Essential fatty acid metabolism in patients with essential hypertension, diabetes mellitus and coronary heart disease

Mortality and morbidity from coronary heart disease (CHD), diabetes mellitus (DM) and essential hypertension (HTN) are higher in people of South Asian descent than in other groups. There is evidence to believe that essential fatty acids (EFAs) and their metabolites may have a role in the pathobiology of CHD, DM and HTN. Fatty acid analysis of the plasma phospholipid fraction revealed that in CHD the levels of gamma-linolenic acid (GLA), arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are low, in patients with HTN linoleic acid (LA) and AA are low, and in patients with non-insulin dependent diabetes mellitus (NIDDM) and diabetic nephropathy the levels of dihomo-gamma-linolenic acid (DGLA), AA, alapha-linolenic acid (ALA) and DHA are low, all compared to normal controls. These results are interesting since DGLA, AA and EPA form precursors to prostaglandin E₁, (PGE₁), prostacyclin (PGI₂), and PGI₃, which are potent platelet anti-aggregators and vasodilators and can prevent thrombosis and atherosclerosis. Further, the levels of lipid peroxides were found to be high in patients with CHD, HTN, NIDDM and diabetic nephropathy. These results suggest that increased formation of lipid peroxides and an alteration in the metabolism of EFAs are closely associated with CHD, HTN and NIDDM in Indians. Since insulin resistance and hyperinsulinemia and features of obesity, NIDDM, HTN and CHD, diseases that are common in Indians, and as decreased insulin sensitivity is associated with decreased concentrations of polyunsaturated fatty acids (PUFAs) in skeletal muscle phospholipids and, possibly, in the plasma, the possibility is raised that changes in the metabolism of EFAs may have a fundamental role in the pathobiology of these conditions. If this is true, this suggests that supplementation of GLA, DGLA, AA, EPA and/or DHA may be indicated to prevent CHD, HTN and NIDDM in Indians.     

Studies of the modulation of essential fatty acid metabolism by fatty acids in cultured neuroblastoma and glioma cells

In cultured neuroblastoma cells (N1E-115), the metabolism of the essential fatty acid, linoleic acid (18:2 (n-6)), to arachidonic acid (20:4(n-6)) can be altered by other fatty acids in a manner supporting a concerted action of the modulating fatty acid on the desaturation and chain elongation enzymes. In further examination of mechanisms involved, cultured glioma (C-6) or neuroblastoma-glioma hybrids (NG-108-15) cells showed similar patterns of activation by some fatty acids (e.g., 20:3(n-6) and 20:4(n-6)), and inhibition (e.g., 18:3(n-3) or 22:6(n-3)) or no effect (e.g., 18:1(n-9), 20:3(n-3)) by others. In contrast, only inhibition by 20:4(n-6) was seen in cultured HeLa cells, suggesting that the intracellular interactions may not be universal in all cell lines. For fatty acids that activate 20:4(n-6) formation, the lag observed when substrate and activator were administered simultaneously was eliminated by preincubation with activator. Maximal activation occurred within 4 h for neuroblastoma and 2 h for glioma; in each cell line activation declined steadily for 10 h after removal of the activator. Inhibition of protein synthesis did not alter activation. As 98% of the fatty acid incorporated was esterified to triacylglycerol or phospholipid and only the triacylglycerol mass expanded, several manipulations to potentially alter the flow of acyl chains between these lipid pools were evaluated using dual-label and pulse-chase experiments. Results suggested that competition between 18:2(n-6) utilization for esterification to phospholipid and the desaturation-chain elongation sequence as well as a more direct and specific interaction of certain fatty acids with the enzymes may influence 20:4(n-6) formation. A model to explain these observations is discussed.     

Sex differences in the metabolism of essential fatty acids studied in isolated rat liver cells

The triacylglycerol synthesis from exogenous linoleic acid (18:2(n-6], linolenic acid (18:3(n-3], dihomogammalinolenic acid (20:3(n-6], eicosapentaenoic acid (20:5(n-3] and oleic acid (18:1(n-9] was observed to be significantly increased in isolated liver cells from female rats compared with males. The rate of fatty acid oxidation and phospholipid biosynthesis was concomitantly more important in male cells. With the C22-polyenoic fatty acids, adrenic acid (22:4(n-6] and docosahexaenoic acid (22:6(n-3), only a minor sex-related difference in fatty acid metabolism was found.     

肠道短链脂肪酸与2型糖尿病相关性研究进展

2型糖尿病(type 2 diabetes,T2DM)是一种以高血糖为特征的代谢性疾病.随着经济的发展,人们的生活方式发生了巨大的变化,T2DM患者数量不断增加.T2DM的发病机制复杂,与遗传、环境、年龄、种族及生活方式等密切相关.近年来,许多研究表明肠道菌群通过多种途径参与T2DM的发生,其中短链脂肪酸起着主要作用....     

Brain metabolism of nutritionally essential polyunsaturated fatty acids depends on both the diet and the liver

Plasma alpha-linolenic acid (alpha-LNA, 18:3n-3) and linoleic acid (LA, 18:2n-6) do not contribute significantly to the brain content of docosahexaenoic acid (DHA, 22:6n-3) or arachidonic acid (AA, 20:4n-6), respectively, and neither DHA nor AA can be synthesized de novo in vertebrate tissue. Therefore, measured rates of incorporation of circulating DHA and AA into brain exactly represent their rates of consumption by brain. Positron emission tomography (PET) has been used to show, based on this information, that the adult human brain consumes AA and DHA at rates of 17.8 and 4.6 mg/day, respectively, and that AA consumption does not change significantly with age. In unanesthetized adult rats fed an n-3 PUFA "adequate" diet containing 4.6% alpha-LNA (of total fatty acids) as its only n-3 PUFA, the rate of liver synthesis of DHA was more than sufficient to maintain brain DHA, whereas the brain's rate of DHA synthesis is very low and unable to do so. Reducing dietary alpha-LNA in the DHA-free diet led to upregulation of liver but not brain coefficients of alpha-LNA conversion to DHA and of liver expression of elongases and desaturases that catalyze this conversion. Concurrently, brain DHA loss slowed due to downregulation of several of its DHA-metabolizing enzymes. Dietary alpha-LNA deficiency also promoted accumulation of brain docosapentaenoic acid (22:5n-6), and upregulated expression of AA-metabolizing enzymes, including cytosolic and secretory phospholipases A(2) and cyclooxygenase-2. These changes, plus reduced levels of brain derived neurotrophic factor (BDNF) and cAMP response element-binding protein (CREB) in n-3 PUFA diet deficient rats, likely render their brain more vulnerable to neuropathological insults.     

Effect of glucose ingestion on the metabolism of free fatty acids in human subjects

The rate of appearance of (14)CO(2) in expired air after the injection of a single dose of NaH(14)CO(3) has been determined in normal individuals both in the fasted and fed states. These data were combined with previously obtained results on the rate of disappearance of injected palmitate-(14)C from the bloodstream, to give a multicompartmental analysis of free fatty acid oxidation and esterification. The results confirm that glucose feeding promptly inhibits the rate of free fatty acid oxidation to CO(2). The "irreversible disposal rate," or irreversible flux of free fatty acids from the plasma, was also consistently reduced by glucose feeding. The diminution in irreversible disposal, not accounted for entirely by reduction of direct oxidation, must indicate suppression of other disposal mechanisms, including net esterification of free fatty acids. An average drop of 49% in "net esterification" when glucose was given may be compared with the 65% inhibition of rapid free fatty acid oxidation.     

Differential effect of saturated, monounsaturated, and polyunsaturated fatty acids on alloxan-induced diabetes mellitus

Earlier, we reported that oils rich in omega-3 eicosapentaenoic acid and docosahexaenoic acid and omega-6 gamma-linolenic acid and arachidonic acid prevented the development of alloxan-induced diabetes mellitus in experimental animals. Here we report the results of our studies with pure saturated stearic acid (SA), monounsaturated oleic acid (OA) and omega-6 arachidonic acid (AA) on alloxan-induced diabetes mellitus in Wistar male rats. Prior oral supplementation with AA prevented alloxan-induced diabetes mellitus, whereas both SA and OA were ineffective. Cyclo-oxygenase (COX) and lipoxygenase (LO) inhibitors did not block this protective action of AA against alloxan-induced diabetes, suggesting that both prostaglandins and leukotrienes are not involved, and that AA by itself is effective. Furthermore, AA restored the anti-oxidant status to normal range in various tissues. These results suggest that AA protects pancreatic beta cells against alloxan-induced diabetes in experimental animals by attenuating oxidant stress.