Hyperlipidemias: Chmielewski M

Rutkowski B, Chmielewski M. · Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk, Poland. · Rocz Akad Med Bialymst. · Pubmed #15631330 No free full text.

Abstract: Lipid disturbances are a constant feature of chronic renal failure (CRF). They compose a significant risk factor for vascular complications, leading to increased morbidity and mortality in this patients group. The major lipid abnormality in the course of CRF is hypertriglyceridemia, but increased cholesterol level is also common. Numerous studies, including these from our Centre, point to the conclusion that hypertriglyceridemia is a consequence of both, increased TG production and impaired TG removal. In contrast hypercholesterolemia is mainly due to enhanced cholesterol biosynthesis. HMG-CoA reductase inhibitors (statins) compose the most promising group of drugs to treat lipid abnormalities in CRF. Apart from their lipid-lowering abilities they possess non-lipid, so called pleiotropic activities, which make them especially useful in proliferative and inflammatory kidney diseases.

Chmielewski M, Zdrojewski Z, Rutkowski B. · Klinika Nefrologii, Transplantologii i Chorób Wewnetrznych Akademii Medycznej w Gdańsku. · Przegl Lek. · Pubmed #12516241 No free full text.

Abstract: The great importance of HMGCoA reductase inhibitors (statins) in treatment of hyperlipidemia is well known, and accepted. Numerous multicenter trials have shown the effectiveness of statins in lowering cholesterol concentration, slowing down progression of atherosclerosis, and in decreasing number of cardio-vascular incidents. However, since the discovery of statins experiments have been carried out showing other mechanisms of action of these drugs. Many circumstances expose the antiproliferative, and antiinflammatory influence of HMGCoA reductase inhibitors. This paper presents a review of the studies on these mechanisms with a special emphasis on their nephroprotective role.

Chmielewski M, Zdrojewski Z, Rutkowski B. · Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk. · Ann Transplant. · Pubmed #12416466 links to  free full text

Abstract: Hypercholesterolemia in patients after renal transplantation composes a significant risk factor of cardio-vascular disease, it may also worsen graft survival. Statins are the most potent drugs to lower blood cholesterol. They also posses numerous pleiotropic abilities. The paper presents benefits of the use of statins in patients after renal transplantation, as well as the dangers related to the side effects of these drugs. It underlines that adequate use of statins is worth considering in patients after renal transplantation, taking into account not only their ability to lower cholesterol but also their additional properties positively influencing graft survival.

Chmielewski M, Sucajtys-Szulc E, Kossowska E, Swierczynski J, Rutkowski B, Boguslawski W. · Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdansk, ul. Debinki 7, 80-211 Gdansk, Poland. · Atherosclerosis. · Pubmed #16814791 No free full text.

Abstract: 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.

Rutkowski B, Łososowska R, Król E, Kisielnicka E, Zdrojewski Z, Szołkiewicz M, Niewegłowski T, Chmielewski M, Sucajtys E, Swierczyński J, Korczyńska J, Stelmańska E, Goyke E, Bogusławski W. · Klinika Nefrologii, Transplantologii i Chorób Wewnetrznych AM w Gdańsku. · Pol Merkur Lekarski. · Pubmed #14974358 No free full text.

Abstract: Lipid disorders are one of the known metabolic changes associated with chronic renal failure (CRF) [1, 2]. They are present as: hypertriglyceridemia--existed in 60% of CRF patients and hypercholesterolemia observed in 20-30% of people with this syndrome. These disorders, what was shown also in our own studies, are existing in different intensity in patients treated with maintenance haemodialysis [3], peritoneal dialysis [4] and after renal transplantation as well [5]. Mechanism of hypertriglyceridemia, despite over thirty years of studies, is still not finally elucidated. The opinion that it is a result of impaired triglyceride removal (due to decreased activities of both lipoprotein and hepatic lipases) is well documented, however the role of lipogenesis in its development is obscure [6, 7]. The reports concerning this problem contain contradictory data. In our studies performed several years ago we have shown that lipogenesis rate in white adipose tissue of uremic rats is significantly augmented [8, 9, 10] due to activation of free fatty acid synthase. Therefore, recently we paid once again our attention on the activity of this lipogenesis rate limiting enzyme responsible for the long term regulation. We measured its activity, protein abundance and mRNA level in liver and epididymal white adipose tissue of rats with surgically induced renal failure (two-stage subtotal nephrectomy). The results support the thesis that lipogenesis takes a part in a hypertriglyceridemia found in renal failure. There have been observed a significant increase in plasma triglyceride and VLDL concentrations in uremic animals and it was associated with the increase of FAS activity, FAS protein abundance and FAS mRNA. The results were similar in both studied tissues. Moreover, there have been also observed the increased activities of malic enzyme, glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase. All these enzymes participate in NADPH production, which is a necessary substrate for fatty acid biosynthesis [11, 12, 13]. Concluding, it appears that the rise in plasma triglyceride and VLDL concentrations observed in CRF rats is not only the result of increased liver and white adipose tissue lipogenesis rate. One has to remember, that these date are strictly original and enabling to elucidation further pathogenesis of hyperlipidemia in CRF. In the second set of experiments performed also in rats with experimentally induced CRF we have found that hypercholesterolemia observed in those animals is dependent on the significant activation of cholesterol synthase, induced by increased production of this enzyme (increment of protein abundance and synthase mRNA [14, 15]. Simultaneously, we have performed original studies on the diurnal rhythm of cholesterologenesis, showing that activity of this process is significantly augmented during whole twenty four hours [15]. Summarizing, one have to underline that our observations have important impact to the elucidation of lipid disturbances pathomechanism. Nevertheless further studies are necessary to establish how experimental data are corresponding with human pathology.

Chmielewski M, Sucajtys E, Swierczynski J, Rutkowski B, Bogusławski W. · Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk, Gdańsk, Debinki, Poland. · Mol Cell Biochem. · Pubmed #12841361 No free full text.

Abstract: The aim of the present study was to examine hypothesis that the enhanced cholesterologenesis, found in rats with experimental chronic renal failure (CRF) resulted from the increased gene expression of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase--the rate limiting enzyme in the cholesterologenesis pathway, responsible for mevalonate synthesis. Wistar rats were used and experimental CRF was achieved by 5/6 nephrectomy model. We examined: (a) the changes in the rat liver microsomal HMG-CoA reductase activity, (b) the rat liver HMG-CoA reductase mRNA abundance in various times of day. Obtained data indicates that the increased activity of HMG-CoA reductase in the liver of rats with experimental CRF parallel enhanced mRNA level and suggests that enhanced cholesterol biosynthesis, observed in experimental CRF is at least in part due to the increased HMG-CoA reductase gene expression. The results also indicate that the physiological diurnal rhythm of HMG-CoA reductase activity is preserved in the course of experimental CRF.

Szolkiewicz M, Sucajtys E, Chmielewski M, Wolyniec W, Rutkowski P, Boguslawski W, Swierczynski J, Rutkowski B. · Department of Nephrology, Medical University of Gdansk, ul.Debinki 7, 80-211 Gdansk-Wrzeszcz, Poland. · Horm Metab Res. · Pubmed #12063635 No free full text.

Abstract: Hypercholesterolemia plays an important role in the lipid abnormalities in chronic renal failure (CRF). It is thought to contribute to both a progression of renal failure and atherosclerosis. Despite intensive research, the etiopathogenesis of hypercholesterolemia in CRF patients is still obscure. The present study was designed to evaluate the possible role of cholesterol overproduction in the development of hypercholesterolemia associated with experimental CRF. We found that plasma total cholesterol and cholesterol distributed in VLDL, LDL and HDL concentrations were significantly enhanced in CRF rats. Simultaneously, the rate of liver cholesterol biosynthesis in vivo (measured by determining the incorporation of tritium from tritiated water intraperitoneally injected into cholesterol ), liver microsomal 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity and liver HMG-CoA reductase mRNA presence were elevated. Significant increases in activity of liver malic enzyme, glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, NADPH-producing enzyme (required for cholesterol synthesis) have also been observed in CRF rats. In conclusion, the increased rate of liver cholesterol biosynthesis due to increase of HMG-CoA reductase and NADPH-producing enzyme gene expression could be one of the possible causes of hypercholesterolemia in CRF animals.

Chmielewski M, Nieweglowski T, Swierczynski J, Rutkowski B, Boguslawski W. · Department of Nephrology, Medical University of Gdańsk, Poland. · Mol Cell Biochem. · Pubmed #11855739 No free full text.

Abstract: Changes in lipid metabolism are an important risk factor for vascular complications during chronic renal failure (CRF). In experimental CRF hypercholesterolemia has been found to be the main lipid disorder. It is probably due to enhanced cholesterologenesis. Mechanisms of these changes remain poorly understood. It is well known that activity of cholesterologenesis undergoes a significant diurnal rhythm. However, there was no evidence that this rhythm is still present in the course of experimental CRF. Results of our studies indicate that in contrast to puromycin induced nephrotic syndrome, diurnal rhythm of cholesterologenesis in CRF rats is preserved both in liver and in the intestine tissue. Significant higher incorporation of tritiated water into cholesterol fraction was found in vivo both in liver as well as in intestine of CRF rats, as compared to control animals. Increased (with comparison to the controls) incorporation of 14C-acetate, and 3H-mevalonate into CRF rat liver sterols indicate that mechanism of enhanced cholesterologenesis is more complex than simply due to the elevated level of mevalonate (potential substrate for cholesterologenesis) which has been reported in plasma of CRF animals.