Mitochondrial fatty acid synthesis,fatty acids and mitochondrial physiology

Mitochondria and fatty acids are tightly connected to a multiplicity of cellular processes that go far beyond mitochondrial fatty acid metabolism. In line with this view, there is hardly any common metabolic disorder that is not associated with disturbed mitochondrial lipid handling. Among other aspects of mitochondrial lipid metabolism, apparently all eukaryotes are capable of carrying out de novo fatty acid synthesis (FAS) in this cellular compartment in an acyl carrier protein (ACP)-dependent manner. The dual localization of FAS in eukaryotic cells raises the questions why eukaryotes have maintained the FAS in mitochondria in addition to the “classic” cytoplasmic FAS and what the products are that cannot be substituted by delivery of fatty acids of extramitochondrial origin. The current evidence indicates that mitochondrial FAS is essential for cellular respiration and mitochondrial biogenesis. Although both β-oxidation and FAS utilize thioester chemistry, CoA acts as acyl-group carrier in the breakdown pathway whereas ACP assumes this role in the synthetic direction. This arrangement metabolically separates these two pathways running towards opposite directions and prevents futile cycling. A role of this pathway in mitochondrial metabolic sensing has recently been proposed. This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum.     

Visual function, fatty acids and dyslexia

There is mounting evidence that developmental dyslexia is a neurodevelopmental disorder which involves abnormalities of fatty acid metabolism, particularly with respect to certain long-chain highly unsaturated fatty acids (HUFAs). Psychophysical evidence also strongly suggests that dyslexics may have visual deficits as well as phonological problems. Specifically, these visual deficits appear to be related to the magnocellular pathway, which is specialized for processing fast, rapidly-changing information about the visual scene. It remains unclear how these two aspects of dyslexia - fatty acid processing and visual magnocellular function - could be related. We propose some hypotheses - necessarily speculative, given the paucity of biochemical research in this field to date - which address this question.     

Correlation between medium C-chain fatty acids and polyunsaturated fatty acids

The medium C-chain fatty acids increased in the muscle, lungs, pancreas and adipose tissue (and not in the liver) of the rats injected with CCl4 or nourished with "balanced" diet for the lipids. When CCl4 and balanced diet are furnished together, these acids decrease strongly: the discussion of the results is difficult.     

Chemoenzymatic synthesis of surfactants from carbohydrates, amino acids, and fatty acids

The chemoenzymatic synthesis of new surfactants is reported; they were prepared from unprotected carbohydrates, amino acids, and fatty acids. This study pointed out the factors that govern the possibility to enzymatically bind the carbohydrate to the amino acid.     

Polyunsaturated fatty acids,neuroinflammation and well being

The innate immune system of the brain is principally composed of microglial cells and astrocytes, which, once activated, protect neurons against insults (infectious agents, lesions, etc.). Activated glial cells produce inflammatory cytokines that act specifically through receptors expressed by the brain. The functional consequences of brain cytokine action (also called neuroinflammation) are alterations in cognition, mood and behaviour, a hallmark of altered well-being. In addition, proinflammatory cytokines play a key role in depression and neurodegenerative diseases linked to aging. Polyunsaturated fatty acids (PUFA) are essential nutrients and essential components of neuronal and glial cell membranes. PUFA from the diet regulate both prostaglandin and proinflammatory cytokine production. n-3 fatty acids are anti-inflammatory while n-6 fatty acids are precursors of prostaglandins. Inappropriate amounts of dietary n-6 and n-3 fatty acids could lead to neuroinflammation because of their abundance in the brain and reduced well-being. Depending on which PUFA are present in the diet, neuroinflammation will, therefore, be kept at a minimum or exacerbated. This could explain the protective role of n-3 fatty acids in neurodegenerative diseases linked to aging.     

Essential fatty acids, lipid peroxidation and apoptosis

Essential fatty acids (EFAs) and their metabolites, especially gamma-linolenic acid, arachidonic acid, eicosapentaenoic acid and decosahexaenoic acid are known to induce apoptotic death of tumour cells. But the exact mechanism by which these fatty acids are able to induce apoptosis is not clear. Recent studies suggest that these fatty acids are able to induce apoptosis in cells over expressing cytochrome P450 following depletion of cellular glutathione and inhibition of carnitine palmitoyl transferase I (CPTI) activity. On the other hand, BCL-2 prevented apoptosis induced by these long-chain fatty acids, where as n-3 fatty acids suppressed ras expression leading to suppression of development of overt neoplasia. Phosphorylation of BCL-2 inhibits its ability to interfere with apoptosis and enhances lipid peroxidation leading to the occurrence of apoptosis. Tumour cells treated with long-chain fatty acids show increase in lipid peroxidation process, depletion of antioxidants and phosphorylation of proteins. Based on these results, it is suggested that long-chain fatty acids induce apoptosis by enhancing lipid peroxidation, suppressing BCL-2 expression possibly by phosphorylation and augmentation of P450 activity. Thus, these long-chain fatty acids may, infact act at the level of gene/oncogene expression in producing their cytotoxic action on tumour cells.     

Hydrocarbons,free fatty acids,and amino acids of sclerotia of Sclerotinia sclerotiorum

Summary Sclerotia of Sclerotinia sclerotiorum (Lib.) D By. were obtained from commercial pea-and bean-cleaning operations or grown on potato-dextrose agar and synthetic glucose-and sucrose-salts agar media. The crude fat (ether extract) content of sclerotia varied from 0.8 to 1.5%. Extraction and fractionation of the lipids followed by gas chromatographic analysis showed that sclerotia from pea cleanings contained one predominant hydrocarbon which was absent from sclerotia produced in the laboratory. Sclerotia from natural sources and grown in the laboratory contained a similar distribution of C₁₈ unsaturated free fatty acids, however, quantitative differences were noted. Palmitic, oleic and linoleic were the major free fatty acids of the laboratory-grown sclerotia while a high proportion of linoleic acid was also found in sclerotia from natural sources. Sclerotia were fractionated into water-soluble and water-insoluble fractions. After acid hydrolysis of the waterinsoluble fraction, both fractions were analyzed for amino acids. Twenty-one compounds, including 2 unknowns, were detected in the soluble fraction. The hydrolyzates contained 19 amino acids, including the same 2 unknowns. Two compounds tentatively identified as ornithine and -aminobutyric acid were found only in the water-soluble fraction. The relative amino acid composition of the water-insoluble fraction of sclerotia from various sources was fairly constant but the arginine content decreased on the synthetic media.     

Partition of fatty acids

The partition ratios of radioactive fatty acids between n-heptane and a physiological buffer at 37 degrees C were measured. The fatty acids included the saturated acids with an even number of carbons from 10 to 18 and the unsaturated acids oleic, linoleic, and linolenic. In addition, the partition ratios of decanoate, myristate, and palmitate were determined over a wide pH range. Any single plot of partition ratio vs. aqueous concentration of an acid gave a nearly straight line, a finding consistent with very little association in the aqueous phase. In the case of the acids with 16 and 18 carbon atoms, however, comparison of the constants calculated from these plots with the assumption of no aqueous phase association revealed several inconsistencies. These inconsistencies cannot be resolved completely by assuming the existence of fatty acid association in the aqueous solution. We believe that at least some of the deviations are due to the presence of trace quantities of radioactive impurities in the labeled fatty acids. For example, purification of a sample of supposedly pure [1-(14)C]myristate by a series of solvent extractions increased the partition ratio by a factor of 1.5. Although all of the observations cannot be explained by this interpretation, we believe that our studies suggest that there is no appreciable association of fatty acids under the usual physiological conditions.     

Mono-unsaturated fatty acids protect against beta-cell apoptosis induced by saturated fatty acids, serum withdrawal or cytokine exposure

Long-chain saturated fatty acids are cytotoxic to pancreatic β-cells while shorter-chain saturated and long-chain unsaturated molecules are better tolerated. Mono-unsaturated fatty acids are not, however, inert since they inhibit the pro-apoptotic effects of saturated molecules. In the present work we show that the mono-unsaturates palmitoleate (C16:1) or oleate (C18:1) also cause marked inhibition of apoptosis induced by exposure of clonal BRIN-BD11 β-cells to serum withdrawal or a combination of interleukin-1β plus interferon-γ. This response was dose-dependent and not accompanied by changes in NO formation. Taken together, the results suggest that mono-unsaturated fatty acids regulate a distal step common to several apoptotic pathways in pancreatic β-cells.     

Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4

Results from our previous studies demonstrated that activation of Toll-like receptor 4 (Tlr4), the lipopolysaccharide (LPS) receptor, is sufficient to induce nuclear factor kappaB activation and expression of inducible cyclooxygenase (COX-2) in macrophages. Saturated fatty acids (SFAs) acylated in lipid A moiety of LPS are essential for biological activities of LPS. Thus, we determined whether these fatty acids modulate LPS-induced signaling pathways and COX-2 expression in monocyte/macrophage cells (RAW 264.7). Results show that SFAs, but not unsaturated fatty acids (UFAs), induce nuclear factor kappaB activation and expression of COX-2 and other inflammatory markers. This induction is inhibited by a dominant-negative Tlr4. UFAs inhibit COX-2 expression induced by SFAs, constitutively active Tlr4, or LPS. However, UFAs fail to inhibit COX-2 expression induced by activation of signaling components downstream of Tlr4. Together, these results suggest that both SFA-induced COX-2 expression and its inhibition by UFAs are mediated through a common signaling pathway derived from Tlr4. These results represent a novel mechanism by which fatty acids modulate signaling pathways and target gene expression. Furthermore, these results suggest a possibility that propensity of monocyte/macrophage activation is modulated through Tlr4 by different types of free fatty acids, which in turn can be altered by kinds of dietary fat consumed.