Phytosterols and human lipid metabolism: efficacy,safety, and novel foods

Plant sterols have been known for several decades to cause reductions in plasma cholesterol concentrations. These plant materials have been granted a conditional health claim in the United States regarding their effects in the prevention of cardiovascular disease and are being sold in functional foods in several countries in Europe as well as in the United States and Australia. It is generally suggested that daily consumption of ∼2 g of plant sterols can lower cholesterol concentrations as part of a dietary prevention strategy. However, phytosterols have been added and tested for their cholesterol-lowering effects mainly in spreads. Consumption of these high-fat foods seemingly flies in the face of current recommendations for the promotion of heart health, which suggest lowering total fat and energy intake to maintain weight. Hence, new food formulations are being evaluated using phytosterols incorporated into low-fat and reduced-fat food items. The purpose of this review is to examine the cholesterol-lowering efficacy of plant sterols, focusing on novel food applications, their mechanism of action, and safety. These novel food formulations include new solubilization processes that lead to improved uses for plant sterols, as well as new foods into which phytosterols have been incorporated, such as breads, cereals, and beef. Such new foods, and formulations should pave the way for greater use of phytosterols in heart health promotion, increasing the longer-term potential for the creation of innovative functional foods containing plant sterols and their derivatives.     

New drugs affecting lipid metabolism

The search for an ideal hypolipidemic agent still is underway. A relatively large number of the newer hypolipemic agents are related to ethyl p-chlorophenoxyisobutyrate—among them are compounds with the trivial names or designations of SU 13,437; Sah 42-348; halofenate, treloxinate, S-8527, and two valeric acid derivatives. Other lipopenic agents, whose modes of action are described, are linoleic acid amides, Colestipol, antidiabetic agents, bis (hydroxyethylthio) 1,10-decane, pyridinol carbamate, and some nicotinic acid derivatives. One of six papers presented in the symposium, “Effect of Drugs on Lipid Metabolism,” AOCS Spring Meeting, New Orleans, April 1973.     

Hepatic participation in lipid metabolism

Summary and Conclusions During alimentary lipemia induced in dogs by the feeding of saturated or unsaturated fats no significant alteration occurred in phagocytic function as indicated by colloidal carbon removal and colloidal gold tissue distribution studies. The cellular distribution of intravenously administered triglyceride indicated that most of the injected triglyceride was found in the isolated hepatic parenchymal cell. The distribution of an intravenously administered free cholesterol emulsion indicated initial localization in the parenchymal cell and a later elevation in the Kupffer cell. These findings suggest that both hepatic parenchymal and Kupffer cells participate in the removal of chylomicra; the parenchymal cell has the greatest role. The late elevation in cholesterol content of the Kupffer cell is indicative of a metabolic or excretory function of these cells in cholesterol metabolism. Presented at the 33rd Fall Meeting, American Oil Chemists’ Society, Los Angeles, Calif., Sept. 28–30, 1959. Supported in part by a grant from the Public Health Service (H-2320) and the Atomic Energy Commission. Lederle Medical Faculty Awardee.     

Cardiac and vascular structure and function are related to lipid peroxidation and metabolism

The present study investigated possible relationships between left ventricular mass, intima-media thickness of the carotid artery (IMT), total arterial compliance, and lipid status in a population sample of 58 apparently healthy subjects aged 20 to 69. By stepwise multiple regression analysis, including age, blood pressure, and smoking, left ventricular mass index, measured by M-mode echocardiography, increased by 13.0 g/m² for each 1 standard deviation (SD=0.11 μM, r=0.60, P<0.01) increase in plasma malondialdehyde and 9.50 g/m² per SD increase in plasma 8-iso-prostaglandin F_2α in women only (SD=8.88 ng/L, r=0.44, P=0.01). Each 1-SD (SD=0.27 g/L) increase in apolipoprotein B was associated with a 63 μm increase in IMT (r=0.47, P=0.01) and a 0.27 mL/min/m²/mm Hg (r=−0.60, P<0.01) decrease in stroke index/pulse pressure ratio, reflecting total arterial compliance in women. In men, each 1-SD increase in the proportion of stearic acid (18∶0) in serum cholesterol esters (SD=0.12 percent units) reduced the transmitral E/A ratio, measured by Doppler echocardiography, reflecting left ventricular diastolic function, by 0.10 units (r=−0.29, P<0.05). Thus, important cardiovascular characteristics, such as left ventricular mass, left ventricular diastolic function, carotid IMT, and total arterial compliance, were independently predicted by indices of lipid metabolism and peroxidation in apparently healthy subjects.     

Dietary lipid,fatty acid synthesis and cholesterol metabolism in aging rats

Male and female rats were fed diets containing 2% of calories as corn oil or that plus 40% of calories as beef tallow or corn oil. After 3, 6, 12 and 18 months groups were given 4-¹⁴C-cholesterol ip, and feces were collected for 9 days. Just prior to necropsy³H-acetate was administered ip. Samples of serum, liver, heart and carcass were obtained for analysis. Concentrations of fatty acids and cholesterol, synthesis of those and recovery of ring-labeled steroid are reported. Mortality from acute respiratory disease was very high in male rats fed beef tallow or low fat diets and very low in those fed the corn oil diet. In females, only beef tallow diet resulted in a high mortality rate, and this was lower and at a later age than in males. The most notable effects of age were in relation to fatty acid synthesis and presence of¹⁴C-acidic steroid in the carcass. In 3-month-old rats both fats depressed fatty acid synthesis in comparison to the low fat diet. At later ages beef fat ceased to depress fatty acid synthesis in both sexes. Corn oil continued to depress fatty acid synthesis up to 12 months in males and 18 months in females. The presence of¹⁴C-acidic steroid in carcass was substantial in 6-month-old rats and constituted ca. 40% of recovered¹⁴C in 18-month-old rats. The possibility that the increase in acetate incorporation into fatty acids with age in fat feeding is related to chain elongation rather than de novo synthesis is discussed. Both the presence and amount of acidic steroid in the carcass are notable and may be of importance in constructing models of cholesterol turnover. Presented in part at the AOCS Sterol Symposium, April 1970, and the Federation of American Societies for Experimental Biology, April 1971. Scientific Series Paper No. 1536, Colorado Agricultural Experiment Station.     

Perfluorodecanoic acid and lipid metabolism in the rat

Alterations in lipid metabolism were axamined in adult male Sprague-Dawley rats seven days after a single intraperitoneal injection of perfluorodecanoic acid (PFDA; 20, 40 or 80 mg/kg). Because PFDA treatment caused a dose-related reduction in feed intake, the response of vehicle-treated rats pair-fed to those receiving PFDA was monitored to distinguish direct effects of the perfluorinated fatty acid from those secondary to hypophagia. Carcass content of lipid phosphorus and free cholesterol decreased in dose-dependent fashion in both PFDA-treated and pair-fed rats. Carcass triacylglycerols diminished in a similar manner, yet PFDA-treated rats at each dose had a higher concentration of neutral acylglycerols than their vehicle-treated, pair-fed counterparts. In vehicle-treated, pair-fed rats at the 80 mg/kg dose level, lipid phosphorus and free cholesterol as a proportion of carcass fat increased, whereas the share of the triacyl-glycerols declined. Because of the higher concentration of triacylglycerols in the carcass of rats treated with 80 mg/kg PFDA, enrichment of lipid phosphorus and free cholesterol in carcass fat was less than in their pair-fed partners. The amount of lipid phosphorus and free cholesterol per hepatocyte was similar in both PFDA-treated rats and their pair-fed partners. Liver triacyl-glycerols were markedly increased in PFDA-treated rats. A similar but less extensive augmentary effect of PFDA on hepatic esterified cholesterol was found. Concentration of triacylglycerols in plasma was not elevated in PFDA-treated rats, in spite of hepatic accumulation of esterified compounds. Also, the plasma level of free fatty acids and 3-hydroxybutyrate was similar in all treatment groups, including those receiving PFDA. Thus, the administration of PFDA appears to divert fatty acids from oxidation toward esterification in the liver.     

The prostaglandins and their influence on lipid metabolism

Isolation, characterization, occurrence, and physiological action of the prostaglandins are reviewed.     

原花青素经肠道微生态途径对脂质代谢的调节

目的研究原花青素(Proanthocyanidin,PC)经肠道微生态途径调节脂质代谢。方法取成年雄性SD大鼠和长爪沙鼠,经基础饲料适应性喂养1周后,采集尾静脉血,收集血清,检测血清总胆固醇(Total cholesterol,TC)水平,并按TC及体重分为基础对照组、模型对照组、低剂量组(25 mg/kg PC)、中剂量组(100 mg/kg PC)、高剂量组(150 mg/kg PC)、阳性对照组(非诺倍特80 mg/kg),基础对照组饲以普通基础饲料,其余各组均饲以高脂饲料,每天灌胃1次,大鼠连续灌胃8周,沙鼠连续灌胃2周。大鼠8周末、沙鼠2周末,经股动脉采血,分离血清,处死前3 d收集72 h粪便。采用全自动生化仪检测TC、甘油三酯(Triglyceride,TG)、高密度脂蛋白胆固醇(High-density lipopro-tein cholesterol,HDL-C)、低密度脂蛋白胆固醇(Low-density lipoprotein cholesterol,LDL-C)、血总胆汁酸(Total bileacid,TBA)水平;循环酶法试剂盒测定粪TBA排出量水平;双抗体两步夹心ELISA法测定卵磷脂胆固醇酰基转移酶(Lecithin-cholesterol acyltransferase,LCAT)活性。解剖处死的大鼠和沙鼠,进行病理组织学分析。提取大鼠、沙鼠小肠、盲肠细菌基因组DNA,采用PCR-变性梯度凝胶电泳(Denatured gradient gel electrophoresis,DGGE)进行动物模型肠道微生态菌群多样性变化分析。结果模型对照组大鼠和沙鼠TC、TG水平明显高于基础对照组,差异有统计学意义(P<0.05),表明高脂模型建模成功。与模型对照组相比,各剂量组和阳性对照组大鼠、沙鼠TC、TG、LDL-C、血TBA水平均降低,LCAT活性、粪TBA排出量均明显升高,差异有统计学意义(P<0.05);各剂量组大鼠肝脏损伤、肝细胞肿胀、变性等病变程度明显减轻,肝组织病理变化明显改善。DGGE检测及图像分析显示,大鼠各剂量组肠道优势菌群多样性明显增加,随着PC干预剂量加大,中、高剂量组肠道菌群多样性明显减少;沙鼠低剂量组与模型对照组的肠道菌群结构基本相似,而中、高剂量组肠道菌群多样性明显减少,肠道优势菌群结构明显恢复。结论 100、150 mg/kg PC干预的实验动物模型中,肠道菌群结构多样性明显恢复,提示PC可通过肠道菌群这一靶标,进行脂质代谢的调节。     

Age-strain interrelations in lipid metabolism of rats

Various aspects of lipid metabolism were compared in Fisher 344 (F) and Sprague-Dawley (SD) rats aged 2, 6, 12, 18 and 24 months. The analyses included free and total cholesterol of serum and liver, LCAT, hepatic HMG-CoA reductase, cholesterol 7α-hydroxylase, fatty acid synthetase, acetyl CoA carboxylase and cholesterol synthesis from acetate or mevalonate. The body weight of SD rats increases with age whereas that of F rats plateaus at 9–12 months. Liver and aorta cholesterol levels were comparable for the 2 strains. Serum cholesterol varied but was usually lower in F rats. HMG-CoA reductase and cholesterol 7α-hydroxylase activities were not significantly different. Cholesterol synthesis from acetate was significantly higher only in 2-month-old F rats; synthesis from mevalonate was similar at each level. Acetyl CoA carboxylase and fatty acid synthetase activity were generally higher in F rats at every age level. The major difference between F and SD rats is in their pattern of weight gain with age. Differences in lipid metabolism are most marked between the young (2-month) rats.     

Hyperthyroidism affects lipid metabolism in lactating and suckling rats

Two per thousand pregnant women have hyperthyroidism (HT), and although the symptoms are attenuated during pregnancy, they rebound after delivery, affecting infant development. To examine the effects of hyperthyroidism on lactation, we studied lipid metabolism in maternal mammary glands and livers of hyperthyroid rats and their pups. Thyroxine (10 μg/100 g body weight/d) or vehicle-treated rats were made pregnant 2 wk after commencement of treatment and sacrificed on days 7, 14, and 21 of lactation with the litters. Circulating triiodothyronine and tetraiodothyronine concentratins in the HT mothers were increased on all days. Hepatic esterified cholesterol (EC) and free cholesterol (FC) and triglyceride (TG) concentrations were diminished on days 14 and 21. Lipid synthesis, measured by incorporation of [³H]H₂O into EC, FC, and TG, fatty acid synthase, and acetyl CoA carboxylase activities increased at day 14, while incorporation into FC and EC decreased at days 7 and 21, respectively. Mammary FC and TG concentrations were diminished at day 14. Incorporation of [³H]H₂O into TG decreased at days 7 and 21, and incorporation of [³H]H₂O into FC increased at day 14. In the HT pups, growth rate was diminished, tetraiodothyronine concentration rose at days 7 and 14 of lactation, and triiodothyronine increased only at day 14, Liver TG concentrations increased at day 7 and fell at day 14, while FC increased at day 14 and only acetyl CoA carboxylase activity fell at day 14. Thus, hyperthyroidism changed maternal liver and mammary lipid metabolism, with decreased lipid concentration in spite of increased liver rate of synthesis and decreased in mammary synthesis. These changes, along with the mild hyperthyroidism of the litters, may have contributed to their reduced growth rate.     

Control of lipid metabolism in cultured cells

Several studies are presented which indicate that composition of cell lipid is regulated by interaction between intracellular metabolism and lipid transport processes. When the fatty acid composition of cells cultured in essential fatty acid deficient conditions was studied, activation of synthesis of unusual polyun-saturated fatty acids was observed for a number of cell lines. In addition cells contained persistent residual amounts of linoleic acid, presumably owing to efficient scavenging mechanisms. The source of cell lipids was studied in both chemically defined and serum-supplemented media. In the absence of exogenous lipid, cells synthesize lipids from simple precursors, a process which is inhibited by adding serum. When serum lipid is present, cells preferentially utilize fatty acids as a source of nonsterol lipid. These are subsequently esterified intracellularly to make glycerides and phospholipids. When triglyceride is utilized as a source of cell lipid, it is first hydrolyzed before being taken up. By use of a nonhydrolyzable cholesterol ester analog, it is confirmed that both free and ester cholesterol are taken up and excreted by cells. Intracellular cholesterol content is thus regulated by rates of uptake, hydrolysis and excretion as well as by biosynthesis. One of 13 papers presented at the symposium “Lipid Metabolism in Cells in Culture,” AOCS Meeting, Houston, May 1971.     

Long-term feeding of dietary oils alters lipid metabolism, lipid peroxidation, and antioxidant enzyme activities in a teleost (Anabas testudineus bloch)

Anabas testudineus (climbing perch), average body weight 21±1 g, were maintained in culture tanks and fed a 35% protein feed plus an additional supplementation of three dietary oils (20% each of coconut oil, palm oil, or cod liver oil). Body weight gain was similar among all groups. However, several hepatic lipogenic enzymes such as malic enzyme (ME), NADP-isocitrate dehydrogenase (ICDH), glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconate dehydrogenase (6PGDH) and β-hydroxy-β-methyl glutaryl CoA reductase (HMG CoA reductase) were assayed, and they responded differently. Hepatic ME and G6PDH activities showed a significant decrease in the coconut oil and palm oil groups, but there was no significant change in ICDH activity. The 6PGDH activities were reduced, whereas HMG CoA reductase activity was increased in the palm oil-treated group. Cholesterol synthesis in the liver and muscle increased in the palm oil-treated group, but liver phospholipids did not show any significant change in fish supplemented with oils rich in saturated fatty acids. Triacyl-glycerol and free fatty acid concentrations were high in the coconut oil- and palm oil-supplemented groups. Lipid peroxidation products such as thiobarbituric acid-reactive substances and conjugated dienes decreased in the same two groups. Antioxidant potential was high in all groups as evidenced by increased activity of superoxide dismutase, glutathione peroxidase, and glutathione content. The results of this study indicate that in fish, dietary lipids depress hepatic lipogenic activity as well as lipid peroxidation products by maintaining high levels of antioxidant enzymes.