The apolipoprotein E and beta-fibrinogen G/A-455 gene polymorphisms are associated with ischemic stroke involving large-vessel disease.

The relationship between the apolipoprotein E (apoE) and beta-fibrinogen G/A-455 polymorphisms and cerebrovascular disease (CVD) was examined in the present study. We compared 227 patients with the subtypes of CVD (large-vessel disease, lacunar stroke, cardiac embolism, or undetermined pathomechanisms) with 225 control subjects. The occurrence of apoE isoforms (E2, E3, and E4) and the beta-fibrinogen G/A-455 genotype was determined in these individuals. No differences in apoE polymorphisms or allele frequencies between the CVD patients and control subjects were found. However, analysis of apoE genotypes as a function of stroke subtype revealed that the apoE4 allele was significantly more common in those patients with macroangiopathy-associated CVD. The only CVD risk factor that distinguished patients with the E4 allele from those with other apoE genotypes was elevated cholesterol. No association between the beta-fibrinogen G/A-455 polymorphism and CVD was found. However, homozygosity for the A allele was more common in patients with CVD resulting from large-vessel disease. These data demonstrate that the apoE4 allele and the AA genotype of the beta-fibrinogen G/A-455 polymorphism occur significantly more frequently in patients with CVD resulting from stenosis of large, brain-supplying vessels. Such genetic analyses may further our understanding of the etiology of cerebrovascular disease.

Some aspects of lipid metabolism in the liver of Wistar rats with fat diet-induced obesity.

Diet-induced obesity in rats can be produced by high-fat feeding. Comparing high-fat with low-fat feeding, the present study was designed to characterize the phases of development of obesity. In the dynamic phase, male rats were investigated at the age of 9-10 weeks after feeding the diets for 4-5 weeks. In the static phase, the animals at the age of 24-26 weeks were tested after 20-22 weeks of the nutritional regime. In this phase, the effects of switching high-fat to low-fat diet for 4 weeks were also examined. Fractionating lipid extracts by thin layer chromatography the concentrations of several lipids in epididymal adipose tissue, in serum, and in liver were determined. In liver, the enhancement of cholesteryl-ester (CE) concentration after high-fat feeding besides the accumulation of triglycerides (TG) is remarkable. Cell fractionation studies of the livers by differential ultracentrifugation showed the major part of the accumulated CE in the supernatant. In vitro incorporation of (1-14C)acetate and (2-14C)mevalonate into liver slices indicated that cholesterol synthesis in the liver of the obese rats was not increased. Although the offered fat diet with 0.1% of cholesterol can not be considered as high in cholesterol, the 2.5-fold higher amount of the high-fat diet in comparison with the low-fat diet (0.04% cholesterol) could be responsible for the enlargement of CE in the liver of the fat fed rats. This possibility was proved by measurement of the cholesterol absorption and transport to the liver after oral administration of (4-14C)cholesterol. Estimation of TG secretion rates of the liver using Triton WR 1339 pointed out higher rates in the obese rats in the dynamic phase. In the static phase, the rates were not different between both feeding groups, while fat restriction in the food produced a striking increase of TG secretion. It is assumed that only in the dynamic phase metabolism is able to compensate the liver TG accumulation by an enhanced transport to the adipose tissue. In the static phase this ability is diminished but not lost.

[Lipid concentrations in liver cell fractions in the rat in diet induced obesity]. / Lipidkonnzentrationen in Leberzellfraktionen der Ratte bei nahurungsinduzierter Fettsucht.

The changes of lipid parameters induced in male Wistar rats by feeding a high-fat diet for several weeks were studied in cell fractions of the liver. For this purpose subcellular fractionations of liver tissue from 12-week-old animals receiving food containing, respectively, 3% fat (controls) and 50% fat, were performed by means of differential centrifugation, and the lipids in the cell fractions were determined quantitatively. The levels of triglycerides and cholesteryl esters both in total liver and in the cell fractions had risen several fold against the controls. Most of the accumulated lipids were retrieved in the cytosolic supernatant. In contrast, for the phospholipids and the free cholesterol only a slight increase in free cholesterol was observed in total liver, and increases of both lipids had occurred in the cytosolic supernatant, while the particulate fractions showed no alterations. It is pointed out in the discussion that the accumulation of triglycerides and cholesteryl esters in the liver largely concerns the particulate fractions too (observed so far in the literature only for single particulate fractions), which might be of interest for the function of the cell nucleus, the mitochondria and the endoplasmatic reticulum. The increase of phospholipids and free cholesterol in the supernatant has to be considered not only as a passive process of deposition, but could represent necessary contributions to the building up of lipid droplets in the cytosol during deposition of triglycerides and cholesterol in this region of the cell. The studies confirm that the fatty degeneration of the liver, true, is always the result of triglyceride accumulation but that, under certain conditions, cholesterol is also enriched in the form of its esters.

[Changes in lipid metabolism of Wistar rats by changing a high fat to a low fat diet and vice versa]. / Anderungen im Lipidstoffwechsel von Wistarratten bei Fütterungsumstellungen von fettreicher auf fettarme Nahrung und vice versa.

Wistar rats, 24 weeks of age, with alimentary obesity after fat feeding (50% fat in the diet) for 19 weeks were restricted to fat (3% fat in the diet) for 4 weeks in order to compare the alterations of body and organ weights as well as those of lipid concentrations in epididymal adipose tissue, liver and serum with earlier results [1], obtained before food changing. On these conditions decreases of body weight by about 20%, of the relative mass of epididymal adipose tissue and of the triglyceride content per fat cell were observed. In liver a decline of triglycerides and cholesterylesters (by about 2/3 and 1/3, respectively) and in serum a drop of free fatty acids, but increases of phospholipids, and of free and esterified cholesterol were found. In another series, animals of the same age that had been fed the low fat diet for 19 weeks were administered the high fat diet for 4 weeks and also compared with the state before. Thereby the body weight (by about 20%) and the relative mass of the epididymal adipose tissue gained, but lipid concentrations in this tissue were not affected. In liver the concentrations of triglycerides and cholesteryl esters increased threefold and tenfold, respectively; in serum augmented contents of triglycerides and phospholipids were observed. Besides the changes in adipose tissue, reasons for the forced accumulation of cholesteryl esters in the liver during fat feeding and their retarded removal out of the liver after fat restriction are especially discussed in comparison with that of the triglycerides.

[Changes in the lipid concentration in serum, liver and adipose tissue in alimentary obesity in Wistar rats]. / Veränderung von Lipidkonzentrationen in Serum, Leber und Fettgewebe bei nahrungsbedingter Fettsucht von Wistarratten

In colony-bred Wistar rats maintained for several weeks on a high-percent fatty food (fat content 50%) compared with controls (3% fat in food) the concentrations of the following lipids were determined quantitatively: In serum lipid phosphorus (Lip. P.), free fatty acids (FFA), triglycerides (TG), free cholesterole (FC) and cholesteryl ester (CE), in liver Lip. P,TG, FC and CE, in epididymal adipose tissue Lip. P. FFS and TG. With increasing weight differences between the two animals groups, in the phase of steady weight growth (,,dynamic phase", age of investigation 9 weeks, after 4 weeks on fatty food) a significant rise in serum FFS over the controls is observed with increases in TG and CE concentrations in the liver. After about 20 weeks of life the weight growth slows down; in this subsequent "static phase" the TG and CE accumulation in the liver further increases. Investigation of the epididymal adipose tissue suggests hypertrophy of the adipose cells. The results obtained with both phases are discussed with regard to possible metabolic alterations.