Low-density lipoprotein (LDL) behavior after in vitro oxidation in three groups of diabetics

Diabetes is associated with increased morbidity and mortality resulting from cardiovascular disease. It has been established that oxidized LDLs are involved in the genesis of atherosclerosis. We have studied LDL oxidizability in three types of diabetics: insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM) and insulin-treated diabetes mellitus type 2 (ITDM2) and a control group. LDLs have been isolated using ultracentrifugation and oxidized by addition of cupric chloride. With the oxidation kinetic, we calculated the lag time and the oxidation rate. Total fatty acids, alpha-tocopherol, and malondialdehyde (MDA) have been measured in native and oxidized LDLs. Diabetics have a significantly lower lag time and a lower level of alpha-tocopherol. Oxidized LDLs of diabetics show an important decrease of their polyunsaturated fatty acids with an increase of MDA compared to the control. Our study demonstrates a higher susceptibility to oxidation of LDL from diabetics; this can be explained by alteration in LDL composition or by the oxidative process occurring in this disease.     

Inhibition of rat lipoprotein oxidation after tetradecylthioacetic acid feeding

We have previously shown that tetradecylthioacetic acid (TTA), a sulfur containing saturated fatty acid analogue, inhibits the oxidative modification of human low-density lipoprotein (LDL) in vitro. The oxidative modification of LDL is believed to be a crucial step in the progression of atherosclerosis. In the present study, we investigated the effect of TTA oral administration on the susceptibility of rat lipoprotein to undergo oxidative modification ex vivo. Lipoprotein resistance to copper-induced oxidation was highly improved after TTA administration to rats. Conjugated dienes produced after 150 min of lipoprotein oxidation were dramatically lowered in the TTA treated rats compared to controls. Malondialdehyde and lipid peroxides production by oxidation was highly limited. These effects were independent of any Vitamin E effects. More than 50% relative reduction in polyunsaturated fatty acids of the n-3 family, and more than 30% relative increase in 18:1n-9 fatty acid in the triacylglycerol (TAG)-rich lipoprotein were observed. TAG-rich lipoprotein lipids of TTA fed rats were decreased with more than 50% reduction in TAG. The data reported in this paper indicate a potent in vivo antioxidant capability of TTA that beside its hypolipidemic effect might be of importance in relation to the development of atherosclerosis.     

Fatty acids and atherosclerotic risk

Most research concerning the effects of dietary fatty acids on atherosclerotic risk has focused on their effects on lipid and lipoprotein metabolism. However, it is known that fatty acids also influence a number of other relevant mechanisms involved in atherosclerosis such as lipid peroxidation, inflammation and haemostasis. The most favourable distribution of cholesterol over the various lipoproteins is achieved when saturated and trans fatty acids are replaced by a mixture of cis-unsaturated fatty acids. Furthermore, fatty acids from fish oil lower triacylglycerol concentrations. Effects on other atherosclerotic risk markers are less evident. Monounsaturated fatty acids maybe preferable above other fatty acids with respect to low-density lipoprotein oxidation as measured by indirect in vitro assays. The relevance of these assays for the in vivo situation is, however, limited. With respect to inflammation, mainly the effects of n-3 polyunsaturated fatty acids from fish oil have been studied, but results were inconsistent. Also results from studies evaluating the effects of fatty acids on haemostatic risk markers were inconsistent, which may be partly related to the use of different analytical methods. The most consistent finding however is the potential beneficial effect of moderate intakes of fish oil on platelet aggregation. Furthermore, reducing total fat intake rather than changing the fatty acid composition of the diet may beneficially affect the coagulation system. In conclusion, while beneficial effects on atherosclerotic risk are mainly ascribed to cis-unsaturated fatty acids, it remains debateable whether trans and saturated fatty acids in the diet have to be replaced by cis-unsaturated fatty acids or by carbohydrates. To answer this question adequately more validated methods are needed that reflect in vivo lipid peroxidation, inflammation and haemostasis.     

Dietary antioxidants and paraoxonases against LDL oxidation and atherosclerosis development

Oxidative modification of low-density lipoprotein (LDL) in the arterial wall plays a key role in the pathogenesis of atherosclerosis. Under oxidative stress LDL is exposed to oxidative modifications by arterial wall cells including macrophages. Oxidative stress also induces cellular-lipid peroxidation, resulting in the formation of 'oxidized macrophages', which demonstrate increased capacity to oxidize LDL and increased uptake of oxidized LDL. Macrophage-mediated oxidation of LDL depends on the balance between pro-oxidants and antioxidants in the lipoprotein and in the cells. LDL is protected from oxidation by antioxidants, as well as by a second line of defense--paraoxonase 1 (PON1), which is a high-density lipoprotein-associated esterase that can hydrolyze and reduce lipid peroxides in lipoproteins and in arterial cells. Cellular paraoxonases (PON2 and PON3) may also play an important protective role against oxidative stress at the cellular level. Many epidemiological studies have indicated a protective role for a diet rich in fruits and vegetables against the development and progression of cardiovascular disease. A large number of studies provide data suggesting that consumption of dietary antioxidants is associated with reduced risk for cardiovascular diseases. Basic research provides plausible mechanisms by which dietary antioxidants might reduce the development of atherosclerosis. These mechanisms include inhibition of LDL oxidation, inhibition of cellular lipid peroxidation and consequently attenuation of cell-mediated oxidation of LDL. An additional possible mechanism is preservation/increment of paraoxonases activity by dietary antioxidants. This review chapter presents recent data on the anti-atherosclerotic effects and mechanism of action of three major groups of dietary antioxidants-vitamin E, carotenoids and polyphenolic flavonoids.     

Effect of chronic clofibrate administration on mitochondrial fatty acid oxidation.

The effect of chronic clofibrate administration on fatty acid oxidation by isolated liver and skeletal muscle mitochondria was studied to determine if the hypolipidemic action of clofibrate may be mediated by reducing levels of fatty acyl substrates via enhanced fatty acid oxidation. Oxygen consumption and CO₂ production associated with the oxidation of fatty acids were decreased 30 per cent in liver mitochondria from clofibrate-treated rats. By contrast, CO₂ production from acetate and citric acid cycle intermediates was not significantly affected. This indicates impairment of β-oxidation of fatty acids to the level of acetyl CoA, an interpretation supported by the findings of a decrease in ketone body production. In liver mitochondria, oxygen consumption associated with the oxidation of glutamate, succinate and ascorbate was depressed. The per cent decrease was comparable in the absence or presence of ADP or dinitrophenol, suggesting impairment of the respiratory chain. There was no effect on energy production or utilization, as evidence by unchanged respiratory control, ADP/O ratio, ATP?³²P exchange reaction, and substrate- or ATP-supported Ca²⁺ uptake. Unlike isolated liver mitochondria, there were no effects on oxygen uptake or fatty acid oxidation by muscle mitochondria. It is unlikely that the hypolipidemic effects of clofibrate are mediated by reducing fatty acyl substrate levels via enhanced fatty acid oxidation.     

Comparative effects of oxygen and sulfur-substituted fatty acids on serum lipids and mitochondrial and peroxisomal fatty acid oxidation in rat.

Feeding tetradecyloxyacetic acid (a 3-oxa fatty acid) to rats led to decreased serum cholesterol and decreased serum triacylglycerol, resembling the effects of the corresponding 3-thia fatty acid (tetradecylthioacetic acid). The 3-oxa fatty acid inhibited strongly the mitochondrial fatty acid oxidation and led to the development of fatty liver, while the 3-thia fatty acid stimulated the mitochondrial fatty acid oxidation. Feeding tetradecyloxypropionic acid (a 4-oxa fatty acid) had less effect on the serum lipids. It stimulated fatty acid oxidation in the mitochondria and lowered the hepatic level of triacylglycerol. The corresponding 4-thia fatty acid (tetradecylthiopropionic acid) inhibited mitochondrial fatty acid oxidation and induced development of fatty liver. All these compounds, both the oxa and the thia fatty acids, induced some increase in the activity of the peroxisomal acyl-CoA oxidase. Repeated administration of 3-oxadicarboxylic acid to rats resulted in no lipid lowering effects, and marginal changes of fatty acyl-CoA oxidase activity. Oxidation of the S-atom of the 3-thia fatty acid to the corresponding sulfoxide or sulfone eliminated the metabolic effects of the thia fatty acid. The study has shown that the effects of 3- and 4-oxa fatty acids are in some ways opposite to those of the 3- and 4-thia fatty acids. The possibility that the lipophilicity of the fatty acid analogues may be an important factor behind the differences observed are discussed. It is suggested that these oxa- and thia-analogues of fatty acids may be useful in studies on the regulation of fatty acid metabolism.     

Characterization of the hyperlipidemia in guinea pigs induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin

Treatment of adult male guinea pigs with a single dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 6.2 nmol (2.0 μg)/kg body wt, induces a marked hyperlipidemia characterized by a 19-fold increase in very low density lipoproteins (VLDL) and a 4-fold increase in low-density lipoproteins (LDL) compared to pair-fed control animals. VLDL from TCDD-treated animals were similar in size and electrophoretic mobility to VLDL from pair-fed control animals, but they contained less cholesteryl ester and an altered pattern of C apoproteins on sodium dodecyl sulfate-polyacrylamide gels. LDL from TCDD-treated animals were larger than LDL from pair-fed controls and contained more phospholipid and less protein than LDL from pair-fed control animals. In addition, LDL from TCDD-treated animals contained increased amounts of apoprotein C as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. No change in the concentration or properties of serum high-density lipoproteins was observed. Serum free fatty acids, triglycerides, and cholesteryl esters from TCDD-treated animals were enriched in linoleic acid (18:2), a principal fatty acid of adipose tissue. This suggests that mobilization of adipose tissue fatty acids in TCDD-treated animals may lead to increased hepatic lipoprotein production. However, weight-paired control animals did not become hyperlipidemic. Thus, in addition to mobilizing adipose tissue fatty acids, TCDD may alter the relative rates of anabolic and/or catabolic processes controlling serum VLDL and LDL concentrations in the guinea pig.     

Decreased susceptibility to copper-induced oxidation of rat-lipoproteins after fibrate treatment: influence of fatty acid composition.

1. The effect of clofibrate (CFB), bezafibrate (BFB), and gemfibrozil (GFB) on plasma lipoprotein (VLDL and LDL) concentration, composition and resistance to copper-induced oxidation has been studied in male Sprague-Dawley rats after a 15 day treatment. 2. Plasma triglyceride levels were reduced by CFB (41%) and BFB (39%). This effect was related to a significant reduction (67% for CFB and 56% for BFB) in the amount of circulating VLDL-protein. 3. Plasma total cholesterol was reduced by 28% and 45% in CFB- and BFB-treated animals, respectively, mainly by modification of the cholesteryl ester fraction. In contrast, GFB significantly increased total cholesterol (27%). No modification in the LDL protein or lipid content was introduced by fibrates, although GFB decreased the proportion of LDL-triglycerides, at the expense of an increase in total cholesterol. 4. The fatty acid species carried by VLDL and LDL were affected after fibrate treatment. In general, both particles showed an increase in monounsaturated fatty acids (MUFA) (18:1) and a decrease in polyunsaturated fatty acids (PUFA) species (18:2 n-6, 20:4 n-6, 18:3 n-3, 20:5 n-3). As a consequence, the ratio of PUFA/(SFA+MUFA) for the whole lipoproteins was markedly reduced. 5. The degree of copper-induced VLDL- and LDL-oxidation was assessed by means of the analysis of lysine content, thiobarbituric acid reactive substances (TBARS) production and conjugated dienes formation. Lipoproteins obtained from fibrate-treated rats were more resistant to the oxidative challenge. For each lipoprotein, BFB was the most effective drug, followed by CFB and GFB. 6. The observed antioxidant effect can be ascribed to two independent phenomena produced by fibrates: the reduction of the amount of substrate for the oxidation process due to their hypolipidemic activity, and the alteration in the type of fatty acids transported by the lipoproteins towards an enrichment in species resistant to the oxidation process. 7. As similar lipoprotein fatty acid changes have been reported after fibrate treatment in human subjects, an antioxidant effect of fibrates in human therapy, independent of their well known hypolipidaemic activity, should be expected.     

Cardioprotective effects of a proanthocyanidin-rich fraction from Croton celtidifolius Baill: Focus on atherosclerosis

Proanthocyanidins are the most abundant polyphenols in human diets. Epidemiological studies have pointed to proanthocyanidins as promising molecules that could prevent the development of several coronary syndromes by inhibiting the atherogenic process. The present study was designed to investigate the antiatherogenic effects of a proanthocyanidin-rich fraction (PRF) obtained from Croton celtidifolius Baill (Euphorbiaceae) barks. In isolated human LDL, PRF caused a concentration-dependent inhibition of Cu²⁺-induced oxidative modifications, evidenced by the increasing of the lag phase of lipid peroxidation and decreasing in the oxidation rate (V_max), moreover, the protein moieties from LDL were protected against Cu²⁺-induced oxidation. In human umbilical vein endothelial cells (HUVECs), PRF reduced the ROS production stimulated by oxidized LDL. Herein, we demonstrate that oral treatment with PRF improved endothelium-dependent vasorelaxation in hypercholesterolemic LDL receptor knockout mice (LDLr^−/−), however, the fraction did not modify plasma lipids and atherosclerotic lesion size in this experimental model. Finally, our results showed for the first time that PRF prevent isolated LDL oxidation, decrease oxidative stress in endothelial cells and improve endothelial function in mice.     

Inhibitory effects of saturated and polyunsaturated fatty acids on the cytochrome P450 3A activity in rat liver microsomes

This study was conducted to investigate the inhibitory effects of saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs) on cytochrome P450 3A (CYP3A). The inhibition of 6beta-hydroxy testosterone formation from testosterone in rat liver microsomes was used as an index of CYP3A activity. In the present study, among the three types of fatty acids, the rank order of inhibitory effects of fatty acids was SFAs相似文献   

Protective effect of hydroxytyrosol and its metabolite homovanillic alcohol on H(2)O(2) induced lipid peroxidation in renal tubular epithelial cells

We investigated the capacity of hydroxytyrosol (HT), 3,4-dihydroxyphenylethanol, and homovanillic alcohol (HVA), 4-hydroxy-3-methoxy-phenylethanol, to inhibit H(2)O(2) induced oxidative damage in LLC-PK1, a porcine kidney epithelial cell line, studying the effect of H(2)O(2) on specific cell membrane lipid targets, unsaturated fatty acids and cholesterol. Exposure to H(2)O(2) induced a significant increase of the level of MDA together with a disruption of the membrane structure, with the loss of unsaturated fatty acids, cholesterol and alpha-tocopherol, and the formation of fatty acids hydroperoxides and 7-ketocholesterol. Pretreatment with HT protected renal cells from oxidative damage: the level of membrane lipids was preserved and there was no significant detection of oxidation products. HVA exerted a comparable activity, thus both HT and HVA were able to prevent in renal cells the lipid peroxidation process that plays a central role in tubular cell injury.     

Carnitine Palmitoyltransferase-I,a New Target for the Treatment of Heart Failure

Although the heart is capable of extracting energy from different types of substrates such as fatty acids and carbohydrates, fatty acids are the preferred fuel under physiological conditions. In view of the presence of diverse defects in myocardial metabolism in the failing heart, changes in metabolism of glucose and fatty acids are considered as viable targets for therapeutic modification in the treatment of heart failure. One of these changes involves the carnitine palmitoyltransferase (CPT) enzymes, which are required for the transfer of long chain fatty acids into the mitochondrial matrix for oxidation. Since CPT inhibitors have been shown to prevent the undesirable effects induced by mechanical overload, e.g. cardiac hypertrophy and heart failure, it was considered of interest to examine whether the inhibition of CPT enzymes represents a novel approach for the treatment of heart disease. A shift from fatty acid metabolism to glucose metabolism due to CPT-I inhibition has been reported to exert beneficial effects in both cardiac hypertrophy and heart failure. Since the inhibition of fatty acid oxidation is effective in controlling abnormalities in diabetes mellitus, CPT-I inhibitors may also prove useful in the treatment of diabetic cardiomyopathy. Accordingly, it is suggested that CPT-I may be a potential target for drug development for the therapy of heart disease in general and heart failure in particular.     

Human apolipoprotein AI mimetic peptides for the treatment of atherosclerosis

The effects of apolipoprotein (Apo) AI mimetic peptide synthesized from D- and L-amino acids on atherosclerotic lesion formation were investigated in low-density lipoprotein (LDL) receptor-deficient mice on a Western diet and in apoE null mice. In addition, their effects on the inflammatory changes induced in LDL-receptor mice fed a Western diet following influenza A infection were studied. When apolipoprotein AI mimetic peptides synthesized from either D- or L-amino acids were administered to LDL-receptor null mice, only peptides synthesized from D-amino acids were stable in the circulation and enhanced the ability of high-density lipoprotein (HDL) to protect LDL against oxidation. Administration of the peptide D-4F to LDL-receptor null mice and apoE null mice decreased lesion size. Additionally, in LDL receptor null mice after influenza infection, D-4F treatment increased plasma HDL levels and paraoxonase activity, and inhibited increased in LDL-cholesterol and peak levels of interleukin-6 post-infection. Injection of female mice with male macrophages, and subsequent measurement of the male 'sry' gene, revealed a marked increase in macrophage traffic into the aortic arch after infection that was prevented by administration of D-4F. This indicates that: (i) oral D-4F has powerful anti-atherosclerotic properties, and (ii) the loss of the anti-inflammatory properties of HDL after influenza infection in mice is associated with increased arterial macrophage traffic that can be prevented by administration of D-4F.     

Polyunsaturated fatty acids as antioxidants

The susceptibility of fatty acids to oxidation is thought to be directly dependent on their degree of unsaturation. However, some in vitro and in vivo studies suggest that the relation between chemical structure and susceptibility to oxidation is not as straightforward as hypothesized from theoretical viewpoints. Indeed, long chain polyunsaturated fatty acids (LC-PUFAs) might be less oxidizable than others under specific experimental conditions. We investigated the free radical-scavenging potential of PUFA and the production of reactive oxygen/nitrogen (ROS/RNS) species by human aortic endothelial cells (HAECs) supplemented with different fatty acids. Fatty acid micelles scavenged superoxide in an unsaturation-dependent manner, up to eicosapentaenoic acid, which was the most effective fatty acid. Supplementation of HAEC with polyunsaturated fatty acids of the omega 3 series resulted in lower formation of ROS, as compared with cells supplemented with saturates, monounsaturates, or polyunsaturates of the omega 6 series. This effect was maximal at concentrations of 10muM. The effects of omega 3 fatty acids on reactive species production appear to be stronger when ROS were evaluated, as a milder, albeit significant effect was observed on RNS generation. Based on in vivo data showing reduced excretion of lipid peroxidation products after omega 3 intake and our data on ROS production and direct superoxide scavenging by LC-PUFAs, notably those of the omega 3 series, we propose that this series of fatty acid might act as indirect anti- rather than pro-oxidant in vascular endothelial cells, hence diminishing inflammation and, in turn, the risk of atherosclerosis and cardiovascular disease.     

Inhibition of long-chain acyl-CoA synthetase by the peroxisome proliferator perfluorodecanoic acid in rat hepatocytes

Perfluorodecanoic acid (PFDA) is a potent peroxisome proliferator and is known to affect hepatic lipid metabolism in rats. The effects of PFDA on fatty acid utilization were examined in isolated rat hepatocyte suspensions and in rat liver mitochondria and microsomes. PFDA inhibited the oxidation of palmitic acid but not octanoic or pyruvic acids when hepatocytes were incubated with 1 mM PFDA. At this PFDA concentration the esterification of palmitic acid into triacylglycerols was also reduced. The activity of long-chain acyl-CoA synthetase (ACS), an enzyme essential for both oxidation and esterification of fatty acids, was reduced in hepatocytes incubated with 1 mM PFDA. Carnitine palmitoyltransferase (CPT), an important enzyme for the oxidation of long-chain fatty acids, was not altered in hepatocytes incubated with this PFDA concentration. In rat liver mitochondria, palmitate oxidation and ACS activity were reduced significantly (P less than 0.01) at a PFDA concentration that had no effect on CPT activity. The inhibition of ACS by PFDA was similar in liver mitochondria and microsome preparations. In mitochondria incubated with PFDA, the inhibition of ACS appears to be noncompetitive for the substrates palmitic acid and CoA. However, the ACS inhibition by PFDA appeared to be competitive for the ATP binding site of the enzyme. Several chain length perfluorinated fatty acids were examined for their ability to inhibit mitochondrial ACS. Short-chain perfluorinated fatty acids (perfluoroproprionic and -butyric acid) did not inhibit ACS activity. However, medium-chain perfluorinated acids (perfluorooctanoic, -ananoic and -decanoic acid) were found to be potent inhibitors of ACS in isolated mitochondria. Whether ACS inhibition is causally related to PFDA-induced peroxisome proliferation and altered lipid metabolism seen in vivo is yet to be determined.     

Quantitative analysis of acrolein-specific adducts generated during lipid peroxidation-modification of proteins in vitro: identification of N(τ)-(3-propanal)histidine as the major adduct

Acrolein, a ubiquitous pollutant in the environment, is endogenously formed through oxidation reactions and is believed to be involved in cytopathological effects observed during oxidative stress. Acrolein exerts these effects because of its facile reactivity with biological materials, particularly proteins. In the present study, we quantitatively analyzed the acrolein-specific adducts generated during lipid peroxidation-modification of proteins and identified the acrolein adduct most abundantly generated in the in vitro oxidized low-density lipoproteins (LDL). Taking advantage of the fact that the acrolein-lysine adducts, N(ε)-(3-formyl-3,4-dehydropiperidino)lysine (FDP-lysine) and N(ε)-(3-methylpyridinium)lysine (MP-lysine), have stable core structures resistant to the acid hydrolysis condition of proteins, we examined the formation of these adducts in proteins using high performance liquid chromatography with online electrospray ionization tandem mass spectrometry. However, only MP-lysine was detected as a minor product in the iron/ascorbate-mediated oxidation of polyunsaturated fatty acids in the presence of proteins and in the oxidized low-density lipoproteins (LDL). However, using a reductive amination-based pyridylamination method, we analyzed the acrolein-specific adducts with a carbonyl functionality and found that acrolein modification of the protein produced a number of carbonylated amino acids, including an acrolein-histidine adduct. On the basis of the chemical and spectroscopic evidence, this adduct was identified as N(τ)-(3-propanal)histidine. More notably, N(τ)-(3-propanal)histidine appeared to be one of the major adducts generated in the oxidized LDL. These data suggest that acrolein generated during lipid peroxidation may primarily react with histidine residues of proteins to form N(τ)-(3-propanal)histidine.     

Targets for modulation of fatty acid oxidation in the heart

Fatty acids are a major source of fuel used by the heart to provide large amounts of energy necessary to sustain contractile function. In the healthy heart, a balance between fatty acid and carbohydrate use ensures that energy supply to the heart matches demand. However, myocardial ischemia causes profound changes in metabolism, including alterations in glucose and fatty acid metabolism that can lead to excessive myocardial fatty acid oxidation, which occurs at the expense of glucose oxidation. This contributes to cellular acidosis, a decrease in cardiac efficiency and contractile dysfunction in the ischemic heart. Inhibition of fatty acid oxidation has recently emerged as a promising approach to the prevention of these adverse effects of fatty acids. As a result, a number of key enzymes involved in the metabolism of fatty acids are potential targets for therapeutic intervention in myocardial ischemia. This includes inhibition of fatty acid uptake into the myocyte, inhibition of mitochondrial fatty acid uptake and direct inhibition of fatty acid beta-oxidation. This review describes these potential targets for modulation of energy metabolism in the heart.     

单不饱和脂肪酸对心血管疾病的作用机制

单不饱和脂肪酸是碳链上只有一个双键的脂肪酸。研究表明,MUFA可以通过对血脂、内皮、凝血和纤溶系统、HGM-CoA还原酶及LDL氧化敏感性的调节,对血脂产生正向调节的作用,从而降低心血管疾病的发生率。     

The effect of dietary fat on tumor growth

Experiments in animals have shown that high-fat diets can enhance tumor growth. Animals receiving high-fat diets routinely ingest up to 5 times the level of fat (by weight) found in standard chow diets. Rats given oil by gavage can triple caloric intake from fat compared to untreated controls. In laboratory animals, high-fat diets appear to play a role during the postinitiation phase of tumorigenesis. The type, level, and nature of the dietary fat may also affect the outcome of bioassays. Fat does not initiate the tumorigenic process. Additional factors must be considered when studying and interpreting the effects of dietary fat. Animal diets and dietary fats should be protected against oxidation. Antioxidants protect against oxidation but may also modify the tumorigenic process. Adequate levels of essential fatty acids must be provided. Dietary fat level can alter nutrient density and palatability; each of these factors can affect nutrient intake which can in turn influence metabolic processes.     

RECENT INSIGHTS INTO DIETARY FATS AND CARDIOVASCULAR DISEASE

1. Fat deposition in the arterial intima is fundamental to the atheroma process. Circulating lipoproteins are thought to be the source of much of the deposited fat. The interplay of dietary fat has not been fully clarified. 2. Observational studies have furnished evidence of relationships between the different dietary fats and clinical cardiovascular events. In these, total fat and in particular, saturated fat appear culprit. Mono-unsaturated (MUFA) and polyunsaturated (PUFA) fats have less consistent relationships with cardiovascular disease, though all classes of fatty acid are found in atheroma. 3. Comparing the effects on lipoproteins of saturates, mono-unsaturates and polyunsaturates, they all increase high density lipoproteins (HDL) and reduce triglycerides when substituted isocalorically for carbohydrate. Saturates increase low density lipoproteins (LDL), while PUFA > MIJFA reduce LDL. 4. Upon oxidative modification, lipoproteins are more liable to arterial deposition and, in vitro at least, LDL oxidizability is enhanced by enrichment with PUFA. 5. Trans-MUFA have some unique properties in that they somewhat resemble saturates and seem to predispose to coronary disease, quite possibly because of their adverse effects on LDL, HDL and Lp(a) levels. 6. ω-3 fatty acids seem unique among the dietary fats in that they inhibit thrombosis and platelet aggregation, and can lower blood pressure. 7. The net effect of these various potential influences of fatty acids on atherogenesis in vivo is unclear. It may well be that all fats, with the exception of the ω-3 class, are detrimental with respect to atherogenesis. Modification of the diet, with particular attention to fat, has been demonstrated to reduce clinical coronary events in several studies. Restriction of all fats, save for that in fish, preferably along with weight reduction, appears desirable in order to effectively reduce cardiovascular disease risk.