The role of dietary oxidized cholesterol and oxidized fatty acids in the development of atherosclerosis

The etiology of atherosclerosis is complex and multifactorial but there is extensive evidence indicating that oxidized lipoproteins may play a key role. At present, the site and mechanism by which lipoproteins are oxidized are not resolved, and it is not clear if oxidized lipoproteins form locally in the artery wall and/or are sequestered in atherosclerotic lesions following the uptake of circulating oxidized lipoproteins. We have been focusing our studies on demonstrating that such potentially atherogenic oxidized lipoproteins in the circulation are at least partially derived from oxidized lipids in the diet. Thus, the purpose of our work has been to determine in humans whether oxidized dietary oxidized fats such as oxidized fatty acids and oxidized cholesterol are absorbed and contribute to the pool of oxidized lipids in circulating lipoproteins. When a meal containing oxidized linoleic acid was fed to normal subjects, oxidized fatty acids were found only in the postprandial chylomicron/chylomicron remnants (CM/RM) which were cleared from circulation within 8 h. No oxidized fatty acids were detected in low density lipoprotein (LDL) or high density lipoprotein (HDL) fractions at any time. However, when alpha-epoxy cholesterol was fed to human subjects, alpha-epoxy cholesterol in serum was found in CM/RM and also in endogenous very low density lipoprotein, LDL, and HDL and remained in the circulation for 72 h. In vitro incubation of the CM/RM fraction containing alpha-epoxy cholesterol with human LDL and HDL that did not contain alpha-epoxy cholesterol resulted in a rapid transfer of oxidized cholesterol from CM/RM to both LDL and HDL. We have suggested that cholesteryl ester transfer protein is mediating the transfer. Thus, alpha-epoxy cholesterol in the diet is incorporated into CM/RM fraction and then transferred to LDL and HDL contributing to lipoprotein oxidation. We hypothesize that diet-derived oxidized fatty acids in chylomicron remnants and oxidized cholesterol in remnants and LDL accelerate atherosclerosis by increasing oxidized lipid levels in circulating LDL and chylomicron remnants. This hypothesis is supported by our feeding experiments in animals. When rabbits were fed oxidized fatty acids or oxidized cholesterol, the fatty streak lesions in the aorta were increased by 100%. Moreover, dietary oxidized cholesterol significantly increased aortic lesions in apo-E and LDL receptor-deficient mice. A typical Western diet is rich in oxidized fats and therefore could contribute to the increased arterial atherosclerosis in our population.     

Effects of a rumen-protected mixture of conjugated linoleic acids on hepatic expression of genes involved in lipid metabolism in dairy cows

Supplementation of conjugated linoleic acids (CLA) reduces milk fat content in dairy cows and, thus, may be a useful dietary strategy to improve energy balance during early lactation. The present study was performed to investigate whether supplementation of CLA could have adverse effects on hepatic lipid metabolism such as observed in rodents. For this aim, 40 Holstein cows were allotted to 2 groups, which were fed daily 172 g of either a CLA-free, rumen-protected control fat (control group) or a rumen-protected CLA fat supplying 4.3g of cis-9,trans-11 CLA and 3.8 g of trans-10,cis-12 CLA per day (CLA group). To identify potential changes of lipid metabolism, expression of several genes involved in lipid metabolism was determined in liver biopsy samples taken at wk 5 of lactation, using a whole-genome gene chip. In the CLA group, milk fat content and daily milk fat yield were lower than in the control group. Milk yield was higher, whereas fat-corrected milk and energy-corrected milk were lower in the CLA group than in the control group. The CLA group, moreover, had an improved energy balance. To study potential effects of CLA on hepatic lipid metabolism, we considered 6 genes encoding fatty acid transporters, 7 genes involved in intracellular fatty acid transport, 21 and 7 genes, respectively, involved in mitochondrial and peroxisomal β-oxidation, 6 genes of carnitine metabolism, 3 genes of ketogenesis, 21 genes involved in fatty acid and triacylglycerol synthesis, 17 genes involved in cholesterol metabolism, and 20 genes involved in lipoprotein metabolism. None of these genes was differentially regulated between the CLA group and the control group. Gene chip data were confirmed by quantitative PCR analysis, which revealed no difference in the expression of key enzymes of various pathways such as lipogenesis, β-oxidation, and ketogenesis between the 2 groups of cows. In line with those findings, concentrations of triacylglycerols and cholesterol in liver and plasma were not different between the 2 groups of cows. In conclusion, the present study shows that CLA supplementation at a dose effective for milk fat depression does not induce adverse effects on hepatic lipid metabolism in dairy cows.     

虾青素对肝脂代谢与昼夜节律的调节作用

研究虾青素对非酒精性脂肪性肝病（non-alcoholic fatty liver disease,NAFLD）的干预作用及与代谢相关的昼夜节律紊乱的缓解作用。采用高脂/高胆固醇饲喂建立NAFLD小鼠模型和添加虾青素的干预模型。动物实验选用SPF级C57BL/6小鼠,随机分成正常组、高脂模型组和高脂添加虾青素组。采用常规酶联免疫吸附测定法测定血清中甘油三酯、总胆固醇（total cholesterol,TC）、高密度脂蛋白胆固醇（high density lipoprotein cholesterol,HDL-C）、低密度脂蛋白胆固醇（low density lipoprotein cholesterol,LDL-C）浓度及谷丙转氨酶（alanine aminotransferase,ALT）、谷草转氨酶（aspartate transaminase,AST）活力等肝损伤指标,苏木精-伊红染色法观察肝组织形态学变化,荧光定量聚合酶链式反应（real-time quantitative polymerase chain reaction,qPCR）检测与肝脂代谢、胆固醇代谢、昼夜节律相关的基因表达及昼夜节律变化。结果显示：与正常组相比,高脂模型组小鼠体质量、肝脏指数、肥胖指数均高度显著增加（P＜0.001）,虾青素干预后肝脏指数、肥胖指数均极显著降低（P＜0.01）。高脂饲喂导致小鼠血脂水平升高（HDL-C除外）,尤其是LDL-C浓度升高明显,而虾青素干预可以有效降低TC和LDL-C浓度,并升高HDL-C浓度,改善脂质的代谢。高脂/高胆固醇饲喂会高度显著升高小鼠血清ALT、AST活力（P＜0.001）,造成肝损伤。与高脂模型组相比,虾青素干预可极显著降低小鼠ALT、AST活力（P＜0.01）,缓解肝脏损伤,并明显改善肝脏脂质代谢关键酶的基因表达,包括脂肪酸合成酶和胆固醇合成关键酶羟甲基戊二酸单酰辅酶A还原酶。同时,虾青素干预也增加了胆固醇7α-羟化酶的表达量,促进胆固醇氧化。虾青素调节上述基因的表达具有昼夜节律性,能够缓解或修正由高脂导致的生物钟节律相关因子时钟昼夜节律调节器及脑和肌肉芳香烃受体核转运体样蛋白1以及肝脏脂质代谢关键基因昼夜节律表达的紊乱。本研究表明虾青素具有改善高脂所致肝代谢紊乱的节律性调节作用。     

The effect of taurine on cholesterol metabolism

The elevated plasma cholesterol level, in particular, LDL cholesterol is regarded as an important risk factor for the development of atherosclerosis and coronary artery disease. A number of studies provide the evidence that taurine has the efficient action to reduce plasma and liver cholesterol concentrations, especially to decrease VLDL and LDL cholesterol in hypercholesterolemia animal induced by high cholesterol diet. Cholesterol lowering effect of taurine is actually involved in the regulatory mechanism of cholesterol and bile acid homeostasis that mediated by CYP7A1, which has become a biomarker for cholesterol metabolism and itself is also regulated by several factors and nuclear receptors. This review summarizes the change of cholesterol concentration in metabolism observed in feeding studies of hypercholesterolemia animal dealing with taurine, and then, addresses the possible metabolic and molecular mechanisms of cholesterol lowering effect by taurine in three aspects, cholesterol clearance from blood circulation, bioconversion of cholesterol to bile acid in liver, and excretion of cholesterol and bile acid from intestine.     

Potential for enhancing the nutritional properties of milk fat.

Milk fat has been identified as a hypercholesterolemic fat because it contains cholesterol and is primarily saturated. However, different types of dietary saturated fats do not have equivalent effects on plasma cholesterol levels relevant to ingestion of polyunsaturated fats. Research suggests that the hypercholesterolemic effect of saturated fats in human diets is largely due to 12, 14, and 16 carbon chain length fatty acids. Evidence also suggests that stearic acid (C18:0) is as effective as oleic acid (C18:ln-9) in lowering plasma cholesterol levels when either replaces palmitic acid (C16:0) in the diet of men. Milk fat has a unique fatty acid profile with approximately 10% short- and medium-chain length saturated fatty acids (less than 12 carbons) and 35% of total fatty acids from stearic and oleic acids. The contribution of milk products to fat and cholesterol intake in the typical American diet is less than that provided by other animal products. This paper will review the recommendations of the National Cholesterol Education Program, the effects of milk fat ingestion on blood cholesterol, and the rationale and feasibility of three approaches to modifying the lipid composition of milk fat.     

摄入反式脂肪对大鼠脂质代谢的影响

人群跟踪调查表明,反式脂肪酸(trans fatty acids,TFA)增加冠心病危险及死亡率,可能主要通过影响血脂和炎症反应引起某些慢性疾病。实验在脂肪供能33%(目前中国居民膳食供能比)的情况下,通过 90d 的大鼠饲养实验探讨以TFA 为主的脂肪摄入对大鼠体内脂质代谢的影响。结果表明：与基础饲料对比,以TFA 为主的脂肪摄入显著升高大鼠血液甘油三酯(TG)含量,显著降低大鼠高密度脂蛋白胆固醇(HDL-C)含量,显著降低血浆肝素前脂蛋白脂酶(LPL)和肝脂酶(HL)的活力,显示TFA 可能改变大鼠脂肪酸代谢,引起甘油三酯代谢异常;TFA 同时显著降低大鼠血液血清总胆固醇(TC)和低密度脂蛋白胆固醇(LDL-C)含量,且对C 反应蛋白(CRP)没有影响,显著升高HDL-C/ LDL-C,表明以TFA 为主的脂肪摄入可能并不引起大鼠胆固醇代谢异常,这可能是由于除基础饲料外,植物油的摄入没有引入外源胆固醇,且大鼠本身缺乏胆固醇转移蛋白(CETP)。     

Relation of the lipid level of the blood plasma to the nature of the nutrition of the population

The incidence of disorders in the lipid and lipoprotein metabolism and the character of nutrition were studied in a non-organized population of males aged 20-59 (n-2888). Strictly standardized methods applicable in epidemiologic investigations were used. A reliable relationship has been revealed between the excessive consumption of fats, saturated fatty acids, cholesterol, saccharose, the insufficient content of polyunsaturated fatty acids, starch, ascorbic acid, retinol, and magnesium in the diets and the incidence of disorders in the lipid metabolism.     

山茶油对游离脂肪酸诱导的HepG2细胞脂质代谢的影响

目的:探究山茶油对游离脂肪酸诱导的HepG2细胞脂质代谢的影响。方法:首先,利用CCK8法测定不同浓度山茶油对HepG2细胞活性的影响以选定适宜浓度进行后续实验。其次,采用不同浓度山茶油对HepG2细胞进行24 h干预,再使用0.5 mmol/L游离脂肪酸处理24 h诱导建立脂肪肝细胞模型。然后,通过油红O染色法判断各组间的脂滴生成情况,并参照相关试剂盒测定各干预下细胞内脂质水平的变化情况。最后,通过qRT-PCR法测定细胞内脂质代谢相关基因的表达,以探讨山茶油调节脂质代谢的作用及其可能的机制。结果:与正常对照组相比,造模干预组细胞内的甘油三酯(TG)和低密度脂蛋白胆固醇(LDL-C)含量显著升高(P<0.05),高密度脂蛋白胆固醇(HDL-C)含量显著降低(P<0.05);与造模干预组相比,茶油预处理显著逆转了游离脂肪酸诱导细胞内TG、HDL-C和LDL-C含量的变化(P<0.05)。qRT-PCR结果表明,与造模干预组相比,山茶油预处理显著降低了游离脂肪酸诱导的HepG2细胞内脂肪酸转运酶(CD36)、固醇调节元件结合蛋白-1c(SREBP-1c)、脂肪酸合成酶(...     

Effects of dietary broccoli fibre and corn oil on serum lipids, faecal bile acid excretion and hepatic gene expression in rats

To determine the effects of broccoli fibre and corn oil on lipid metabolism, male Sprague-Dawley rats were fed diets containing high (30%) or low (5%) corn oil, in combination with either 7.5% broccoli fibre or cellulose, for 4 months. High corn oil groups had significantly lower serum cholesterol and triglycerides than had low corn oil groups (p < 0.001). Broccoli fibre also lowered serum cholesterol and triglyceride levels compared to cellulose fibre. Faecal bile acid concentrations were higher in high corn oil-fed rats than in low corn oil-fed rats, with broccoli fibre inclusion in high corn oil diets resulting in higher faecal bile acid concentrations. Regardless of corn oil level, broccoli fibre supplementation in the diet resulted in an increase (p = 0.018) in hepatic cytochrome P450, family 7A1 (CYP7A1) expression. High corn oil feeding resulted in reduced expression of fatty acid synthase (FAS) and increased expression of carnitine palmitoyl transferase 1a (CPT1a) and 3-hydroxy-3-methyl-coenzyme A reductase (HMGCR) (p < 0.05). Our findings suggest that high dietary corn oil and broccoli fibre have beneficial effects on lipid metabolism. Corn oil lipid-lowering effects may be due to alteration of hepatic expression of genes involved in lipid synthesis and increased rate of cholesterol catabolism to bile acids. Broccoli fibre may also act via its physical properties to reduce enterohepatic bile acid recycling and intestinal lipid absorption, and increase luminal binding of bile acids, resulting in increased faecal bile acid excretion.     

部分水解瓜尔豆胶对高脂高糖饮食诱导小鼠代谢紊乱的调节作用

部分水解瓜尔豆胶(partially hydrolyzed guar gum,PHGG)是一种有益于代谢平衡的可溶性膳食纤维,但其对糖脂代谢紊乱的调节效果及其潜在机制尚不明确.利用高脂高糖饮食诱导小鼠16周,使其产生明显的脂代谢紊乱和胰岛素抵抗,进一步通过检测小鼠糖耐量、血清生化指标、脂肪形态、肠道短链脂肪酸及相关mRNA的表达,考察PHGG对模型小鼠的糖脂代谢稳态及肠道环境的调节作用.结果表明:长期高脂高糖饮食条件下,PHGG组小鼠比模型组小鼠的体质量增长率减缓,空腹血糖降低,葡萄糖耐量和胰岛素耐量显著提升;血清中的甘油三酯、总胆固醇、低密度脂蛋白胆固醇和游离脂肪酸可分别降低21.56％、32.67％、25.66％和22.91％,明显抑制了脂肪积累.PHGG将肠道胰高血糖素样肽-1的分泌提升并恢复到67.76 pmol/L,盲肠中的丁酸含量比模型组提升了7.14倍.定量PCR显示,PHGG干预后小鼠短链脂肪酸受体GPR43的蛋白表达水平比模型组提升了63.30％.本研究表明,PHGG通过调节短链脂肪酸影响脂联素、胰岛素的分泌,进而改善高脂高糖饮食引起的糖脂代谢紊乱,可以应用于辅助糖脂代谢调控的功能性食品开发中.     

Fat assimilation and indicators of lipid metabolism in the blood of premature infants fed milk mixtures with different fat composition

The efficacy and adequacy of fat component depending on the feeding type (breast milk, Malyutka, Malyutka with a new fatty composition and Similak mixtures) were defined in the course of feeding 90 premature infants aged 33 to 37 weeks on the basis of clinical observations, determination of fat assimilation and the main indicators of lipid metabolism. All the mixtures were shown to be tolerated well. No significant differences were revealed in the mean daily weight gain and in the monthly body length gain. The children fed breast milk showed a higher assimilation of fats and an increase in the cholesterol level in the blood serum. The indicators of fat retention in children fed Similak and Malyutka with a new fatty composition mixtures were similar to those in children on natural feeding. The milk mixtures under consideration are found to be effective enough and thus can be used for feeding premature children born to mothers with hypo- and agalactia.     

Plasma Concentration and Lipid Composition of Lipoproteins in Lactating Dairy Cows Fed Control and High Grain Diets

Six multiparous Holstein cows ranging from 7 to 19 wk postpartum were in a switchback design to determine effects of feeding high grain diets on lipoprotein concentration and composition in blood. Percents concentrate, alfalfa haylage, and corn silage of control and high grain diets were 50, 83; 25, 9; and 25, 8 dry matter. Milk yield (kg/day), milk fat percentage, and fat yield (g/day) averaged 27.7, 3.58, 997 and 30.2, 2.45, 729 for control and high grain treatments. Very low density, low density, and high density lipoproteins were isolated by gel filtration of total lipoproteins obtained by ultracentrifugation. Lipoprotein concentrations in blood plasma of cows fed the control or high grain diets were similar. Triglyceride, phospholipid, cholesterol, and cholesterol ester contents of each lipoprotein class were not altered by treatment. High grain feeding increased octadecadienoic fatty acid content of low density and high density lipoprotein cholesterol esters and decreased octadecenoic and octadecatrienoic acids. The trend was similar for the very low density lipoprotein fraction. Phospholipid octadecenoic acid decreased in all lipoprotein fractions but only significantly for high density lipoproteins. It is unlikely that differences in lipid composition of plasma lipoproteins caused alterations in lipoprotein metabolism leading to fat depression in this and other similar studies.     

Lipid‐based fat substitutes

Fats and oils account for 38% of the total calories in the diet of Western populations, especially in the U.S. They provide the most concentrated source of energy, 9 kcal/g of a triacylglycerol molecule compared with 4 kcal/g provided by carbohydrate and protein. In response to consumer demands for low‐calorie or calorie‐free fats and their reluctance to give up the taste of fat, current research efforts have been directed toward the development of lipid‐like fat substitutes. These fat substitutes contain the fatty acids found in conventional fats and oils, with all the physical and organoleptic properties of fats, but provide few or no calories in the diet. Some of the fat substitutes are modified triacylglycerols (glycerol backbone) with reduced digestion and absorption; others are digestible and nondigestible carbohydrate fatty acid esters and polyesters, respectively. Sucrose polyester (Olestra^®), a sucrose molecule esterified with six to eight fatty acids, is the most studied of the lipid‐based fat substitutes containing a carbohydrate backbone. If approved by the FDA, sucrose polyester will find application in almost all fat‐containing foods. Specialty fats or fat substitutes targeted to certain individuals with special needs are being developed. Among these are the medium‐chain triacylglycerols and structured lipids (glycerol backbone), or “nutraceuticals” with reduced absorption and medical applications. Enzyme biotechnology is another tool available to lipid chemists to selectively modify, esterify, transform, transesterify, and interesterify fats and oils or synthesize new lipids such as structured lipids of food, nutritional, and medical importance. These designer fats may be the trend in the future to produce medical lipids that do not occur normally in nature. The different types of lipid‐based fat substitutes are reviewed with respect to their synthesis, analysis, metabolism, potential applications/uses, and the future of fat substitutes.     

Lipid Modification Strategies in the Production of Nutritionally Functional Fats and Oils

Rapid improvements in the understanding of the nutritional requirements of both infants and adults has led to new developments in the modification of fats and oils. Specific targets include the improvement in growth and development of infants, treatment of disease in adults, and disease prevention. Efforts have been focussed on the production of structured lipids using medium-chain acids and long-chain polyunsaturated fatty acids (PUFAs), as well as the concentration of long-chain PUFAs from new and existing sources. Short- and medium-chain fatty acids are metabolized differently than long-chain fatty acids and have been used as a source of rapid energy for preterm infants and patients with fat malabsorption-related diseases. Long-chain PUFAs, specifically docosahexaenoic acid and arachidonic acid, are important both in the growth and development of infants, while n-3 PUFAs have been associated with reduced risk of cardiovascular disease in adults. Based on the requirements for individual fat components by different segments of the population, including infants, adults, and patients, ideal fats can be formulated to meet their needs. By using specific novel fat sources and lipid modification techniques, the concentrations of medium-chain, long-chain saturated, and long-chain polyunsaturated fatty acids as well as cholesterol can be varied to meet the individual needs of each of these groups. While genetic modification of oilseeds and other novel sources of specific lipid components are still being developed, chemical and lipase-catalyzed interesterification reactions have moved to the forefront of lipid modification technology. Fractionation of fats and oils to provide fractions with different nutritional properties has potential, but little work has been performed on the nutritional applications of this method. The choice of suitable lipid modification technologies will depend on the target lipid structure, production costs, and consumer demand. A combination of some or all of the present lipid modification techniques may be required for this purpose.     

Tropical oils: nutritional and scientific issues.

Individually and in combination with other oils, the tropical oils impart into manufactured foods functional properties that appeal to consumers. The use of and/or labeling in the ingredient lists give the impression that these oils are used extensively in commercially processed foods. The estimated daily intake of tropical oils by adult males is slightly more than one fourth of a tablespoon (3.8 g), 75% of which consists of saturated fatty acids. Dietary fats containing saturated fatty acids at the beta-position tend to raise plasma total and LDL-cholesterol, which, of course, contribute to atherosclerosis and coronary heart disease. Health professionals express concern that consumers who choose foods containing tropical oils unknowingly increase their intake of saturated fatty acids. The saturated fatty acid-rich tropical oils, coconut oil, hydrogenated coconut oil, and palm kernel oil, raise cholesterol levels; studies demonstrating this effect are often confounded by a developing essential fatty acid deficiency. Palm oil, an essential fatty acid-sufficient tropical oil, raises plasma cholesterol only when an excess of cholesterol is presented in the diet. The failure of palm oil to elevate blood cholesterol as predicted by the regression equations developed by Keys et al. and Hegsted et al. might be due to the dominant alpha-position location of its constituent saturated fatty acids. If so, the substitution of interesterified artificial fats for palm oil in food formulations, a recommendation of some health professionals, has the potential of raising cholesterol levels. A second rationale addresses prospective roles minor constituents of palm oil might play in health maintenance. This rationale is founded on the following observations. Dietary palm oil does not raise plasma cholesterol. Single fat studies suggests that oils richer in polyunsaturated fatty acid content tend to decrease thrombus formation. Anomalously, palm oil differs from other of the more saturated fats in tending to decrease thrombus formation. Finally, in studies comparing palm oil with other fats and oils, experimental carcinogenesis is enhanced both by vegetable oils richer in linoleic acid content and by more highly saturated animal fats. The carotenoid constituents of red palm oil are potent dietary anticarcinogens. A second group of antioxidants, the tocotrienols, are present in both palm olein and red palm oil. These vitamin E-active constituents are potent suppressors of cholesterol biosynthesis; emerging data point to their anticarcinogenic and antithrombotic activities. This review does not support claims that foods containing palm oil have no place in a prudent diet.