed by treatment of HepG2 cells with MC. A luciferase reporter assay revealed that LXRalpha- and SREBP-1c-mediated transactivations were inhibited by MC via AHR. Based on these lines of evidence, we propose that down-regulation of the LXRalpha-regulated genes by PAHs is one of the causes responsible for atherosclerosis induced by PAHs.
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PMID:A possible mechanism for atherosclerosis induced by polycyclic aromatic hydrocarbons. 1606 Dec

Plasma sphingomyelin (SM) has been suggested as a risk factor for coronary heart disease independent of cholesterol levels. A decrease of SM in lipoproteins is known to improve the activities of lecithin:cholesterol acyltransferase (LCAT) and lipoprotein lipase (LPL) in vitro. Inhibition of SM biosynthesis may reduce lipoprotein SM content and thus improve cholesterol distribution in lipoproteins by enhancing reverse cholesterol transport and clearance of triglyceride-rich lipoproteins. To examine this hypothesis, ApoE KO mice were fed a western diet and treated for 4 weeks with various concentrations of myriocin, a specific inhibitor of serine palmitoyltransferase. Myriocin treatment lowered plasma cholesterol and TG levels in a dose-dependent manner. In addition, myriocin treatment reduced cholesterol contents in VLDL and LDL and elevated HDL-cholesterol. Observed lipid-lowering effects of myriocin were associated with suppression of HMG CoA reductase and fatty acid synthase via reduced levels of SREBP-1 RNA and protein. Induction of apoAI and lecithin:cholesterol acytransferase (LCAT) in the liver by myriocin was associated with an increased HDL. Lesion area and macrophage area were also diminished in the cuffed femoral artery of ApoE KO mice. In conclusion, inhibition of sphingolipid biosynthesis can be a novel therapeutic target for dyslipidemia and atherosclerosis.
Atherosclerosis 2006 Dec
PMID:Modulation of lipoprotein metabolism by inhibition of sphingomyelin synthesis in ApoE knockout mice. 1645 17

Fenofibrate, a selective (1)PPAR-alpha activator, is prescribed to treat human dyslipidemia. The aim of this study was to delineate the mechanism of fenofibrate-mediated reductions in adiposity, improvements in insulin sensitivity, and lowering of triglycerides (TG) and free fatty acids (FFA) and to investigate if these favorable changes are related to the inhibition of lipid deposition in the aorta. To test this hypothesis we used male LDLr deficient mice that exhibit the clinical features of metabolic syndrome X when fed a high fat high cholesterol (HF) diet. LDLr deficient mice fed HF diet and simultaneously treated with fenofibrate (100 mg/kg body weight) prevented development of obesity, lowered serum triglycerides and cholesterol, improved insulin sensitivity, and prevented accumulation of lipids in the aorta. Lowering of circulating lipids occurred via down-regulation of lipogenic genes, including fatty acid synthase, acetyl CoA carboxylase and diacyl glycerol acyl transferase-2, concomitant with decreased liver TG and cholesterol, and TG output rate. Fenofibrate also suppressed liver apoCIII mRNA levels and markedly increased lipoprotein lipase mRNA levels, known to enhance serum TG catabolism. In addition, fenofibrate profoundly reduced epididymal fat and mesenteric fat mass to the levels seen in lean mice. The reductions in body weight were associated with elevation of hepatic uncoupling protein 2 (UCP2) mRNA, a concomitant increase in the ketone body formation, and improved insulin sensitivity associated with tumor necrosis factor-alpha reductions and phosphoenol pyruvate carboxykinase down-regulation. These results demonstrate that fenofibrate improves lipid abnormalities partly via inhibition of TG production and partly via clearance of TG-rich apoB particles by elevating LPL and reduced apoCIII. The prevention of obesity development occurred via energy expenditure. Fenofibrate-mediated hypolipidemic effects together with improved insulin sensitivity and loss of adiposity led to the reductions in the aortic lipid deposition by inhibiting early stages of atherosclerosis possibly via vascular cell adhesion molecule-1 (VCAM-1) modulation. These results suggest that potent PPAR-alpha activators may be useful in the treatment of syndrome X.
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PMID:Peroxisome proliferator-activated receptor-alpha selective ligand reduces adiposity, improves insulin sensitivity and inhibits atherosclerosis in LDL receptor-deficient mice. 1647 80

In spite of a progressive fall in the incidence of traditional risk factors of cardiovascular morbidity (cigarette smoking, high blood pressure, and hyperlipidemia), there is an upward trend in the prevalence of obesity and chronic kidney disease (CKD). Furthermore, there is a strong correlation between body mass indices and the relative risk of progression of CKD. The close biophysiological interaction between obesity and CKD is evident by a similar occurrence of comorbidities including insulin resistance, hyperlipidermia, endothelial dysfunction, and sleep disorders. Truncal obesity is a primary component of metabolic syndrome; unlike peripheral fat, the visceral adipocytes are more resistant to insulin. In addition, lipolysis results in a release of free fatty acid and TG, whereas hypertriglycedemia is potentiated by uremic activation of fatty acid synthase. Hypertriglycedemia and low HDL cholesterol increase the relative risk of progression of CKD. Furthermore, endothelial inflammation and premature atherosclerosis are promoted by hyperhomocysteinemia and oxidation of LDL, both of which are commonly observed in CKD and obesity. Predominance of oxidative stress in both obesity and azotemia stimulate synthesis of angiotensin II, which in turn increases TGF-B and plasminogen activator inhibitor-1, thereby propagating glomerular fibrosis. Furthermore, local synthesis of angiotensinogen by adipocytes, leptin activation of sympathetic nervous system, and hyperinsulinemia contribute to the development of hypertension in obesity and CKD. In addition, increased renal tubular expression of Na-K-ATPase and a blunted response to natiuretic hormones in obesity promote salt and water retention. Glomerular hyperfiltration from systemic volume load and hypertension results in mesangial cellular proliferation and progressive renal fibrosis. In addition, maternal nutritional deprivation increases the incidence of obesity, hypertension, and diabetes in adulthood. Reduced fetal protein synthesis contributes to oxidative glomerular injury and impairment of renal morphogenesis. Thus, kidneys are poorly equipped to handle physiologic stress that may result from the rapid body growth and programmed metabolic dysfunction later in life. Finally, in order to minimize morbidity of obesity-related kidney disease, preventive strategy must include optimal maternal health care, promotion of healthy nutrition and routine physical exercise, and early detection of CKD.
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PMID:The role of obesity and its bioclinical correlates in the progression of chronic kidney disease. 1704 21

Resveratrol may protect against metabolic disease through activating SIRT1 deacetylase. Because we have recently defined AMPK activation as a key mechanism for the beneficial effects of polyphenols on hepatic lipid accumulation, hyperlipidemia, and atherosclerosis in type 1 diabetic mice, we hypothesize that polyphenol-activated SIRT1 acts upstream of AMPK signaling and hepatocellular lipid metabolism. Here we show that polyphenols, including resveratrol and the synthetic polyphenol S17834, increase SIRT1 deacetylase activity, LKB1 phosphorylation at Ser(428), and AMPK activity. Polyphenols substantially prevent the impairment in phosphorylation of AMPK and its downstream target, ACC (acetyl-CoA carboxylase), elevation in expression of FAS (fatty acid synthase), and lipid accumulation in human HepG2 hepatocytes exposed to high glucose. These effects of polyphenols are largely abolished by pharmacological and genetic inhibition of SIRT1, suggesting that the stimulation of AMPK and lipid-lowering effect of polyphenols depend on SIRT1 activity. Furthermore, adenoviral overexpression of SIRT1 stimulates the basal AMPK signaling in HepG2 cells and in the mouse liver. AMPK activation by SIRT1 also protects against FAS induction and lipid accumulation caused by high glucose. Moreover, LKB1, but not CaMKKbeta, is required for activation of AMPK by polyphenols and SIRT1. These findings suggest that SIRT1 functions as a novel upstream regulator for LKB1/AMPK signaling and plays an essential role in the regulation of hepatocyte lipid metabolism. Targeting SIRT1/LKB1/AMPK signaling by polyphenols may have potential therapeutic implications for dyslipidemia and accelerated atherosclerosis in diabetes and age-related diseases.
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PMID:SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. 1848 75


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