Diet induced atherogenic hyperlipoproteinaemia and liver injury in cynomolgus macaques.

This study was conducted to determine the efficacy of an experimental anti-atherosclerosis drug in the adult male cynomolgus monkey. A semipurified diet containing 0.5% cholesterol and 25.5% butter was fed to groups of 20, each, drug and placebo-treated animals for 18 months. Similar liver and arterial changes were present in both groups. However, we report here tissue changes seen in animals given placebo only, with plasma lipid and lipoprotein values of placebo-treated animals compared to those in animals fed nonatherogenic commercial ration. Animals fed atherogenic diet had enlarged livers (mean 3.9% b.w.), and all had evidence of hepatocellular lipid accumulation which was often marked and diffuse. Cholangitis was common including mononuclear cell infiltration, bile ductule proliferation and portal tract fibrosis. Five animals had severe portal fibrosis with bands of connective tissue extending into and around lobules (bridging fibrosis). All animals fed atherogenic diet developed hypercholesterolemia (greater than 600 mg/dl) which was the result of a three-fold increase in five cholesterol and cholesterol ester. Oleic acid was increased and linoleic acid was reduced in plasma phospholipids and cholesterol esters. Plasma lipoprotein distribution was altered with a marked increase in low density lipoproteins, increased very low density lipoproteins and decreased high density lipoproteins. These changes were undoubtedly caused by diet, i.e., high in cholesterol and saturated fat and limiting in linoleic acid. It is probable that diet-induced liver injury would affect the pathogenesis of atherosclerosis in this model since the liver is central in the synthesis and metabolism of lipoproteins.     

Hyperlipoproteinaemia and atherosclerosis in rabbits fed low-level cholesterol and lecithin

Dutch-Belted rabbits were fed for 18 months an atherogenic semipurified gel diet containing 14% hydrogenated coconut oil and 0.06% cholesterol (approximately 0.15 mg/kcal) or a non-atherogenic basal gel diet containing the same ingredients but with no coconut oil or cholesterol. Rabbits fed atherogenic diet developed hypercholesterolaemia (means 733 mg/dl at 16 months) and plasma lipoprotein (LP) distribution shifted from a pattern in which high-density lipoproteins (HDL) predominated to one in which very-low-density lipoproteins (VLDL) were predominant. Total cholesterol/triglyceride ratio in d less than 1.006 LP changed from 0.3 to 1.8. Plasma cholesterol and LP distribution returned to normal in rabbits fed atherogenic diet for 18 months followed by atherogenic diet plus 3% soya lecithin for an additional 4 months. Rabbits fed atherogenic diet for 18 months had extensive, usually full circumference fibromuscular plaques in main branches of coronary arteries and all portions of aorta which compromised lumen area by almost 50%. These lesions were modified in rabbits fed atherogenic diet plus lecithin. The plaques lacked foam cells and cholesterol clefts, were less cellular with a distinct fibrous surface and occupied less space. Animals fed basal diet did not develop hypercholesterolaemia (means 86 mg/dl at 16 months), although distribution of plasma LP shifted slightly in favour of increased low-density lipoproteins (LDL) and decreased HDL compared with rabbits fed standard commercial diet. Basal diet rabbits had no coronary atherosclerosis and only minimal focal foam cell lesions in proximal aorta. Liver injury including fatty change, cholangitis and portal fibrosis occurred in animals fed atherogenic diet. Thus, rabbits fed appropriate diets low in cholesterol accumulate cholesterol-enriched LP in their plasma and develop lesions in abdominal aorta and main branches of coronary arteries which are similar to those in man. Also, in this experimental model, dietary lecithin promotes a return to normal of the LP distribution profile and removal of lipid from established atherosclerotic plaque.     

Hyperlipoproteinaemia and atherosclerosis in rabbits fed low-level cholesterol and lecithin.

Dutch-Belted rabbits were fed for 18 months an atherogenic semipurified gel diet containing 14% hydrogenated coconut oil and 0.06% cholesterol (approximately 0.15 mg/kcal) or a non-atherogenic basal gel diet containing the same ingredients but with no coconut oil or cholesterol. Rabbits fed atherogenic diet developed hypercholesterolaemia (means 733 mg/dl at 16 months) and plasma lipoprotein (LP) distribution shifted from a pattern in which high-density lipoproteins (HDL) predominated to one in which very-low-density lipoproteins (VLDL) were predominant. Total cholesterol/triglyceride ratio in d less than 1.006 LP changed from 0.3 to 1.8. Plasma cholesterol and LP distribution returned to normal in rabbits fed atherogenic diet for 18 months followed by atherogenic diet plus 3% soya lecithin for an additional 4 months. Rabbits fed atherogenic diet for 18 months had extensive, usually full circumference fibromuscular plaques in main branches of coronary arteries and all portions of aorta which compromised lumen area by almost 50%. These lesions were modified in rabbits fed atherogenic diet plus lecithin. The plaques lacked foam cells and cholesterol clefts, were less cellular with a distinct fibrous surface and occupied less space. Animals fed basal diet did not develop hypercholesterolaemia (means 86 mg/dl at 16 months), although distribution of plasma LP shifted slightly in favour of increased low-density lipoproteins (LDL) and decreased HDL compared with rabbits fed standard commercial diet. Basal diet rabbits had no coronary atherosclerosis and only minimal focal foam cell lesions in proximal aorta. Liver injury including fatty change, cholangitis and portal fibrosis occurred in animals fed atherogenic diet. Thus, rabbits fed appropriate diets low in cholesterol accumulate cholesterol-enriched LP in their plasma and develop lesions in abdominal aorta and main branches of coronary arteries which are similar to those in man. Also, in this experimental model, dietary lecithin promotes a return to normal of the LP distribution profile and removal of lipid from established atherosclerotic plaque.     

Dietary induced hyperbetalipoproteinemia in chimpanzees: comparison to the human hyperlipoproteinemia

Fasting plasma from chimpanzees fed normal and atherogenic diet was separated into alpha (HDL) and beta (LDL) lipoproteins by electrochromatography. Both lipoproteins were analyzed for lipid and fatty acid composition.Beta lipoproteins, esterified cholesterol, free cholesterol, and phospholipids were increased in chimpanzees fed the atherogenic diet. The cholesterol/phospholipid ratio was increased. These lipid changes occurred chiefly in the beta lipoproteins. A disproportionate increase of plasma phosphatidylcholine to sphingomyelin was confirmed. Differences in the fatty acid composition of both lipoproteins were noted and cholesterol oleate was elevated more than cholesterol linoleate so that the $\text{18:1}\text{18:2}$ ratio was increased. The intima of one animal which died from myocardial infarction after 4–5 years diet showed an increase of cholesterol oleate.Similarities between cholesterol-induced lipoprotein changes in chimpanzees and those obtained in human hyperbetalipoproteinemia are discussed. These similarities stress the usefulness of these nonhuman primates as a model for experimental atherosclerosis and for studying the molecular changes in lipoprotein patterns.     

Angiochemical and tissue cholesterol changes of Macaca fascicularis fed an atherogenic diet for 3 years.

Angiochemical and tissue cholesterol changes were investigated in Macaca fascicularis fed either an atherogenic containing 1 mg cholesterol/Cal or a control diet for 3 years. The thoracic and abdominal aortas and the carotid and femoral arteries were visually examined for the extensiveness of atherosclerosis and analyzed for lipid, collagen, elastin, and mineral content. Cholesterol accumulation in other tissues was assessed by measuring concentrations in liver, kidney, skin, and tendon. The cynomolgus macaques fed the atherogenic diet had between 77 and 97% of the intimal surface of all arteries studied affected with atherosclerotic lesions. The arteries of animals fed the atherogenic diet were between 1.6–2.5 times heavier than the arteries of control animals. This increased weight was attributed largely to collagen and elastin. When animals fed the atherogenic diet were compared with controls, significant increases in arterial total cholesterol, esterified cholesterol, phospholipid, calcium, phosphorus, and magnesium were seen. The liver, skin and tendon, but not the kidney, had significant increased concentrations of total and esterified cholesterol compared to control tissues. Comparison of our findings with the results of other studies of nonhuman primates indicates that the atherosclerotic plaques induced in the cynomolgus macaques are most nearly comparable to atherosclerosis in man, primarily because of the marked accumulation of mineral and connective tissue components.     

Haemorheological Characterisation of a Model of Diet-induced Hypercholesterolaemia in Rats

This investigation examined the haemorheological changes that occurred in rats during and after administration of high-fat diets containing 10% lard and 1% cholic acid, both with and without 2% cholesterol for a period of 2 weeks. Rats fed the high-fat diet enriched with cholesterol showed markedly impaired fluidity of whole blood, increases of blood viscosity, plasma low-density lipoprotein (LDL)-cholesterol, VLDL-cholesterol, and impaired skin microcirculation shortly after the start of this diet regimen. Additionally, increased liver mass, and lipid accumulation in hepatocytes were observed after two weeks. In contrast, rats fed the high-fat, cholesterol-free diet had less pronounced haemorheological disorders, increased liver mass and lipid accumulation in the liver than rats given the cholesterol-enriched diet. Histopathologically, there were no marked changes in blood vessels or liver in rats fed these diets for 2 weeks, except for fatty liver changes. Dietary induced hypercholesterolaemia therefore contributes to the haemorheological disorder, impaired microcirculation and fatty liver change.     

Unusual resistance of the ground squirrel to the development of dietary-induced hypercholesterolemia and atherosclerosis

This study was designed to examine the apparently unusual resistance to atherosclerosis in the adult male ground squirrel. In one study, serum lipid and lipoprotein patterns and concentrations of ground squirrels were observed after feeding for 26 weeks with either rodent chow or rodent chow supplemented with cholesterol. These two groups were compared to a third group fed chow diet for three weeks, then killed for baseline values to distinguish between aging effects and those induced by cholesterol feeding. No outstanding changes in the concentration and patterns of the serum cholesterol, triglycerides, and lipoproteins were observed in any groups. A higher serum phospholipid concentration in cholesterol-fed animals compared to animals fed chow diet alone for three weeks suggested that the rise was associated with aging rather than diet. The predominant lipoprotein fraction in all three groups was high-density lipoprotein (HDL). No lesions were found in the coronary arteries or thoracic and abdominal aortas.In a second study a primate diet with 50% egg yolk was given for 1 year. This diet caused elevation of serum cholesterol and phospholipid levels, and increased HDL, which had an unusual ability to carry as much cholesterol as the low-density lipoprotein (LDL). However, no arterial lipid accumulation was observed. Light microscopic and ultrastructural studies of the coronary artery and aorta revealed nothing unusual, and in structure, they resembled those of other small rodents. The only striking finding was that very few degenerative aging changes were found in the aorta when compared to rats of a similar age. The study demonstrates that the ground squirrel does not develop marked hypercholesterolemia with cholesterol feeding and that the majority of the elevated levels of serum lipids, particularly cholesterol, are transported as α-lipoprotein. Both of these factors, plus the lack of degenerative aging changes in the arterial wall may play an important role in the resistance of this particular species to atherosclerosis.     

Antioxidant and anti-atherogenic activities of three Piper species on atherogenic diet fed hamsters

Atherogenic diet is known to induce high plasma lipid concentration, oxidative stress and early atherosclerosis. Antioxidants have potentials to counter the effect of atherogenic diet.The present research aims at evaluating the antioxidant and anti-atherosclerotic activities of three Piper species (Piper guineense, Piper nigrum and Piper umbellatum) on atherogenic diet fed hamsters.Hamsters divided into 8 groups: normal control, atherosclerotic control and six test groups. The normal animals fed normal rodent chow, the atherosclerotic control animals fed the same rodent chow supplemented with 0.2% cholesterol and 10% coconut oil (high cholesterol diet). The 6 test groups’ animals fed same diet as the atherosclerotic control group but with additional supplementation of 2 graded doses (1 and 0.25 mg/kg body weight, o.p.) of plant extracts for 12 weeks.The atherogenic diet induced a collapse of the erythrocyte antioxidant defense system (significant decrease in superoxide dismutase, catalase and glutathione peroxidase activities). Atherogenic diet also induced an increase in plasma total cholesterol, triglyceride, thiobarbituric acid reactive substances (TBARS), oxidation of low density lipoprotein cholesterol (LDL) and accumulation of foam cells in the aorta a hall mark for atherosclerosis. Administration of the Piper species prevented the collapse of the antioxidant system and the increase of plasma parameters maintaining them towards normality. The Piper species also prevented LDL oxidation by increasing the time (lag time) for its oxidation.The results suggest that these Piper species have significant antioxidant and anti-atherogenic effect against atherogenic diet intoxication.     

Overexpression of human lecithin:cholesterol acyltransferase in mice offers no protection against diet-induced atherosclerosis

Human lecithin:cholesterol acyltransferase (LCAT) is a key enzyme in the metabolism of cholesterol. We have used homozygous transgenic mice overexpressing the human LCAT transgene to study the effect of a "Western-type" atherogenic diet (30% fat, 5% cholesterol and 2% cholic acid) on their LCAT expression, activity, lipoprotein profile and tendency to develop atherosclerosis. The LCAT activity was 35-fold higher in serum of the homozygous transgenic mice than in murine control serum, and decreased 11-20% in the transgenic mice when fed the atherogenic diet. The total cholesterol and high-density lipoprotein cholesterol (HDL-C) concentrations were approximately doubled in the transgenic mice compared with the controls when both groups were fed a regular chow diet. In mice on the atherogenic diet, the triglyceride concentration decreased about 50% to the same level in transgenic and control mice. Total cholesterol and HDL-C concentrations increased and were 60-80% higher in the transgenic mice. The expression of LCAT mRNA in the liver was decreased by 49-60% in the transgenic mice when fed the atherogenic diet. The development of atherosclerosis was similar in transgenic and control mice. Thus, the 14- to 27-fold higher LCAT activity and the higher HDL-C concentrations in the homozygous LCAT transgenic mice had no significant protective influence on the development of diet-induced atherosclerosis.     

Protective effect of grape seed proanthocyanidins against cholesterol cholic acid diet-induced hypercholesterolemia in rats

BackgroundDietary cholesterol plays an important role in the development of atherogenesis and cardiovascular diseases. We explored the prospective effect of grape seed proanthocyanidins in controlling hypercholesterolemia induced oxidative injury and apoptosis in atherogenic animals.MethodsFour groups of male Wistar rats (250–300 g) were used for the study. Group I served as control and received vehicle (saline) alone, Group II served as the induction group fed with a high-cholesterol diet (rat chow supplemented with 4% cholesterol and 1% cholic acid—CC diet) for 30 days, Group III served as drug control and was treated with grape seed proanthocyanidins (100 mg/kg body weight) orally for 30 days, and Group IV animals were fed with CC diet for 30 days along with grape seed proanthocyanidins (100 mg/kg body weight) orally.ResultsCC diet induced an abnormal increase in lipid peroxidation, tissue cholesterol, triglyceride, serum low-density lipoprotein, and very low density lipoprotein, and decreased the high-density lipoprotein concentration. Altered activity of cardiac and serum creatine kinase, accompanied by a decreased cardiac enzymatic and nonenzymatic antioxidant defense system and an increase in the expression of cytochrome c and caspases-3, was observed in CC diet-fed rats. These changes were partially restored in the grape seed proanthocyanidin-treated group.ConclusionGrape seed proanthocyanidins have cardioprotective effects against CC diet-induced hypercholesterolemia via their ability to reduce, directly or indirectly, free radicals in the myocardium.     

Comparative primate atherosclerosis: I. Tissue Cholesterol Concentration and Pathologic Anatomy

Stump-tailed macaques (Macaca arctoides), African green monkeys (Cercopithecus aethiops), squirrel monkeys (Saimiri sciureus), and woolly monkeys (Lagothrix lagothricha) were fed control, solid atherogenic (1 mg cholesterol/cal) or liquid diets containing 0, 0.5, or 1 mg cholesterol/cal.Stump-tailed macaques fed the solid atherogenic diet had the highest tissue and serum cholesterol concentration (about 700 mg/dl) and the most extensive atherosclerosis. These monkeys appeared to respond differently to diets containing 1 mg cholesterol/cal. Those animals fed the liquid diet had higher liver cholesterol concentration but lower serum cholesterol concentration than animals fed the solid diet. African green monkeys fed the solid atherogenic diet had serum cholesterol concentrations of about 450 mg/dl. A greater percentage of the abdominal aorta was covered by plaque than the thoracic aorta. Coronary artery atherosclerosis was focal with the largest plaques being found in the left main coronary artery. The microscopic appearance of these plaques was similar to that of plaques from people.Squirrel monkeys fed the atherogenic diet were the most variable group. The average serum cholesterol concentration averaged about 450 mg/dl (range: 291 to 716). The percentage of aorta covered by plaque ranged from 0 to 55% with more thoracic than abdominal aortic atherosclerosis. There were findings consistent with hemorrhage in plaques from two animals. These monkeys, like stump-tailed macaques but unlike African green monkeys had relatively high liver cholesterol concentrations.Woolly monkeys appeared to develop atherosclerosis when fed 1 mg cholesterol/cal but did not have greatly elevated serum cholesterol concentrations.     

Clerodendron glandulosum.Coleb leaf extract attenuates in vitro macrophage differentiation and expression of VCAM-1 and P-selectin in thoracic aorta of atherogenic diet fed rats

Present inventory evaluates the anti-atherogenic potential of C. glandulosum.Coleb leaf extract (CG) using in vivo and in vitro experimental models. Serum markers of low density lipoprotein (LDL-C) oxidation, cholesterol, triglycerides, lipoproteins, auto-antibody titer, ex vivo LDL-C oxidation, LDL-C aggregation, aortic lipids, histopathological evaluations and immunolocalization of macrophage surface marker (F4/80), vascular cell adhesion molecule-1 (VCAM-1) and P-selectin were performed in CON [rats treated with single dose of saline (i.p.) and fed with laboratory chow], ATH [rats treated with single dose of vitamin D3 (600,000 IU, i.p) and fed with atherogenic diet] and ATH+CG [rats treated with single dose of vitamin D3 (600,000 IU, i.p.) and fed with atherogenic diet and simultaneously treated with 200?mg/kg CG extract, p.o.] for 8 weeks. CG extract supplementation to atherogenic diet fed rats significantly prevented increment in serum cholesterol, triglycerides, and lipoproteins, markers of LDL-C oxidation, auto-antibody titer and aortic lipids. Also, LDL-C isolated from ATH+CG rats recorded mimimal aggregation and susceptibility to undergo ex vivo LDL-C oxidation. Microscopic evaluation of thoracic aorta of ATH+CG rats reveled prevention of atheromatous plaque formation, accumulation of lipid laden macrophages, calcium deposition, distortion/defragmentation of elastin, accumulation of macrophages and, down regulation of cell adhesion molecules (VCAM-1 and P-selectin) expression. Further, in vitro monocyte to macrophage differentiation was significantly attenuated in presence of CG extract (200 μg/mL). It can be concluded from the present study that, CG extract is capable of controlling induction of experimental atherosclerosis and warrants further scrutiny at the clinical level as a possible therapeutic agent.     

Comparative characteristics of the lipid composition of lipoproteins of the blood plasma and ascitic fluid in liver cirrhosis

Comparison of phospholipid content in different fractions of lipoproteins of the ascitic fluid and blood plasma showed selective accumulation of high density lipoproteins (HDLP) in the ascitic fluid. The ascitic fluid HDLP differed from blood plasma HDLP in a larger fraction of triglycerides and cholesterol oleate. No significant difference was revealed in the lipoprotein (LP) low density lipid spectrum in the two fluids. The very low density LP (VLDLP) of the ascitic fluid differed from blood plasma VLDLP by higher ratios of phosphatidylcholine (PC) (sphingomyelin and PC) unesterified cholesterol; the PC in VLDLP of the ascitic fluid had a relatively higher content of linoleic and oleic acids. It is suggested that the detected differences are associated with dynamic insufficiency of lymph drainage in portal hypertension, as the result of which LP of intestinal genesis, spreading in the interstitium of the wall of the small intestine, enter the abdominal cavity by bypassing the blood plasma.     

Anti-hypercholesterolemic effect of melatonin in rats

The effects on plasma lipids of daily intraperitoneal injections of 4 mg of melatonin (N-acetyl-5-methoxytryptamine) for 10-27-day periods were examined biochemically and morphologically in rats fed regular and high-cholesterol (1% cholesterol, 0.5% cholic acid) diets. Melatonin administration had no significant effect on plasma lipids and lipoproteins in the rats on a normal diet but blunted the effects of a high-cholesterol diet on these parameters. No effects of melatonin on lipase activity were noted. Melatonin also diminished the fatty infiltration in the liver of animals on the high-cholesterol diet. The high-cholesterol diet produced major increases in VLDL and LDL cholesterol and protein content, and decreases in HDL cholesterol and protein. Melatonin decreased the extent of this plasma lipoprotein increase, although it did not completely prevent the phenomenon. Therefore, the effect is thought to be quantitative and not qualititative in nature.     

Canine hyperlipoproteinemia and atherosclerosis. Accumulation of lipid by aortic medial cells in vivo and in vitro.

Dogs maintained for 1 year on a semisynthetic diet containing hydrogenated coconut oil and cholesterol developed hypercholesterolemia. In those cases where plasma cholesterol levels exceeded 750 mg/100 ml, the animals also developed severe atherosclerosis. This atherogenic hyperlipoproteinemia was characterized by the presence of beta very low density lipoproteins (B-VLDL), increased levels of low density lipoproteins (LDL), and the occurrence of the HDLc lipoproteins. In all of these cholesterol-rich lipoproteins the arginine-rich apoprotein (ARP) was prominent. Moreover, the HDLc (d = 1.006-1.02) contained the ARP as the only detectable apoprotein. The atherosclerosis involved the abdominal aorta, coronary and cerebrovascular arteries, and many of the peripheral arteries. Histologically, the aortic lesions were characterized by a variable intimal proliferative response and extensive medial lipid deposition. In the peripheral, coronary, and cerebral arteries, the lesions were more extensive and involved primarily the media of the vessel wall, with little intimal reaction in many cases. The correlation between the in vivo disease process and the response of aortic smooth muscle cells (SMC) grown in tissue culture to the various cholesterol-induced lipoproteins was examined. B-VLDL, LDL, and HDLc (but not HDL2) caused a marked accumulation of free and esterified cholesterol in the SMC. The cholesterol accumulation was found to be more extensive in canine SMC than in swine smooth muscle cells or smooth muscle cells of other species in response to a similar lipoprotein cholesterol concentration. The enhanced sterol uptake appeared to be a property of canine smooth muscle cells rather than a property of the canine lipoproteins. These in vitro results may be related to the observed propensity for the development of medical disease that was demonstrated in the in vivo studies.     

Atherogenic diet-induced hepatitis is partially dependent on murine TLR4

Diets high in cholesterol and cholate such as the Paigen diet have been used to study atherogenesis, lithogenesis, and proinflammatory microvascular changes induced by nutritional hypercholesterolemia. Although these diets lead to chronic hepatic inflammation and fibrosis, the early inflammatory changes have been poorly characterized. TLR4, a known receptor for LPS, is also a receptor for a variety of endogenous ligands and has been implicated in atheroma formation. Here, we specifically examined the early inflammatory response of the liver to the atherogenic (ATH) diet and the possible contribution of TLR4. Animals fed the high-cholesterol/cholate diet for 3 weeks developed a significant, predominantly mononuclear leukocyte infiltration in the liver, hepatic steatosis, elevated hepatic expression of MCP-1, RANTES, and MIP-2, and increased serum levels of liver enzymes. In TLR4-deleted animals, there was a 30% attenuation in the serum alanine transaminase levels and a 50% reduction in the leukocyte infiltration with a fourfold reduction in chemokine expression. In contrast, hepatic steatosis did not differ from wild-type controls. TLR2 deletion had no effect on diet-induced hepatitis but increased the amount of steatosis. We conclude that the early inflammatory liver injury but not hepatic lipid loading induced by the ATH diet in mice is mediated in part by TLR4.     

Ex vivo investigation of blood monocyte and platelet behaviour in pigs maintained on an atherogenic diet.

Domestic pigs aged 4 months were fed for 16 weeks an atherogenic diet rich in cholesterol and saturated fatty acid. The increase of plasma cholesterol and triacylglycerol levels was found to be accompanied by a significant increase in the number of blood monocytes and platelets when compared to control animals. Furthermore, the atherogenic diet produced a small but significant reduction in the blood monocyte phagocytic capacity and adhesion to plastic surface. No significant differences between both groups were found when spontaneous platelet aggregation in whole blood was studied. However, platelets from pigs fed the atherogenic diet had a smaller mean cell volume compared to controls. The results indicate than an atherogenic diet may affect blood monocytes and platelets in pigs.     

Anti-hypercholesterolemic Effect of Melatonin in Rats

The effects on plasma lipids of daily intraperitoneal injections of 4mg of melatonin (N-acetyl-5-methoxytrypt-amine) for 10 27 day periods were examined biochemically and morphologically in rats fed regular and high-cholesterol (1% cholesterol, 0.5% cholic acid) diets. Melatonin administration had no significant effect on plasma lipids and lipoproteins in the rats on a normal diet but blunted the effects of a high-cholesterol diet on these parameters. No effects of melatonin on lipase activity were noted. Melatonin also diminished the fatty infiltration in the liver of animals on the high-cholesterol diet. The high-cholesterol diet produced major increases in VLDL and LDL cholesterol and protein content, and decreases in HDL cholesterol and protein. Melatonin decreased the extent of this plasma lipoprotein increase, although it did not completely prevent the phenomenon. Therefore, the effect is thought to be quantitative and not quantitative in nature. Acta Pathol Jpn 39: 613-618, 1989.     

Effect of dietary protein and cholesterol on atherosclerosis in swine

Two groups of pigs, each consisting of six animals, were fed on isocaloric amounts of experimental diet with a high cholesterol content but no added fat and with varying levels of protein (5% vs 25% by weight of the diet) for 16 mo.Animals of the low-protein group were confirmed to have developed a protein-deficiency state by the characteristic microscopic changes in the viscera and hypoproteinemia due to reduced albumin fraction. They had a larger surface area of the aorta involved with atherosclerosis, and the lesions had a higher lipid and cholesterol and lower phospholipid content. The serum cholesterol was significantly higher, and the serum cholesterol esters contained larger proportion of oleic acid at the expense of linoleic acid than the animals of the high protein group.The results indicate that very low levels of dietary protein have a promotive effect on the induction of hypercholesterolemia and atherosclerotic lesions in the presence of cholesterol alone and in the absence of additional fats. The precise mechanism of this variation is not understood.     

Atherosclerosis and apoprotein E. An enigmatic relationship

In this article, we consider the role of apoprotein E in lipoprotein metabolism and especially in the metabolism of potentially atherogenic lipoproteins. Particular consideration has been given to three features of apoprotein E involvement in lipid cell interactions. Evidence implicating free cholesterol as a mediator of apoprotein E biosynthesis in cholesterol-loaded macrophages is presented. Experiments pointing to apoprotein E as the ligand promoting the interaction of beta-very-low-density lipoprotein (beta-VLDL) with macrophages are summarized. Finally, we describe the influence of fat and cholesterol fed to rhesus monkeys and baboons on the generation of hepatogenous (from isolated liver perfusates) VLDL enriched in cholesterol ester and apoprotein E. These hepatic VLDLs, none of which exhibits beta-electrophoretic mobility, promote cholesterol esterification in macrophages in proportion to their apoprotein E content. The complex role of apoprotein E in the genesis and reversal of atherosclerosis is briefly discussed.