Feedback inhibition of cholesterol biosynthesis by dietary cholesterol in experimental chronic renal failure.

OBJECTIVE: Enhanced liver cholesterol synthesis is present in experimental chronic renal failure (CRF), even though cholesterol concentrations in blood and liver are increased, suggesting that CRF results in disturbed cholesterolegenesis feedback regulation. DESIGN: This study sought to elucidate whether dietary cholesterol exerts inhibitory effects on liver cholesterologenesis in CRF rats. METHODS: Male Wistar rats were used. Experimental CRF was achieved by a 5/6 nephrectomy model. Cholesterologenesis was measured (1) in vivo by tritiated water incorporation into cholesterol, and (2) in vitro (using liver slices) by [(14)C]-acetate and [(3)H]-mevalonate incorporation into cholesterol. In addition, the mRNA abundance of 3-hydroxy-3-methylglutaryl-CoA reductase, a rate-limiting enzyme in cholesterologenesis pathway, as well as its activity, was determined. Finally, the mRNA level of liver sterol regulatory element-binding protein-2, a nuclear transcription factor engaged in intracellular cholesterol homeostasis, was measured. RESULTS: Experimental CRF was associated with significantly increased concentrations of serum and liver cholesterol. In vitro and in vivo cholesterologenesis was enhanced in CRF rats. A cholesterol-enriched diet resulted in a significant decrease in (1) in vivo and in vitro cholesterol synthesis, (2) 3-hydroxy-3-methylglutaryl-CoA reductase gene expression, and (3) the level of liver sterol regulatory element-binding protein-2 mRNA in CRF rats. CONCLUSIONS: Despite elevated plasma and liver cholesterol concentrations, cholesterologenesis is increased in CRF rats. It is, however, inhibited by dietary cholesterol. These results suggest that a feedback inhibition of cholesterologenesis by dietary cholesterol is preserved in experimental CRF.

Increased gene expression of liver SREBP-2 in experimental chronic renal failure.

Sterol regulatory element-binding protein-2 (SREBP-2) is a transcription factor regarded as the main regulator of cholesterol homeostasis. Therefore, increased level of SREBP-2 could be responsible for hypercholesterolemia, which is observed in experimental chronic renal failure (CRF). This study was designed primary to evaluate the impact of experimental CRF (5/6 nephrectomy model) on rat liver SREBP-2 gene expression. In CRF rats, a twofold increase in SREBP-2 mRNA level, as well as in mature SREBP-2 protein abundance was found, when compared to control animals. It was associated with enhanced activity and mRNA abundance of liver HMG-CoA reductase, a rate-limiting enzyme for cholesterol biosynthesis. A twofold increase in liver cholesterologenesis rate was also noted. We conclude that experimental CRF is associated with increased liver SREBP-2 gene expression. This is probably the cause for enhanced HMG-CoA reductase gene expression and, consequently, for increase in liver cholesterol synthesis in CRF rats. Despite increased SREBP-2 gene expression we found LDL-receptor mRNA level to be lower than in controls, suggesting SREBP-2 independent mechanisms of LDL-receptor transcriptional regulation in CRF rats. Enhanced cholesterol synthesis and decreased LDL-receptor mRNA level are probably responsible for an almost fourfold increase in serum cholesterol concentration in CRF rats.

Fast perinuclear clustering of mitochondria in oxidatively stressed human choriocarcinoma cells.

Mitochondrial dysfunction plays a crucial role in cell types that exhibit necrosis-like death after activation of their death program. Tumour necrosis factor (TNF) induces abnormal, perinuclear clustering of mitochondria from an evenly spread distribution throughout the cytoplasm. The mitochondria withdraw from the cell periphery and aggregate in a unipolar perinuclear cluster. TNF-induced mitochondrial clustering is caused by impaired kinesin-mediated transportation of mitochondria. In this report, we describe a novel activity of menadione (MEN), namely the induction of an altered spatial distribution of mitochondria in the choriocarcinoma JAR cells. Strikingly, 2 hours of cell exposition to menadione did not disrupt the integrity of the plasma membrane, while the intracellular ATP level significantly decreased. Control (untreated) cells displayed a typically scattered distribution of filamentary mitochondria inside the cell. After 2 hours of MEN treatment the spatial distribution of the mitochondria was markedly altered to an asymmetric perinuclear clustered distribution. Menadione-stressed cells displayed a highly asymmetrical perinuclear clustered distribution of the mitochondria. The exposure of cells to MEN also results in a change in shape of the mitochondria into a population of enlarged granular structures. The results of our study demonstrate that in JAR cells menadione causes mitochondria to translocate from the cell periphery into the perinuclear region several hours before disruption of cell membrane integrity and cell death.

The history of pediatric otorhinolaryngology in Poland.

The past few decades have been a time of rapid and constantly-accelerating development in every field of medicine, including pediatrics and laryngology. The first pediatric laryngology unit set up in Poland was in the Warsaw Kopernik Hospital in 1908, and consisted of seven beds in the surgical ward. The actual development of the specialty in Poland began in the nineteen-forties. The first modern department of Pediatric Laryngology was set up in the Mother and Child Institut in 1947, and next in Warsaw University Hospital in 1956. These two were both set up and headed by Associate Professor Jan Danielewicz who is considered to be the father of pediatric otolaryngology in Poland, and one of its co-founders in Europe. The first conference of Polish Pediatric ENT was the result of the efforts of Associate Professor Danielewicz in Zakopane, in 1958. Professors Kossowska and Danielewicz were the joint organisers of the First European Congress of Pediatric Laryngologists in Warsaw, in 1979. At present in Poland exist five Clinic of Pedatric ENT and about 25 ward of this speciality. Pediatric ENT is independent medical specialization.