Fatty acids, oxidation pathogenesis

The pathogenesis of alcoholic liver disease is a multifactorial process involving metabolic repercussions of ethanol oxidation in the liver, dysregulation of fatty acid oxidation and synthesis, and activation of the innate immune system by a combination of direct effects of ethanol and its metabolites and by bacterial endotoxins that access the liver as a result of ethanol-induced changes in the intestinal tract. Tumor necrosis factor- , a proinflammatory cytokine that is consistently... 

VPA. Histologically, microvesicular steatosis induced by 4-en-VPA is accompanied by ultrastructural changes characterized by myeloid bodies, hpid vacuoles and mitochondrial abnormalities. An enhanced excretion of Cg to Cio dicarboxylic acids by patients and rats indicates an interference with mitochondrial P-oxidation as an important pathogenesis. If the normal pathway of fatty acid oxidation is disrupted by VPA, it results in reduced ketone body formation and decrease of free coenzyme-A (CoA) in the liver. Especially, decreased CoA would limit the activities of one or more enzymes in the pathway of fatty acid oxidation. 

A variety of thiokinases probably exist, but only a few of them have been identified. Acetic acid and butyryl thiokinase have been purified from a variety of sources, including yeast, liver, and muscle. These two enzymes differ in their specificity for the substrate. Acetic thiokinase catalyzes only the oxidation of propionic, acetic, and acrylic acids, but butyryl thiokinase activates fatty acids of chain lengths ranging from 4-to 12-carbon units. A third thiokinase was also discovered. It acts on fatty acid chains with 5- to 22-carbon units and is found in the microsomes. This intracellular distribution is in striking contrast with the cellular location of all other enzymes involved in fatty acid oxidation, which are all in mitochondria. The palmityl enzyme, which is active in the presence of ATP and CoA, becomes inactive when incubated in the absence of CoA therefore, it has been proposed that the active form of the enzyme involves the formation of an enzyme-CoA complex. The heart, the skeletal muscle, and the kidney also contain a thiokinase that specifically activates acetoacetic acid. Acetoacetic acid thiokinase is absent in liver this observation is significant in the pathogenesis of ketosis. 

PPARa), an orphan nuclear receptor that acts as a transcription factor to induce the expression of enzymes involved in fatty acid oxidation (Devchand et al, 1996). Abnormal LTB4 production has been implicated in the pathogenesis of inflammatory bowel disease, psoriasis, rheumatoid arthritis, and gout. 

In contrast to MPO, eosinophil peroxidase (EPO) prefers to oxidize plasma level bromide (20-100 pM) to hypobromous acid (HOBr) and several biological targets are implicated, including nucleic acids and nucleosides (1480, 1482, 2376), proteins (1812, 1813, 2377, 2378), unsaturated fatty acids (2379), and low-density lipoprotein (2380, 2381). This EPO-dependent bromination is suggested to be involved in the pathogenesis of asthma (2382). Accordingly, both 3-bromotyrosine and 3,5-dibromotyrosine (1812,1813) are produced by EPO-induced bromination of tyrosine residues in lung tissue (1813, 2382). 

Kumar CA, Das UN. Lipid peroxides, nitric oxide and essential fatty acids in patients with Plasmodium falciparum malaria. Prostaglandins Leukot Essent Eatty Acids 1999 61 255-258. Xiao L, Patterson PS, Yang C, Lai AA. Role of eicosanoids in the pathogenesis of murine cerebral malaria. Am. J. Trop. Med. Hyg. 1999 60 668-673. 

There is substantial evidence that indicates that dietary fat can influence significantly not only serum levels of cholesterol and triacylglycerols but also the lipid composition and content of Apoproteins (156-159). Much attention has been placed on the effects of diet on LDL levels, and saturated fatty acid and cholesterol itself have been identified as the major nutritional factors that can raise serum LDL-cholesterol levels. However, LDL cholesterol is only one of the many risk factors for atherosclerosis, and it is not known if oxidative modification of LDL is an equally or more important factor in the pathogenesis of atherosclerosis than total LDL cholesterol per se. More longitudinal studies are needed to answer these questions. If lipid peroxidation is a major risk factor for atherosclerosis, then excess consumption of highly unsaturated fats may not be advisable. 

An explanation for the pathogenesis of the lesions observed in thiamine deficiency would seem to follow logically from these biochemical observations, for in the thiamine-deficient animal, at least two enzymes involved in the Krebs cycle are blocked. The block of pyruvic decarboxylase prevents the entry of the products of glycolysis into the Krebs cycle. The block of a-ketoglutarate decarboxylase restricts the oxidation of both carbohydrates and fatty acids. A severe metabolic distortion follows, and one of the main manifestations of the distortion is a reduction of the amount of chemical energy available in the form of ATP. Clearly, those organs that suffer the most from such alterations are those that are metabolically most active, and the heart and the peripheral nervous system surely qualify as such. 

McCarty MF (1998) Nitric oxide deficiency, leukocyte activation, and resultant ischemia are crucial to the pathogenesis of diabetic retinopathy/neuropathy-preventive potential of antioxidants, essential fatty acids, chromium, ginkgolides, and pentoxifylline. Med Hypotheses 50(5) 435 9... 

Liver The pathogenesis and clinical characteristics of drug-induced liver injury associated with antiepileptic drugs has been reviewed [41 ]. Reactive metabolites can, in some cases, lead to direct cytotoxicity and liver cell necrosis, whereas in other cases they can cause neoantigen formation, inducing immunoallergic mechanisms. In fact, hypersensitivity features are found in more than 70% of patients with pheny-toin-induced liver injury, whereas this is only observed in 30% of carbamazepine-associated hepatotoxicity and very rarely with valproate-induced liver injury. No specific therapy is of proven value in these cases. However, carnitine, which is an important co-factor in mitochondrial beta-oxidation of fatty acids, is recommended in valproate-associated liver injury, and N-acetylcysteine is an appropriate treatment in patients with liver injury due to pheny-toin and carbamazepine. Liver transplantation may be required for patients with the most severe liver reactions. 

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