The Physiological and Pathological Role of Acyl-CoA Oxidation.

Fatty acid metabolism, including ß-oxidation (ßOX), plays an important role in human physiology and pathology. ßOX is an essential process in the energy metabolism of most human cells. Moreover, ßOX is also the source of acetyl-CoA, the substrate for (a) ketone bodies synthesis, (b) cholesterol synthesis, (c) phase II detoxication, (d) protein acetylation, and (d) the synthesis of many other compounds, including N-acetylglutamate-an important regulator of urea synthesis. This review describes the current knowledge on the importance of the mitochondrial and peroxisomal ßOX in various organs, including the liver, heart, kidney, lung, gastrointestinal tract, peripheral white blood cells, and other cells. In addition, the diseases associated with a disturbance of fatty acid oxidation (FAO) in the liver, heart, kidney, lung, alimentary tract, and other organs or cells are presented. Special attention was paid to abnormalities of FAO in cancer cells and the diseases caused by mutations in gene-encoding enzymes involved in FAO. Finally, issues related to α- and ω- fatty acid oxidation are discussed.

The Role of Acyl-CoA ß-Oxidation in Brain Metabolism and Neurodegenerative Diseases.

This review highlights the complex role of fatty acid ß-oxidation in brain metabolism. It demonstrates the fundamental importance of fatty acid degradation as a fuel in energy balance and as an essential component in lipid homeostasis, brain aging, and neurodegenerative disorders.

High levels of reactive oxygen species in pancreatic necrotic fluid of patients with walled-off pancreatic necrosis.

INTRODUCTION: Walled-off pancreatic necrosis (WOPN) is a life-threatening, late complication of acute pancreatitis, in which a fluid collection containing necrotic material is formed. Infection of the fluid collection significantly increases the mortality of patients with WOPN. AIM: To examine the levels of oxidative stress markers in the pancreatic necrotic fluid (PNF) and serum of patients with sterile and infected WOPN. MATERIAL AND METHODS: Thirty-three adult patients with sterile WOPN and 14 with infected WOPN, as well as 31 patients with mild AP, were included in this study. Concentrations of oxidative stress markers (8-isoprostane, protein carbonyl groups, and 8-hydroxyguanine) were measured in the PNF and serum of patients with sterile and infected WOPN. RESULTS: High concentrations of all measured oxidative stress markers in PNF, but not in serum, were detected in patients with WOPN. Additionally, oxidative stress markers in PNF were significantly increased in patients with infected as compared to sterile WOPN. The serum high sensitive C-reactive protein (hsCRP) concentrations showed the highest correlation with PNF oxidative stress marker levels. Receiver operating characteristics (ROC) curve analysis confirmed that serum hsCRP could be a good predictor of WOPN infection. CONCLUSIONS: Oxidative stress is associated with WOPN development; infection of PNF worsens the course of WOPN, possibly via increased production of reactive oxygen species; and serum hsCRP concentrations seem to be a good, noninvasive indicator of PNF infection.

Effect of estradiol on enzymes of vascular extracellular nucleotide metabolism.

PURPOSE: Estrogens have beneficial effects on the cardiovascular system, promoting vasodilation, endothelial cells growth, relaxation, and regulation of blood pressure. Some of these effects could be associated with the purinergic system known for the control of vasodilation, inflammation, and platelet function. The aim of our study was the evaluation of ATP, AMP, and adenosine extracellular catabolism, catalyzed by ectonucleoside triphosphate diphosphohydrolase-1 (CD39), ecto-5'-nucleotidase (CD73), and ecto-adenosine deaminase (eADA) in mouse aortas. METHODS: Extracellular hydrolysis of ATP, AMP, and adenosine was estimated on the aortic surface of 3-month-old female and male C57BL/6 J wild-type (WT) mice, in female WT mouse aortas incubated for 48 h in the presence or absence of 100 nM estradiol, and in WT female mouse and ApoE-/-LDL-R-/- aortas. The conversion of substrates to products was analyzed by high-pressure liquid chromatography (HPLC). RESULTS: We demonstrated significantly higher adenosine deamination rate in WT male vs. female mice (p = 0.041). We also noted the lower adenosine hydrolysis in aortas exposed to estradiol, as compared with the samples incubated in estradiol-free medium (p = 0.043). Finally, we observed that adenosine conversion to inosine was significantly higher on the surface of ApoE-/-LDL-R-/- aortas compared with WT mice (p = 0.001). No such effects were noted in ATP and AMP extracellular hydrolysis. CONCLUSION: We conclude that estradiol inhibits the extracellular degradation of adenosine to inosine, which may be an element of its vascular protective effect, as it will lead to an increase in extracellular adenosine concentration. We can also assume that during the development of the atherosclerotic process, the protective role of estradiol in the regulation of adenosine degradation may be obscured by other pathogenic factors.

The Pathophysiological Role of CoA.

The importance of coenzyme A (CoA) as a carrier of acyl residues in cell metabolism is well understood. Coenzyme A participates in more than 100 different catabolic and anabolic reactions, including those involved in the metabolism of lipids, carbohydrates, proteins, ethanol, bile acids, and xenobiotics. However, much less is known about the importance of the concentration of this cofactor in various cell compartments and the role of altered CoA concentration in various pathologies. Despite continuous research on these issues, the molecular mechanisms in the regulation of the intracellular level of CoA under pathological conditions are still not well understood. This review summarizes the current knowledge of (a) CoA subcellular concentrations; (b) the roles of CoA synthesis and degradation processes; and (c) protein modification by reversible CoA binding to proteins (CoAlation). Particular attention is paid to (a) the roles of changes in the level of CoA under pathological conditions, such as in neurodegenerative diseases, cancer, myopathies, and infectious diseases; and (b) the beneficial effect of CoA and pantethine (which like CoA is finally converted to Pan and cysteamine), used at pharmacological doses for the treatment of hyperlipidemia.

Statin treatment of patients with calcific aortic valve disease modulates extracellular adenosine metabolism on the cell surface of the aortic valve.

Statins efficiently prevent cardiovascular events by lipid-dependent and independent mechanisms. We hypothesize that part of these protective effects could be associated with an increased extracellular adenosine signaling. We demonstrated previously that aortic valves obtained from patients with calcific aortic valve disease (CAVD) disclosed disturbances in extracellular adenosine metabolism. This study aimed to analyze the impact of statin treatment on extracellular nucleotides and adenosine metabolism in aortic valves originated from CAVD patients and to elucidate potential mechanisms that are involved in the regulation of ecto-enzyme activities by statins. Aortic valves of CAVD patients treated with statins (n = 45) revealed higher adenosine production and its lower degradation than in non-treated patients (n = 28). Statin treatment was also related to the improvement in pre-operative echocardiographic data indicating milder aortic valve stenosis and a better function of the left ventricle. The rates of aortic valve adenosine conversions correlated with plasma lipid profile parameters, within both statin-treated and non-treated groups. Valvular extracellular AMP hydrolysis correlated negatively, while adenosine deamination positively with plasma total and LDL cholesterol. Atorvastatin treatment of murine heart endothelial cells led to the enhanced ecto-5'nucleotidase (CD73) and decreased ecto-adenosine deaminase (eADA) activity. When endothelial cells were stimulated with thrombin that induces endothelial cell exocytosis, activities of both cell-surface CD73 and eADA were increased, while co-treatment with atorvastatin reversed only thrombin-induced eADA activity. In conclusion, early intervention with statins may provide beneficial effects for CAVD therapy. Here, we presented results showing that these protective outcomes could be mediated via the regulation of extracellular adenosine metabolism pathways.

[Dichloroacetate--a healing toxin or a toxic drug?]. / Dichlorooctan--leczaca toksyna czy toksyczny lek?

Dichloroacetate (DCA) is a compound which activity is observed by experimental and clinical toxicologists. DCA is a by-product of chlorination of water, it is toxic to many organs, such as liver, kidneys or nervous system. In a view of its metabolism it is also demonstrated that this substance may be treated as a drug in various medical conditions, such as different types of tumors for example.

Role of abnormal lipid metabolism in development, progression, diagnosis and therapy of pancreatic cancer.

There is growing evidence that metabolic alterations play an important role in cancer development and progression. The metabolism of cancer cells is reprogrammed in order to support their rapid proliferation. Elevated fatty acid synthesis is one of the most important aberrations of cancer cell metabolism. An enhancement of fatty acids synthesis is required both for carcinogenesis and cancer cell survival, as inhibition of key lipogenic enzymes slows down the growth of tumor cells and impairs their survival. Based on the data that serum fatty acid synthase (FASN), also known as oncoantigen 519, is elevated in patients with certain types of cancer, its serum level was proposed as a marker of neoplasia. This review aims to demonstrate the changes in lipid metabolism and other metabolic processes associated with lipid metabolism in pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic neoplasm, characterized by high mortality. We also addressed the influence of some oncogenic factors and tumor suppressors on pancreatic cancer cell metabolism. Additionally the review discusses the potential role of elevated lipid synthesis in diagnosis and treatment of pancreatic cancer. In particular, FASN is a viable candidate for indicator of pathologic state, marker of neoplasia, as well as, pharmacological treatment target in pancreatic cancer. Recent research showed that, in addition to lipogenesis, certain cancer cells can use fatty acids from circulation, derived from diet (chylomicrons), synthesized in liver, or released from adipose tissue for their growth. Thus, the interactions between de novo lipogenesis and uptake of fatty acids from circulation by PDAC cells require further investigation.

[Mechanisms of bile acid biosynthesis regulation--autoregulation by bile acids]. / Mechanizmy regulacji biosyntezy kwasów zólciowych--autoregulacyjna rola kwasów zólciowych.

Bile acids play significant role in body homeostasis regulation. They are products of cholesterol catabolism and ligands for some nuclear receptors regulating crucial metabolic pathways. The main enzyme regulating bile acids biosynthesis is CYP7A1 (7alpha-cholesterol hydroxylase). Its activity is controlled mainly at the transcription level and the key transcription factor is FXR. It is activated by other nuclear receptors like SHP, HNF-4alpha or LRH-1 and bile acids themselves, and represses CYP7A1 gene. The other transcription factors that inhibit CYP7A1 activity, are PXR, VDR, PPARalpha. The main activator is LXR (in rodents), increasing CYP7A1 transcriptional activity. CYP7A1 activity increases in presence of insulin and glucocorticoids. It is also regulated by diurnal rhythm. Some of those factors influence the activities of other bile acids biosynthesis enzymes--CYP7B1, CYP27A1, CYP8B1. Because of bile acids significant function in body metabolism this article presents the newest knowledge on mechanisms of key enzymes activities control.

[Bile acid biosynthesis and its regulation]. / Biosynteza kwasów zólciowych i jej regulacja.

Bile acid biosynthesis is the main pathway of cholesterol catabolism. Bile acids are more soluble than cholesterol so are easier to excrete. As amphipathic molecules they participate in lipid digestion and absorption in the intestine and they help to excrete free cholesterol with bile. They are also ligands for nuclear receptors regulating the expression of genes involved in cholesterol metabolism. Interconversion of cholesterol into bile acids is an important point of its homeostasis. Seventeen enzymes are engaged in this process and many of them are cytochromes P450. Bile acid synthesis initiation may proceed with the "classical" pathway (starting with cholesterol hydroxylation at the C7α position) or the "alternative" pathway (starting with cholesterol hydroxylation at the C27 position). Two additional pathways are possible, though their quantitative significance is small (initiated with cholesterol hydroxylations of C24 and C25 positions). Oxysterols produced are not only intermediates of bile acid biosynthesis but also important regulators of metabolism. Bile acid biosynthesis takes place in the liver, but some enzymes are also present in other organs, where they participate in regulation of cholesterol metabolism. Those enzymes are potential targets for new drugs against cholesterol metabolism disturbances. This article is a brief description of the bile acid biosynthesis pathway and participating enzymes.

Gender- and age-related changes in 6-phosphogluconate dehydrogenase gene expression in white adipose tissue of rats (Rattus norvegicus) are not related to serum testosterone concentration.

Previously, we have shown that the age-related changes in 6-phosphogluconate dehydrogenase (6PGDH) activity depend on sex, and that oestradiol is playing a crucial role in the regulation of 6PGDH gene expression in rat liver, but not in other tissues [Pankiewicz, A., Sledzinski, T., Nogalska, A., Swierczynski, J., 2003. Tissue specific, sex and age-related differences in the 6-phosphogluconate dehydrogenase gene expression. Int. J. Biochem. Cell Biol. 35, 235-245.]. To complete the knowledge on the influence of sex hormones on 6PGDH activity, experiments have been performed on the effect of testosterone on 6PGDH gene expression in rat white adipose tissue and liver. The results presented here disclosed that in young male rats high serum testosterone concentration was associated with high white adipose tissue 6PGDH activity. After orchidectomy, a decrease in serum testosterone concentration (both in young and old rats) was observed. In contrast, no changes in white adipose tissue and liver 6PGDH activity were found. In female rats, both young and old, serum testosterone concentration was below the limit of detection, whereas 6PGDH activity was much higher in young than in old animals. Moreover, the testosterone administration to 9-month old male rats (which displayed much lower serum testosterone concentration that young animals) resulted in no effect on 6PGDH activity either in WAT or in the liver. In conclusion, the results presented in this paper indicate that testosterone does not play any role in the age- and gender-related differences in 6PGDH gene expression in white adipose tissue.