(1/1814) Preventive effects of dehydroepiandrosterone acetate on the fatty liver induced by orotic acid in male rats.
Preventive effects of dehydroepiandrosteone acetate (DHEA-A) and clofibrate (positive control substance) on the fatty liver induced by orotic acid (OA) were examined on the male Sprague-Dawley rats fed a high sucrose based diet containing 1% OA and this diet further mixed with 0.5% DHEA-A or 0.5% clofibrate for 2 weeks. Numerous lipid droplets were observed in the hepatocytes of the rats treated with OA alone, but not in those treated with DHEA-A or clofibrate. In comparison to the group with OA alone, the DHEA-A or clofibrate treated rats showed a larger relative liver weight (to body weight) which was accompanied by increased peroxisomes in the hepatocytes. These results indicate that DHEA-A, as well as clofibrate, may prevent OA-induced fatty liver. (+info)
(2/1814) Contribution of modern cardiovascular treatment and risk factor changes to the decline in coronary heart disease mortality in Scotland between 1975 and 1994.
OBJECTIVE: To estimate the fall in coronary heart disease (CHD) mortality in Scotland attributable to medical and surgical treatments, and risk factor changes, between 1975 and 1994. DESIGN: A cohort model combining effectiveness data from meta-analyses with information on treatment uptake in all patient categories in Scotland. SETTING AND PATIENTS: The whole Scottish population of 5.1 million, including all patients with recognised CHD. INTERVENTIONS: All cardiological, medical, and surgical treatments, and all risk factor changes between 1975 and 1994. Data were obtained from epidemiological surveys, routine National Health Service sources, and local audits. MAIN OUTCOME MEASURES: Deaths from CHD in 1975 and 1994. RESULTS: There were 15 234 deaths from CHD in 1994, 6205 fewer deaths than expected if there had been no decline from 1975 mortality rates. In 1994, the total number of deaths prevented or postponed by all treatments and risk factor reductions was estimated at 6747 (minimum 4790, maximum 10 695). Forty per cent of this benefit was attributed to treatments (initial treatments for acute myocardial infarction 10%, treatments for hypertension 9%, for secondary prevention 8%, for heart failure 8%, aspirin for angina 2%, coronary artery bypass grafting surgery 2%, and angioplasty 0.1%). Fifty one per cent of the reduction in deaths was attributed to measurable risk factor reductions (smoking 36%, cholesterol 6%, secular fall in blood pressure 6%, and changes in deprivation 3%). Other, unquantified factors apparently accounted for the remaining 9%. These proportions remained relatively consistent across a wide range of assumptions and estimates in a sensitivity analysis. CONCLUSIONS: Medical treatments and risk factor changes apparently prevented or postponed about 6750 coronary deaths in Scotland in 1994. Modest gains from individual treatments produced a large cumulative survival benefit. Reductions in major risk factors explained about half the fall in coronary mortality, emphasising the importance and future potential of prevention strategies. (+info)
(3/1814) Cellular distribution of cytochromes P-450 in the rat kidney.
The distribution of several cytochrome P-450 (P-450) isoenzymes between proximal tubular (PT) and distal tubular (DT) cells of the rat kidney was determined. Western blot analysis of microsomes prepared from liver and kidney cortical homogenates revealed that CYP2E1 protein was expressed in rat kidney microsomes at approximately 10% of hepatic levels. Microsomes from renal cortical, PT, and DT cells all expressed CYP2E1, with DT microsomes expressing slightly higher levels than PT microsomes. In contrast, chlorzoxazone hydroxylation activity was markedly higher in microsomes from PT cells than in those from DT cells. Northern blot analysis of total RNA from PT and DT cells exhibited a pattern of CYP2E1 mRNA distribution similar to that of CYP2E1 protein. CYP2C11 protein expression in renal cortical microsomes was approximately 10% of that in liver microsomes but was significantly higher in microsomes from PT cells than in those from DT cells. CYP3A1/2 was not detected in microsomes from either cortical, PT, or DT cells, but was detected in microsomes isolated from total liver or kidney cortical homogenates. CYP2B1/2 expression was detected in all tissues tested. The peroxisomal proliferator clofibrate enhanced the level of CYP2B1/2 in microsomes from both total liver and kidney cortical homogenates but not in microsomes from cortical, PT, or DT cells. CYP4A2/3 protein and CYP4A mRNA expression were detected in microsomes from total liver and kidney cortical homogenates and from renal cortical, PT, and DT cells using Western and Northern blot analyses, respectively. Lauric acid hydroxylation activity, an indicator of CYP4A, was comparable in PT and DT cells. Clofibrate elevation of CYP4A in cortical, PT, and DT microsomes was not as great as that detected in total kidney cortical microsomes. These results establish the distribution of several P-450 isoenzymes between different cell populations of the rat kidney. Furthermore, these results present evidence that the level of induction of certain P-450 isoenzymes in the kidney is cell type-specific. (+info)
(4/1814) Perfluorooctanoic acid, a peroxisome-proliferating hypolipidemic agent, dissociates apolipoprotein B48 from lipoprotein particles and decreases secretion of very low density lipoproteins by cultured rat hepatocytes.
The hypolipidemic effect is evoked by various peroxisome proliferators. Modulation of gene transcription via peroxisome proliferator-activated receptor (PPAR) is generally responsible for this effect. In addition, we have found a PPAR-independent mechanism in which fibrates, known peroxisome proliferators, decrease hepatic secretion of very low density lipoproteins (VLDL) through inhibition of phosphatidylcholine synthesis via methylation of phosphatidylethanolamine (PE) (T. Nishimaki-Mogami et al., Biochim. Biophys. Acta 1304 (1996) 21-31). In the present study, we show a novel mechanism by which perfluorooctanoic acid (PFOA), a potent peroxisome proliferator and inhibitor of PE methylation, exerts its hypolipidemic effect. PFOA (100 microM) added to the medium rapidly decreased the secretion of triglyceride by cultured rat hepatocytes, which was independent of the activity of cellular PE methylation. Analysis of the density of apoB secreted into the medium showed that PFOA decreased apoB48 in VLDL, but increased apoB48 in the bottom d>1.21 fraction. This lipid-poor apoB48 was also generated by incubating medium that had been harvested from control cells with PFOA, indicating that PFOA has the ability to dissociate apoB48 from lipoprotein particles. Exposure of cells to PFOA for 2 h prior to the experiment was sufficient to generate lipid-poor apoB48, indicating that PFOA exerted its effect intracellularly. Taken together, the data suggest that a strong interaction of PFOA with apoB48 disturbs the association of apoB48 with lipids in the process of intracellular VLDL assembly, thereby inhibiting VLDL secretion. This study shows that the mechanisms of hypolipidemic effect caused by various classes of peroxisome proliferators are diverse. (+info)
(5/1814) Identifying and managing patients with hyperlipidemia.
Cardiovascular disease related to hyperlipidemia is a significant cause of morbidity and mortality in the United States. The benefit of lowering lipid levels in patients with and without cardiovascular disease has been demonstrated in numerous clinical trials. The results of these trials prompted the National Heart, Blood, and Lung Institute to form the Nation Cholesterol Education Panel (NCEP). This panel developed guidelines for identifying and treating lipid disorders. Before starting antilipemic therapy, patients should be evaluated for secondary causes of hyperlipidemia, including disease states and medications. Risk factors for cardiovascular disease should be identified and used to determine the patient's goal low-density lipoprotein level. Regardless of the drug therapy used, the cornerstone treatment for hyperlipidemia is dietary changes. The NCEP recommendation for dietary modification follows a two-step plan to reduce intake of cholesterol and dietary fats. Other nonpharmacologic treatments for hyperlipidemia include exercise, weight reduction for obese patients, reduction of excessive alcohol use, and smoking cessation . Drug therapy should be considered in patients who do not respond to an adequate trial of dietary modifications and lifestyle changes. The principal lipid-lowering agents currently used are the bile acid sequestrants, nicotinic acid, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, and fibric acid derivatives. Estrogen, fish oil, and alcohol also can decrease the risk of developing heart disease. In pharmacoeconomic studies, lipid-lowering drug therapy has been shown to decrease the number of procedures, hospitalizations, and other medical interventions required by patients with cardiovascular disease. (+info)
(6/1814) Phytanic acid is ligand and transcriptional activator of murine liver fatty acid binding protein.
Branched-chain phytanic acid is metabolized in liver peroxisomes. Sterol carrier protein 2/sterol carrier protein x (SCP2/SCPx) knockout mice, which develop a phenotype with a deficiency in phytanic acid degradation, accumulate dramatically high concentrations of this fatty acid in serum (Seedorf at al. 1998. Genes Dev. 12: 1189-1201) and liver. Concomitantly, a 6.9-fold induction of liver fatty acid binding protein (L-FABP) expression is observed in comparison to wild-type animals fed standard chow, possibly mediated by the peroxisome proliferator-activated receptor alpha (PPARalpha). Cytosolic transport of phytanic acid to either peroxisomal membranes or to the nucleus for activation of PPARalpha may be mediated by L-FABP, which gives rise to the question whether phytanic acid is a transactivator of this protein. Here we show first that phytanic acid binds to recombinant L-FABP with high affinity. Then the increase of the in vivo phytanic acid concentration by phytol feeding to mice results in a 4-fold induction of L-FABP expression in liver, which is in the order of that attained with bezafibrate, a known peroxisome proliferator. Finally to test in vitro whether this induction is conferred by phytanic acid, we cotransfected HepG2 cells with an expression plasmid for murine PPARalpha and a CAT-reporter gene with 176 bp of the murine L-FABP promoter, containing the peroxisome proliferator responsive element (PPRE). After incubation with phytanic acid, we observed a 3.2-fold induction of CAT expression. These findings, both in vivo and in vitro, demonstrate that phytanic acid is a transcriptional activator of L-FABP expression and that this effect is mediated via PPARalpha. (+info)
(7/1814) Effect of gemfibrozil in vitro on fat-mobilizing lipolysis in human adipose tissue.
Fat-mobilizing lipolysis was studied in rat and human adipose tissue during incubation in vitro by following the release of glycerol into the incubation medium. Gemfibrozil as well as clofibrate consistently and readily inhibited basal as well as noradrenaline-stimulated fat-mobilizing lipolysis in rat fat. With human adipose tissue no effect was observed with gemfibrozil and clofibrate on basal lipolysis. This may be due to the comparatively low rate of the nonstimulated fat-mobilizing lipolysis in human tissue incubated in vitro. When lipolysis was stimulated with noradrenaline as well as isoprenaline, however, both gemfibrozil and clofibrate significantly reduced the fat-mobilizing lipolysis. This inhibition of lipolysis was however not observed in all studies. When lipolysis had been stimulated with theophylline, no inhibition of lipolysis was obtained with either compound. The possibility that reduced fat-mobilizing lipolysis in adipose tissue may cause a lowering of plasma triglycerides by reducing the flow of FFA to the liver is discussed in some detail. It is also suggested that inhibition of lipolysis may be accompanied by increased activity of lipoprotein lipase as well as an increase in the FIAT process. However, the pharmacological implication of the above-mentioned findings, particularly for gemfibrozil, must await further studies, as fairly large doses, around 1 mg/ml of incubation medium, were needed to obtain inhibition of fat-mobilizing lipolysis. (+info)
(8/1814) Gemfibrozil in a group of diabetics.
A group of 14 diabetic patients was treated with gemfibrozil during a variable length of time ranging from nine to 23 weeks in order to establish if a lowering effect on the cholesterol and triglyceride levels could be achieved, as it had been in the case of another group of non-diabetic patients. The present results showed that: (1) The drug is remarkably well tolerated. (2) With doses ranging between 400 and 800 mg per day the magnitude of the effect of the drug was less than that observed in our previous trial with non-diabetic subjects. The effect upon triglycerides seemed to be reduced more than that upon cholesterol when compared with results in higher-dose studies. (3) In this group of diabetic patients (3 insulin dependent, 11 maturity-onset type) control of the diabetic condition was never impaired and appeared in some cases to be slightly improved by gemfibrozil. (4) There was no evidence of undesirable interaction with any of the anti-diabetic drugs used. (+info)