Dietary eicosapentaenoic acid and docosahexaenoic acid are more effective than alpha-linolenic acid in improving insulin sensitivity in rats

In the present study, we investigated whether long-term administration of high dose of alpha-linolenic acid (ALA) is able to mimic the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) or a mixture of both with respect to insulin sensitivity in male Wistar rats. Furthermore, we intended to test whether these n-3 polyunsaturated fatty acids reveal differential effects on glucose and insulin levels. As a result, plasma glucose and insulin levels were lowered by 35 and 38%, respectively, in the EPA and DHA group compared to the ALA group. Insulin sensitivity was substantially improved, as indicated by a 60% decreased HOMA index after an 8-week EPA and DHA administration, as compared to the effect observed for feeding ALA. However, insulin sensitivity did not differ between animals of the EPA and the DHA group. These results demonstrate that ALA intake at the expense of EPA and DHA in a diet high in n-3 fatty acids does not represent an alternative to raising oily fish consumption with regard to insulin sensitivity. Furthermore, a differential effect of the members of the n-3 family was shown for ALA compared to EPA and DHA, but EPA and DHA revealed comparable effects on insulin sensitivity.     

Fat modification in the diabetes diet.

The modification of dietary fat in the diet of diabetic patients is of interest with respect to metabolic and other consequences of this modification. To begin with the data are reviewed for the use of monounsaturated fatty acids (MUFA) in the diabetes diet. Compared to a carbohydrate-rich diet, glucose concentrations are lower. Blood pressure was also found to be lower. There were no major differences with respect to lipid concentrations. HDL-cholesterol levels tended to be higher after a MUFA-rich diet. In type-1 diabetic patients, the number of circulating big VLDL particles was greater after a MUFA diet than after a carbohydrate-rich diet. Comparisons were also made between diets enriched with MUFA and with polyunsaturated fatty acids (PUFA). With respect to lipid concentrations, different groups observed different effects. While one group saw no differences in fasting lipids, they measured a higher remnant-like particle cholesterol after a diet enriched with MUFA. Another group found higher total and LDL-cholesterol levels after a PUFA-rich diet than after a MUFA-diet. In their study, fasting glucose, insulin and fasting chylomicrons and postprandial chylomicrons and VLDL were higher following the PUFA diet. A MUFA-rich diet increased endothelium-dependent flow-mediated dilatation in the superficial femoral artery. Alpha-linolenic acid appears to be a precursor of eicospentaenoic and docosahexaenoic fatty acids. As a diet rich in n-6 PUFA reduces this conversion, a n-6/n-3 PUFA ratio not exceeding 4 - 6 should be observed. No prospective data are available for alpha-linolenic acid in diabetic patients. The review summarizes the results of the Lyon Diet Heart Study and the Nurses' Health Study. Both studies saw a reduced cardiovascular risk associated with a higher intake of alpha-linolenic acid. Finally, data on the effects of fish oil are given. The latter has a clearly expressed triglyceride-lowering effect. Data with respect to glucose control are heterogeneous. Major studies did not find any influence in glucose concentrations. Hepatic glucose production and peripheral insulin sensitivity remained constant. Evidently, nerve function can be improved by fish oil. Data have been compiled comparing the effects of fish oil with those of olive oil, linseed oil and sunflower oil.     

Omega-3 Polyunsaturated Fatty Acids Reduce Vascular Endothelial Growth Factor Production and Suppress Endothelial Wound Repair

Long-chain polyunsaturated omega-3 fatty acids (n-3 PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have diverse beneficial effects on cardiovascular diseases and have been used widely as supplements in reducing the risk of cardiovascular diseases. The beneficial effects are believed to be related to the anti-inflammatory and antioxidant action of n-3 PUFA. EPA and DHA can inhibit inflammatory cytokine-induced endothelial activation and reduce endothelial migration and proliferation. Revascularisation is the major therapeutic approach for end-stage cardiovascular diseases, and endothelial migration and proliferation are essential for the success of revascularisation. The aim of this study was to investigate the role of n-3 PUFAs on vascular endothelial wound repair. A scratch-wound repair assay was carried out in cultured human microvascular endothelial cells (HMEC-1) with and without different concentrations of DHA or EPA. The effect of DHA and EPA on HMEC-1 proliferation was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The effect of DHA and EPA on vegf mRNA expression was detected by real-time RT-PCR and vascular endothelial growth factor (VEGF) protein secretion by enzyme-linked immunosorbent assay. DHA and EPA dose-dependently suppressed HMEC-1 cell proliferation and wound repair. DHA and EPA treatment did not induce significant HMEC-1 cell death. The treatment, however, significantly suppressed vegf mRNA expression and protein secretion in both normoxia and hypoxia culture conditions. The addition of exogenous VEGF prevented DHA- and EPA-mediated suppression of HMEC-1 cell proliferation. DHA and EPA have anti-angiogenic effect partially through vegf suppression. The use of DHA and EPA may benefit angiogenic diseases, but may have potential side effects to patients undergoing revascularisation therapy. Further studies will be required to confirm the effect of n-3 PUFAs on vascular repair.     

Modulation of the atrial specific Kv1.5 channel by the n-3 polyunsaturated fatty acid, alpha-linolenic acid

Epidemiological, clinical and experimental studies suggest that the cardioprotective effect of fish intake is mainly due to the antiarrhythmic properties of marine n-3 polyunsaturated fatty acids (PUFA), which modulate ion currents. Emerging evidences point to similar effects of α-linolenic acid (ALA), a vegetable n-3 PUFA, but much less is known about its effects on the specific cardiac ion channels. Using electrophysiology, protein biochemistry and fluorescence anisotropy measurements, we tested the effects of ALA on the atrial specific Kv1.5 channel. In stably transfected Ltk⁻ cells, ALA blocked Kv1.5 channels in a time- and voltage-dependent manner with an IC₅₀ value of 3.7 ± 0.3 μM. ALA at 2.5 μM inhibited the Kv1.5 current, shifted the midpoint of the activation curve by − 8.8 ± 4.3 mV (p < 0.05), accelerated the activation kinetics of Kv1.5 due to a negative shift in its voltage dependency and slowed its deactivation process. Marine n-3 PUFA eicosapentaenoic and docosahexaenoic (EPA and DHA) acids, but not ALA, reduced the steady-state levels of Kv1.5 protein. DHA, but not ALA, increased the cell membrane order parameter. These results demonstrate that ALA directly blocks atria-specific Kv1.5 channels without modifying their expression or the bilayer order. Together, these effects suggest that the antiarrhythmic potential of diets enriched with plant-derived n-3 PUFA result, in part, from direct effects on cardiac ion channels.     

Docosahexaenoic Acid (DHA) But Not Eicosapentaenoic Acid (EPA) Prevents Trans-10, Cis-12 Conjugated Linoleic Acid (CLA)-Induced Insulin Resistance in Mice

Background: The objective of this study was to investigate if eicosapentaenoic acid (20:5n-3, EPA) or docosahexaenoic acid (22:6n-3, DHA) or both would prevent conjugated linoleic acid (CLA)-induced insulin resistance and fatty liver. Methods: Eight-week-old, pathogen-free C57BL/6N female mice (10 per group) were fed either a control diet or diets containing t10, c12-CLA (0.5 wt %), CLA + DHA (0.5% + 1.5 wt %), or CLA + EPA (0.5% + 1.5 wt %) for 8 weeks prior to sacrifice and tissue collection. Results: CLA supplementation caused an 8.9-fold increase in circulating insulin, a 2.6-fold increase in liver weight, and a 6.2-fold increase in the weight of total lipids in the liver as compared with the corresponding values in the control group. DHA prevented the CLA-induced insulin resistance, while EPA was ineffective. Both EPA and DHA prevented CLA-induced fatty liver and reduced weights of total liver lipids to the levels of the control group. CLA also reduced the plasma leptin and adiponectin concentrations to approximately 15% of those in the control group. Both EPA and DHA partially restored the CLA-induced decrease in leptin, but only DHA partially restored the plasma adiponectin. Conclusions: Our results suggest that DHA but not EPA in fish oils may reduce insulin resistance which may be mediated through an increase in circulating adiponectin. These findings may have clinical implications in the dietary management of patients at risk of insulin resistance and diabetes.     

Aging decreases rate of docosahexaenoic acid synthesis-secretion from circulating unesterified α-linolenic acid by rat liver

Docosahexaenoic acid (DHA, 22:6n-3), an n-3 polyunsaturated fatty acid (PUFA) found at high concentrations in brain and retina and critical to their function, can be obtained from fish products or be synthesized from circulating α-linolenic acid (α-LNA, 18:3n-3) mainly in the liver. With aging, liver synthetic enzymes are reported reduced or unchanged in the rat. To test whether liver synthesis-secretion of DHA from α-LNA changes with age, we measured whole-body DHA conversion coefficients and rates in unanesthetized adult male Fischer-344 rats aged 10, 20, or 30 months, fed an eicosapentaenoic acid (EPA, 20:5n-3)- and DHA-containing diet. Unesterified [U- ¹³?C]α-LNA bound to albumin was infused intravenously for 2 h, while [¹³?C]-esterified n-3 PUFAs were measured in arterial plasma, as were unlabeled unesterified and esterified PUFA concentrations. Plasma unesterified n-3 PUFA concentrations declined with age, but esterified n-3 PUFA concentrations did not change significantly. Calculated conversion coefficients were not changed significantly with age, whereas synthesis-secretion rates (product of conversion coefficient and unesterified plasma α-LNA concentration) of esterified DHA and n-3 DPA were reduced. Turnovers of esterified n-3 PUFAs in plasma decreased with age, whereas half-lives increased. The results suggest that hepatic capacity to synthesize DHA and other n-3 PUFAs from circulating α-LNA is maintained with age in the rat, but that reduced plasma α-LNA availability reduces net synthesis-secretion. As unesterified plasma DHA is the form that is incorporated preferentially into brain phospholipid, its reduced synthesis may be deleterious to brain function in aged rats.     

Dietary sesamin and docosahexaenoic and eicosapentaenoic acids synergistically increase the gene expression of enzymes involved in hepatic peroxisomal fatty acid oxidation in rats

The interaction of sesamin, one of the most abundant lignans in sesame seed, and highly purified docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) in the form of ethyl ester in affecting hepatic fatty acid oxidation was examined in rats. In the first experiment, 3 groups of rats were fed with purified experimental diets free of n-3 fatty acid ethyl ester and containing 0%, 0.2%, and 0.4% sesamin (1:1 mixture of sesamin and episesamin), and 2 groups of animals were fed with a 2% DHA ethyl ester diet containing either 0% or 0.2% sesamin. In the second trial, 4 groups of rats were fed with either a 0% or a 2% EPA ethyl ester diet containing 0% or 0.2% sesamin. After 15 days of feeding, DHA and EPA ethyl esters added to a sesamin-free diet little affected the activity and messenger RNA (mRNA) levels of various enzymes involved in fatty acid oxidation. Sesamin increased the activity levels of various hepatic enzymes involved in fatty acid oxidation irrespective of the presence or absence of n-3 fatty acid ethyl ester in diets. However, the diet containing sesamin and DHA or EPA ethyl ester in combination increased many of these parameters synergistically. In particular, the peroxisomal palmitoyl-coenzyme A oxidation rate and acyl-coenzyme A oxidase activity level were much higher in rats fed with sesamin and DHA or EPA in combination than in animals fed with a diet free of n-3 fatty acid ethyl ester and containing sesamin. Analyses of mRNA levels revealed that a diet simultaneously containing sesamin and n-3 fatty acid ethyl ester increased the gene expression of various enzymes involved in peroxisomal fatty acid oxidation in a synergistic manner. However, the combination of sesamin and n-3 fatty acid ethyl esters was ineffective in causing a synergistic increase in mRNA levels of enzymes of mitochondrial fatty acid oxidation, microsomal cytochrome P-450 IV A1, and cytosolic liver-type fatty acid-binding protein. It was concluded that sesamin and DHA or EPA ethyl ester synergistically increased hepatic fatty acid oxidation primarily through up-regulation of the gene expression of peroxisomal fatty acid oxidation enzymes. The results essentially reproduced those observed in our previous study with a diet containing both fish oil and sesamin despite the fact that DHA and EPA ethyl esters were much less effective than fish oil in increasing hepatic fatty acid oxidation.     

Pretreatment with n-6 PUFA protects against subsequent high fat diet induced atherosclerosis--potential role of oxidative stress-induced antioxidant defense

ObjectivesRecent evidence suggests that oxidative stress can promote antioxidant defense and thus be athero-protective. n-6 polyunsaturated fatty acids (n-6 PUFA) are more prone to oxidation, compared to monounsaturated fatty acids (MUFA) and yet have proven anti-atherosclerotic effects. In this study, we tested whether early exposure to a diet rich in n-6 PUFA, compared to a MUFA rich diet would reduce lesion burden, even with subsequent exposure to a high fat, high cholesterol diet (HF). Further, we tested to determine whether oxidative mechanisms are involved in such protection.Methods and resultsTwenty four, 4 week old, male, LDL receptor knockout (LDL-R^?/?) mice were divided into two groups and fed either a n-6 PUFA rich or a MUFA rich diet for a period of 12 weeks. At this point, 4 mice from each group were euthanized and the remaining 8 mice from each group were fed a HF diet for four weeks. Atherosclerotic lesions, plasma lipids, autoantibodies to lipid peroxide modified proteins, isoprostanes and aortic catalase levels were measured. The n-6 PUFA diet reduced aortic lesions and plasma lipids compared to the MUFA diet and this reduction in lesions continued even after the mice were switched over to the HF diet, despite the fact that the plasma lipids were similar in both groups after the HF diet. n-6 PUFA fed mice had highest plasma isoprostane levels, indicating oxidative stress, but also had higher levels of aortic catalase. On the other hand, MUFA fed mice had comparatively lower levels of isoprostanes and their aortic catalase levels remained low. Finally, aortic lesions were negatively correlated with isoprostanes and catalase.ConclusionAn initial exposure to a n-6 PUFA rich diet compared to a MUFA rich diet reduces atherosclerotic lesions and this protection probably involves oxidative stress induced by PUFA.     

Dietary fatty acids intake: possible role in cognitive decline and dementia

There is a recent increase in the level of interest in the possible role of dietary fatty acids in age-related cognitive decline, and cognitive impairment of both degenerative (Alzheimer's disease, AD) or vascular origin. At present, several studies suggested that an increase of saturated fatty acids (SFA) could have negative effects on cognitive functions. Furthermore, a clear reduction of risk of cognitive decline has been found in a population sample with a high intake of polyunsaturated fatty acids (PUFA) and monounsaturated fatty acids (MUFA). These findings were confirmed by studies in which high intakes of n-6 PUFA, n-3 PUFA, MUFA, and weekly fish consumption, providing large amount of n-3 PUFA, appear to be protective against the risk of AD. In our elderly population from Southern Italy, elevated unsaturated fatty acids intake (MUFA and PUFA), high levels of antioxidant compounds, and very low SFA intake could act synergistically in improving cognitive performance. Epidemiological studies on the association between diet and cognitive decline suggested a possible role of fatty acids intake in maintaining adequate cognitive functioning and possibly in preventing or delaying the onset of dementia, both of degenerative or vascular origin. Appropriate dietary measures or supplementation with specific micro- and macronutrients might open new ways for the prevention and management of cognitive decline and dementia.     

Effects of lipid-lowering diets enriched with monounsaturated and polyunsaturated fatty acids on serum lipoprotein composition in patients with hyperlipoproteinaemia.

Controlled comparisons of the effects of monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) as a part of lipid-lowering diets in persons with hyperlipoproteinaemia are sparse. The present study was carried out at a metabolic ward. Forty hyperlipidaemic patients (25 hypercholesterolaemic and 15 hypertriglyceridaemic) were given a 3-week diet rich in either MUFA (saturated fatty acids 7.3 energy% (E%), MUFA 14.6 E%, PUFA 4.8 E%) or PUFA (saturated fatty acids 7.8 E%, MUFA 8.4 E%, PUFA 10.4 E%), but otherwise with an identical composition. The mean serum cholesterol reduction on the MUFA diet was 12% (P < 0.001), with a low density lipoprotein cholesterol reduction of 11% (P < 0.001). The corresponding reductions on the PUFA diet were 15% (P < 0.001) and 16% (P < 0.001). The serum apolipoprotein B and A-I concentrations decreased highly significantly by 13% and 11% on the MUFA diet and by 14% and 11% on the PUFA diet. None of these changes differed between the two diets. Neither were there any differences between the diets regarding the effects on blood glucose, serum insulin and plasma fibrinogen, but there was a significant decrease in serum insulin with a significant reduction of the insulin/glucose ratio after the MUFA diet. The results of this study indicate that MUFA and PUFA are interchangeable within the given frames in lipid lowering diets even in patients with hyperlipidaemia.     

Changes in phospholipid fatty acid composition of mouse cardiac organelles after feeding graded amounts of docosahexaenoate in presence of high levels of linoleate. Effect on cardiac ATPase activities

Mice were fed diets containing a constant supply of linoleic acid (18:2n-6, LA) as ethyl ester representing 5% by weight of the total fat (5 wt%), in combination with graded amounts of purified docosahexaenoate (22:6n-3, DHA). Cardiac sarcoplasmic reticulum (SR) and mitochondrial phospholipids (PL) from mice fed the diet without DHA contained higher levels of n-6 long chain polyunsaturated fatty acids (PUFA) (22:4n-6 and 22:5n-6) compared to total PL of liver. In the cardiac mitochondrial PL, the level of LA, DHA, the total content of PUFA and the P/S ratio were significantly higher than in SR. A small increase in dietary DHA from 0 to 0.43 wt% induced a 3.6-fold increase in PL DHA content from both cardiac organelles, with a concurrent reduction of n-6 PUFA. The changes in fatty acid PL composition were much more moderate when dietary DHA level was increased to 0.85 and 3.74 wt%. Feeding the lowest amount of DHA resulted in a 6-fold decrease in the value of n-6/n-3 PUFA ratio and a 3.5-fold decrease in the value of 20 carbon chain/22 carbon chain PUFA ratio. DHA was readily depleted from cardiac PL, and only arachidonic acid was retained in the PL from both organelles, after feeding a fat-deficient diet. Despite these drastic modifications in PL fatty acid composition, the maximum velocity (Vm) of SR Ca2+, Mg2+-ATPase was not affected, which indicates that SR cardiac membrane adapts to changes in fatty acid composition to prevent important modifications of its functional properties. However, the Vm of mitochondrial oligomycin-sensitive ATPase was slightly increased in mice fed the lowest amount of DHA. This might be due to an increase in P/S ratio and/or to a modification of cardiolipin fatty acid composition, since this PL is required for optimum function of this enzyme. It is concluded that DHA is strongly taken up by mouse cardiac PL, even in the presence of high dietary LA levels, but its acylation into PL has only little effect on the cardiac ATPase activities.     

Dietary trans-fatty acids alter adipocyte plasma membrane fatty acid composition and insulin sensitivity in rats

The present study was designed to investigate the effects of dietary trans-fatty acids (TFA) present in Indian vanaspati (partially hydrogenated vegetable oils) in comparison with saturated fatty acids (SFA) on adipocyte plasma membrane fatty acid composition, fluidity, and insulin action. The effects of 3% energy (% en) TFA was studied at 2% and 4% en of linoleic acid (18:2 n-6). WNIN male weanling rats were divided into 4 groups and fed casein-based diet containing 10% groundnut oil control (CON), palmolein (SFA), blend of vanaspati and safflower oil (3% en TFA and 2% en 18:2 n-6, TFA-1), or blend of vanaspati and safflower oil (3% en TFA and 4% en 18:2 n-6, TFA-2) for 12 weeks. Compared with CON, rats fed TFA and SFA diets had high levels of fasting plasma insulin and triglycerides. Both TFA- and SFA-fed groups had low levels of arachidonic acid (20:4 n-6) in adipocyte plasma membrane phospholipids. However, adipocyte plasma membrane fluidity decreased only in TFA-fed rats. Norepinephrine-stimulated lipolysis was high, whereas the antilipolytic effect of insulin and insulin-stimulated glucose transport were low in the adipocytes of SFA- and TFA-fed rats. However, the extent of decrease in the antilipolytic effect of insulin and insulin-stimulated glucose transport was greater in TFA-fed rats. These findings suggest that diet providing approximately 10% en SFA (PUFA/SFA [P/S] ratio 0.2) decreased adipocyte insulin sensitivity in rats. In these diets, replacement of approximately 2% en SFA (16:0) and approximately 1% en monounsaturated fatty acid (18:1 cis) with TFA decreased adipocyte insulin sensitivity to a greater extent. However, increasing dietary 18:2 n-6 did not prevent or reduce the TFA-induced adipocyte insulin resistance.     

Relationship between circulating n-3 fatty acid concentrations and endothelial function in early adulthood.

AIMS: Fish consumption is inversely associated with cardiovascular mortality, presumably because of n-3 fatty acids in fish. Whether the protection of n-3 fatty acids extends beyond clinical coronary disease to influence the early vascular biology of atherosclerosis remains unclear. This study determined whether circulating levels of n-3 fatty acids are associated with vascular endothelial function in early adulthood. METHODS AND RESULTS: Three hundred and twenty-six adults (157 males, 169 females, aged 20 to 28 years) had high-resolution ultrasound measurements of flow-mediated brachial artery dilatation (FMD) (endothelium-dependent) and arterial response to glyceryl trinitrate (endothelium-independent). Levels of the n-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid in plasma and erythrocyte membranes of subjects were measured. n-3 Fatty acid levels were not related to vascular function in the whole group. In smokers, however, n-3 fatty acids were positively related to flow-mediated dilatation (plasma DHA vs. FMD: 0.045 mm. %(-1), 95% CI 0.011 to 0.079, P=0.01). Flow-mediated dilatation was also associated with n-3 fatty acid levels in subjects in the top third of the insulin, glucose and triglyceride distributions. CONCLUSION: In young smokers and those with higher fasting insulin, glucose or triglyceride concentrations (factors associated with endothelial dysfunction), n-3 fatty acid levels were positively associated with flow-mediated dilatation. This raises the possibility that physiological levels of circulating n-3 fatty acids may protect the endothelium from early adulthood.     

Plasma polyunsaturated fatty acid profile and delta-5 desaturase activity are altered in patients with type 2 diabetes

Objective

The association between imbalance of polyunsaturated fatty acids (PUFAs), especially low plasma n-3 to n-6 PUFA ratio, and risk of cardiovascular diseases is well known. A balance of plasma PUFAs is determined not only by dietary fatty acid intake, but also by the endogenous fatty acid metabolism, which could be dysregulated by diabetes. In this study, we investigated the plasma n-3 and n-6 PUFA profile and fatty acid desaturase activity in patients with type 2 diabetes (T2D).

Materials/Methods

The subjects were 396 patients with T2D and 122 healthy controls. Plasma eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA), and dihomo-γ-linolenic acid (DGLA) levels were measured by capillary gas chromatography.

Results

Plasma DHA, AA, and DGLA levels were significantly higher, and EPA levels tended to be lower in patients with T2D than in the controls. Patients with T2D also exhibited significantly lower EPA/AA, DHA/AA, and (EPA + DHA)/AA ratios, and a higher AA/DGLA ratio than the controls. Multiple regression analyses, including age, sex, body mass index, and metabolic parameters in the total population, revealed that the presence of T2D was independently associated with elevated plasma DHA, AA, and DGLA levels and decreased EPA/AA, DHA/AA, and (EPA + DHA)/AA ratios. Furthermore, T2D was independently and positively related to the AA/DGLA ratio, which serves as an estimate of delta (Δ)-5 desaturase activity.

Conclusions

Elevated plasma AA levels and decreased n-3 PUFA/AA ratios in T2D are attributable, at least partly, to Δ5 desaturase activation.     

Dietary lipids and NAFLD: suggestions for improved nutrition

Non-alcoholic fatty liver disease (NAFLD) ranges from steatosis and hepatic insulin resistance to non-alcoholic steatohepatitis (NASH), advanced fibrosis and cirrhosis. NAFLD is now considered as the hepatic manifestation of the metabolic syndrome, and both are triggered by mechanisms including inflammation, lipid overload and oxidative stress in adipose tissue and liver. Despite accumulation of numerous data on NAFLD physiopathology, therapeutic modulation of the pathways involved appear insufficiently efficient or associated with serious adverse effects. The increased prevalence of NAFLD and metabolic syndrome during the last decades was associated with deep modifications of dietary habits, especially increased fat intakes. Recent literature provides clues of increased saturated (SFA) and n-6 polyunsaturated fatty acids (PUFA) as well as reduced n-3 PUFA in the diet of NAFLD and NASH patients. Indeed, strong data support the detrimental role of high SFA and n-6/n-3 ratio as well as low monounsaturated fatty acids (MUFA) and n-3 PUFA on metabolic parameters, which are ameliorated by administration of n-3 PUFA and MUFA. Despite governments and health associations having revised their recommendations for n-3 PUFA intakes upward during the last decade, those are still inferior to levels proved of therapeutic efficiency and are still not reached in the general population. This short review discusses these issues and provides consequent pragmatic suggestions for enhanced dietary measures for prevention of NAFLD and metabolic syndrome in the general population.     

The effect of LXRα, ChREBP and Elovl6 in liver and white adipose tissue on medium- and long-chain fatty acid diet-induced insulin resistance

Aims

We aimed to investigate the effects of LXRα, ChREBP and Elovl6 in the development of insulin resistance-induced by medium- and long-chain fatty acids.

Methods

Sprague Dawley rats were fed a standard chow diet (Control group) or a high-fat, high sucrose diet with different fat sources (coconut oil, lard, sunflower and fish oil) for 8 weeks. These oils were rich in medium-chain saturated fatty acids (MCFA group), long-chain saturated fatty acids (LCFA group), n-6 and n-3 long-chain polyunsaturated fatty acids (n-6 PUFA and n-3 PUFA groups), respectively, which had different chain lengths and degrees of unsaturation. Hyperinsulinemic–euglycemic clamp with [6-³H] glucose infusion was performed in conscious rats to assess hepatic insulin sensitivity.

Results

LCFA and n-6 PUFA groups induced hepatic insulin resistance and increased liver X receptor α (LXRα), carbohydrate response element binding protein (ChREBP) and long-chain fatty acid elongase 6 (Elovl6) expression in liver and white adipose tissue (WAT). Furthermore, LCFA and n-6 PUFA groups suppressed Akt serine 473 phosphorylation in liver and WAT. By contrast, in liver and WAT, MCFA and n-3 PUFA groups decreased LXRα, ChREBP and Elovl6 expression and improved insulin signaling and insulin resistance, but Akt serine 473 phosphorylation was not restored by MCFA group in WAT.

Conclusions

This study demonstrated that the mechanism of the different effects of medium- and long-chain fatty acids on hepatic insulin resistance involves LXRα, ChREBP and Elovl6 alternations in liver and WAT. It points to a new strategy for ameliorating insulin resistance and diabetes through intervention on Elovl6 or its control genes.     

Regulation of plasma immunoreactive glucagon in obese hyperglycaemic (ob/ob) mice

This study examines the role of glucagon in the pathogenesis of the obese hyperglycaemic (ob/ob) syndrome in mice. Plasma C-terminal immunoreactive glucagon concentrations were measured in fed and fasted ob/ob mice at different ages between 5-40 weeks, and in 20-week-old mice after the administration of established stimulators and inhibitors of glucagon secretion. Plasma glucagon concentrations were inappropriately raised irrespective of age, nutritional status and the accompanying prominent changes in plasma glucose and insulin concentrations. Glucose suppressed plasma glucagon in the fed but not the fasted state, suggesting a dependence on the marked hyperinsulinaemia associated with feeding. Administration of 0.25 units insulin/kg to fasted mice failed to affect plasma glucagon and glucose concentrations. Increasing the dose to 100 units/kg restored the normal suppressive actions of insulin. Fasted mice showed an exaggerated glucagon response to arginine but not to the parasympathomimetic agent pilocarpine. Fed mice displayed normal plasma glucagon responses to the sympathomimetic agents noradrenaline and adrenaline. Administration of insulin antiserum or 2-deoxy-D-glucose raised plasma glucagon concentrations of fed mice. Contrary to the lack of suppression by glucose in the fasted state, heparin-induced increase in free fatty acids reduced plasma glucagon concentrations. This study demonstrates inappropriate hyperglucagonaemia and defective A-cell function in ob/ob mice. The extent of the abnormality is exacerbated by fasting and appears to result from insensitivity of the A-cell to the normal suppressive action of insulin.     

Evidence that free polyunsaturated fatty acids modify Na+ channels by directly binding to the channel proteins.

The effects of free polyunsaturated fatty acids (PUFA) on the binding of ligands to receptors on voltage-sensitive Na+ channels of neonatal rat cardiac myocytes were assessed. The radioligand was [benzoyl-2,5-(3)H] batrachotoxinin A 20alpha-benzoate ([(3)H]BTXB), a toxin that binds to the Na+ channel. The PUFA that have been shown to be antiarrhythmic, including eicosapentaenoic acid (EPA; C20:5n-3), docosahexaenoic acid (DHA; C22:6n-3), eicosatetraynoic acid (ETYA), linolenic acid (C18:3n-3), and linoleic acid (C18:2n-6), inhibited [(3)H]BTXB binding in a dose-dependent fashion with IC50 values of 28-35 microM, whereas those fatty acids that have no antiarrhythmic effects including saturated fatty acid (stearic acid, C18:0), monounsaturated fatty acid (oleic acid; C18:1n-9), and EPA methyl ester did not have a significant effect on [(3)H]BTXB binding. Enrichment of the myocyte membrane with cholesterol neither affected [(3)H]BTXB binding when compared with control cells nor altered the inhibitory effects of PUFA on [(3)H]BTXB binding. Scatchard analysis of [(3)H]BTXB binding showed that EPA reduced the maximal binding without altering the Kd for [(3)H]BTXB binding, indicating allosteric inhibition. The inhibition by EPA of [(3)H]BTXB binding was reversible (within 30 min) when delipidated bovine serum albumin was added. The binding of the PUFA to this site on the Na+ channel is reversible and structure-specific and occurs at concentrations close to those required for apparent antiarrhythmic effects and a blocking effect on the Na+ current, suggesting that binding of the PUFA at this site relates to their antiarrhythmic action.     

Extending the cardiovascular benefits of omega-3 fatty acids

The cardiovascular benefits of omega (n)-3 fatty acids (FA) become clearer with each passing year. Although useful in large doses for lowering serum triglyceride levels, the primary benefits are likely to arise from smaller, nutritional intakes of eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA). Doses of less than 1 g/d appear to reduce risk for fatal coronary heart disease events, perhaps by stabilizing the myocardium and reducing risk for fatal arrhythmias. New evidence points to a possible benefit on atrial fibrillation, particularly in the immediate post-cardiac surgery setting. Studies in women with coronary heart disease now suggest that plaque progression may be slowed by increased intakes of oily fish, even in women with diabetes. The relative importance of the n-6 FA linoleic acid (LA), the short-chain n-3 FA alpha linolenic acid (ALA), and the long-chain n-3 FAs EPA and DHA is becoming clearer. If intakes of the latter are adequate (perhaps over 250 mg/d), then there appears to be little need to consume more ALA or less LA.