Soy-tibolone combination - effect on lipids in postmenopausal monkeys and women.

OBJECTIVES: To determine whether co-administration of soy during tibolone treatment would prevent tibolone-induced dyslipoproteinemia in postmenopausal monkeys and women. METHODS: Surgically postmenopausal cynomolgus monkeys (n = 18) were assigned randomly to one of four dietary regimens in a Latin Square crossover design, such that all animals received all diets for 14 weeks with a 4-week washout period: (1) casein/lactalbumin (CL); (2) tibolone (Tib, 1.25 mg/day women's equivalent); (3) soy (138 mg isoflavones/day women's equivalent); (4) Soy + Tib. Postmenopausal women on tibolone treatment were randomized to receive soy powder (52 g of soy protein containing 112 mg isoflavones) or placebo (containing 52 g of milk protein) daily in a crossover trial for 8 weeks with a 4-week washout period. RESULTS: Monkeys given Tib alone had approximately 14% increase in plasma LDL + VLDL-C; whereas those given soy combined with tibolone had significant ( approximately 22%) reductions. Tib treated monkeys had reductions in plasma HDL-C of about 48% vs. no reductions in Soy + Tib. In postmenopausal women using tibolone, soy reduced plasma LDL-C concentrations by approximately 10% from baseline without a change in HDL-C. CONCLUSIONS: Co-administration of soy during tibolone treatment improved the lipoprotein profile in both monkeys and women; however, the effects were more robust in monkeys.

[Disorders of lipid and glucose metabolism. Long-term adverse effects of antiretroviral therapy]. / Störungen des Lipid- und Glukosestoffwechsels. Langzeitnebenwirkungen antiretroviraler Therapie.

In addition to readily controllable short-term side effects, highly active antiretroviral therapy (HAART) also has long-term side effects: lipodystrophy syndrome, hyperlipoproteinemia, insulin resistance, elevated glucose tolerance sometimes leading to diabetes mellitus and lactic acidosis. The pathogenesis remains uncertain although various hypotheses have been advanced. A number of approaches for the treatment of lipodystrophy are available, the effects of which, however, have not been confirmed by study results. Hyperlipoproteinemia probably means an increased cardiovascular risk, but a final pronouncement on this is not yet possible. Fibrates and statins are currently applied for treatment, but interactions with HAART medicaments have to be considered. HAART-induced diabetes mellitus presents clinically as type 2 diabetes, and is treated accordingly.

The Arg123-Tyr166 central domain of human ApoAI is critical for lecithin:cholesterol acyltransferase-induced hyperalphalipoproteinemia and HDL remodeling in transgenic mice.

High density lipoprotein (HDL) metabolism and lecithin:cholesterol acyltransferase (LCAT)-induced HDL remodeling were investigated in transgenic mice expressing human apolipoprotein (apo) AI or an apoAI/apoAII chimera in which the Arg123-Tyr166 domain of apoAI was substituted with the Ser12-Ala75 domain of apoAII. Expression of apoAI and of the apoAI/apoAII chimera resulted in a respective 3. 5-fold and 2.9-fold increase of HDL cholesterol. Human LCAT gene transfer into apoAI-transgenic mice resulted in a 5.1-fold increase of endogenous LCAT activity. This increase was associated with a 2. 4-fold increase of the cholesterol ester-to-free cholesterol ratio of HDL, a shift from HDL(3) to HDL(2), and a 2.4-fold increase of HDL cholesterol levels. Agarose gel electrophoresis revealed that human LCAT gene transfer into human apoAI-transgenic mice resulted in an increase of pre-beta-HDL and of pre-alpha-HDL. In contrast, human LCAT gene transfer did not affect cholesterol levels and HDL distribution profile in mice expressing the apoAI/apoAII chimera. Mouse LCAT did not "see" a difference between wild-type and mutant human apoAI, whereas human LCAT did, thus localizing the species-specific interaction in the central domain of apoAI. In conclusion, the Arg123-Tyr166 central domain of apoAI is not critical for in vivo lipoprotein association. It is, however, critical for LCAT-induced hyperalphalipoproteinemia and HDL remodeling independent of the lipid-binding properties of apoAI.

Cyclosporin-induced dyslipoproteinemia is associated with selective activation of SREBP-2.

The use of cyclosporin A has contributed greatly to the success of organ transplantation. However, cyclosporin-associated side effects of hypertension, nephrotoxicity, and dyslipoproteinemia have tempered these benefits. Cyclosporin-induced dyslipoproteinemia may be an important risk factor for the accelerated atherosclerosis observed posttransplantation. Using a mouse model, we treated Swiss-Webster mice for 6 days with a daily dose of 20 microg/g body wt of cyclosporin and observed significant elevations of plasma cholesterol, triglyceride, and apolipoprotein B (apoB) levels relative to vehicle-alone treated control animals. Measurement of the rate of secretion of very low-density lipoprotein (VLDL) by the liver in vivo showed that cyclosporin treatment led to a significant increase in the rate of hepatic VLDL triglyceride secretion. Total apoB secretion was unaffected. Northern analysis showed that cyclosporin A treatment increased the abundance of hepatic mRNA levels for a number of key genes involved in cholesterol biosynthesis relative to vehicle-alone treated animals. Two key transcriptional factors, sterol regulatory element-binding protein (SREBP)-1 and SREBP-2, also showed differential expression; SREBP-2 expression was increased at the mRNA level, and there was an increase in the active nuclear form, whereas the mRNA and the nuclear form of SREBP-1 were reduced. These results show that the molecular mechanisms by which cyclosporin causes dyslipoproteinemia may, in part, be mediated by selective activation of SREBP-2, leading to enhanced expression of lipid metabolism genes and hepatic secretion of VLDL triglyceride.

Drugs causing dyslipoproteinemia.

Diuretics and beta-blockers have a strong tendency to affect serum lipids adversely, whereas the peripherally acting alpha-blocking agents consistently result in beneficial effects. Most of the other antihypertensive agents (calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists, and drugs that act centrally) are lipid neutral. The effect of steroid hormones varies with the drug, dose, and route of administration. In general, androgens lower HDL-C and have a variable effect on LDL-C. The effects of progestins vary greatly depending on their androgenicity, and estrogens are beneficial except when hypertriglyceridemia occurs with oral estrogens. Glucocorticoids raise HDL-C and may also increase triglycerides and LDL-C. Retinoids increase triglycerides and LDL-C and also reduce HDL-C. Interferons can cause hypertriglyceridemia. Following organ transplantation, a dyslipidemia often ensues. This is caused in part by the medications used to prevent rejection (glucocorticoids, cyclosporine, and FK-506) and requires close attention and, in some patients, drug therapy to prevent coronary artery disease.

[Prevalence of dyslipoproteinemia in workers engaged in the production of higher fatty alcohols]. / Rasprostranennost' dislipoproteidemii sredi rabochikh, zaniatykh v proizvodstve vysshikh zhirnykh spirtov.

To reveal serum serum lipoprotein disorders, the authors studied serum lipids and lipoproteins compositions in 116 male workers engaged into production of higher fatty alcohols at oil-processing plant. All the cases of serum lipoprotein disorders were divided into 8 types. Secondary are the disorders of those examines (63.8%) who have chronic diseases. Six types of the disorders were identified in apparently healthy examines (36.2%).

Overexpression of human apolipoprotein A-I in transgenic rats and the hyperlipoproteinemia associated with experimental nephrosis.

Hyperlipoproteinemia contributes both to kidney disease progression and the development of atherosclerosis. Elevated high density lipoprotein cholesterol and apolipoprotein A-I (apoA-I) serum levels are independent factors protective against the atherosclerotic process. We examined the effects in a transgenic rat model of human apoA-I expression on the hyperlipoproteinemia and edema after puromycin aminonucleoside-induced nephrosis in three groups of animals: low line (TgR[hAI]low, human plasma apoA-I = 16.0 mg/dl); high line (TgR[hAI]high, 284 mg/dl); and non-transgenic litter mates (TgR[hAI]non). Nephrosis increased total plasma apoA-I levels 2-fold in TgR[hAI]non rats (75 vs. 162 mg/dl) and 4-fold in the TgR[hAI]low (97 vs. 458 mg/dl) and TgR[hAI]high rats (356 vs. 1,346 mg/dl). In both transgenic lines, this increase was due mainly to elevations of serum human apoA-I. The hepatic steady-state levels of rat apoA-I mRNA increased 5- to 7-fold in all three groups, while human apoA-I mRNA levels increased 21- and 65-fold in the low and high expressing groups, respectively, indicating a different degree of responsiveness of the rat and human genes. While nephrotic TgR[hAI]non and TgR[hAI]low rats showed severe hyperlipoproteinemia and edema, much lower levels of edema and of serum triglycerides, phospholipids, and cholesterol were seen in the TgR[hAI]high group. Urinary excretion of apoA-I, phospholipids, and cholesterol was significantly increased in the TgR[hAI]high group, indicating this as one possible mechanism for the relatively lower serum levels of these lipids. We conclude that the human apoA-I gene is responsive to nephrosis and that human apoA-I-transgenic rats with this syndrome provide an animal model for the study of human high density lipoprotein and apoA-I metabolism.

Mitochondrial abnormalities of muscle tissue in mice with juvenile visceral steatosis associated with systemic carnitine deficiency.

A mouse with juvenile visceral steatosis (the JVS mouse) has been recognized as a novel animal model for systemic carnitine deficiency. We examined cardiac, skeletal and smooth muscle cells in JVS and control mice by light and electron microscopy. Cardiac and skeletal muscle cells of these mice at 4 weeks of age exhibited a ragged-red appearance after trichrome staining. Electron microscopy, demonstrated increased numbers of mitochondria and lipid droplets in the cells. Compression or distortion of the myofibril bundles, primarily due to the increased number of mitochondria, suggests the possible existence of a functional disturbance of the cardiac and skeletal muscle. In the urinary bladder, only one or two large lipid droplets and slightly increased number of mitochondria were recognized in the perinuclear region of the smooth muscle cells. At 8 weeks of age, the mouse enzyme histochemistry specific for mitochondria, such as cytochrome c oxidase and succinic dehydrogenase, and oil red O staining, confirmed further increases in the number of mitochondria and lipid droplets in the heart. However, the accumulation of these organelles in the skeletal and smooth muscle cells was no greater than that noted in JVS mice at 4 weeks of age. In the cardiac muscle cells, autolysosomes or autophagic vacuoles containing electron-dense membranous, lamellar or whorled structures closely associated with mitochondria and pseudoinclusion bodies in the nucleus were recognized, and bundles of myofibrils were buried under numerous mitochondria, suggesting the existence of disturbed contractile function in the heart of JVS mice. These results indicate that this murine strain associated with systemic carnitine deficiency exhibits a generalized mitochondrial abnormality in the muscle system especially in the heart.

Topical timolol maleate might adversely affect serum lipoproteins.

Conflicting observations have been reported about the effects of topically administered timolol maleate on serum lipoproteins. We therefore considered this issue in a series of eight glaucoma patients receiving timolol maleate. Cholesterol and triglycerides were measured in plasma and in low-density lipoproteins (LDL), and high-density lipoproteins (HDL), both before and following three months of treatment. Following the treatment, the mean atherogenic index was increased from 2.72 to 3.38 (p = 0.012). This suggests that the atherogenic index should be determined before and during timolol maleate treatment in high-risk cardiovascular patients.

Copper deficiency and hyperlipoproteinemia induced by a tetramine cupruretic agent in rabbits.

The effectiveness of a cupruretic agent, N,N'-bis-(2 amino ethyl)-1,3-propanediamine HCl or 2,3,2-tetramine HCl (TETA), in the induction of copper (Cu) deficiency and the ability of a Cu-deficient diet in the maintenance of the depressed Cu status 10 wk after TETA treatment were examined in this study. In the first experiment, 42 male New Zealand White rabbits, 35 d of age, were randomly divided into three dietary treatments: a copper (Cu)-deficient (2.3 mg Cu/kg diet), a Cu-adequate (13.5 mg Cu/kg diet), and a commercial ration (21.6 mg Cu/kg diet) group. A single oral dose of 100 mg of 2,3,2-tetramine HCl TETA/kg body wt/d were administered to half of the rabbits from each treatment group for 10 d while the remaining rabbits were untreated. In the second experiment, 10 similar rabbits were assigned to three treatments: Cu-deficient plus TETA (n = 4); Cu-adequate plus TETA (n = 3); and Cu-adequate alone (n = 3). The rabbits were fed a TETA dose of 100 mg/d for three 4-d periods over 3 wk, and thereafter maintained on the diets for another 10 wk. Rabbits from the first experiment fed Cu-deficient diet and treated with TETA demonstrated cardiac hypertrophy and markedly reduced plasma and liver Cu concentrations that indicated that the animals were Cu-deficient. Significant elevations (twofold) in low density lipoprotein (LDL) protein, cholesterol, triglyceride, and apolipoprotein B (apo B) concentrations were observed in TETA treated rabbits fed Cu-deficient diet. In the second experiment, the plasma LDL protein level remained elevated, the plasma Cu level was reduced 45%, and the Cu level of the heart when expressed as microgram/g dry tissue was reduced, 10 wk post TETA treatment in rabbits maintained on Cu-deficient diet. Thus, Cu deficiency and hyperlipoproteinemia was rapidly induced by TETA and was still evident 10 wk posttreatment in rabbits maintained on a Cu-deficient diet.

[Influence of alcohol on plasma lipids and atherogenesis. Epidemiological and biochemical aspects]. / Influence de l'alcool sur les lipides plasmatiques et l'athérogenèse. Aspects épidémiologique et biochimique.

The results of epidemiological and clinical studies published since 1980 concerning the effects of alcohol intake on coronary artery disease are rather contradictory. Although some protective action of alcohol, notably of wine against atherosclerosis, has been described by some authors, the methodological limitations of these studies make it impossible to establish a cause-effect relationship in this matter. Biochemical studies have provided a more precise approach of the effect of alcohol on the mechanism of atherosclerosis. An increase of HDL has been shown in patients who regularly consume alcoholic drinks. However, a detailed analysis of HDL subfractions (and notably HDL2 regarded as an antiatherogenic lipoprotein) has given equally contradictory results. When the antiatherogenic lipoprotein particles present in HDL are accurately identified, the physiopathological consequences of regular alcohol consumption will be more clearly determined. Biochemical and epidemiological information is still insufficient for us to attribute an antiatherogenic effect to alcohol.

Hyperlipoproteinemia in rats fed polychlorinated biphenyls.

Hypercholesterolemia due to feeding of polychlorinated biphenyls (PCB) and due to feeding of high cholesterol was compared. Rats in control group were fed a 25% casein diet, and those in PCB group or cholesterol group were fed the 25% casein diet supplemented with 0.03% PCB or 1% cholesterol and 0.25% cholic acid, respectively. Lipoprotein mass (d less than 1.21 g/ml) was higher 1.9- and 1.3-fold in rats fed PCB and cholesterol, respectively, as compared with controls. In rats fed PCB, protein, cholesterol, and phospholipid in the lipoprotein fraction markedly increased. Cholesterol-feeding resulted in the increase in pre-beta-lipoprotein cholesterol, while PCB-feeding increased alpha-lipoprotein cholesterol and slightly slow migrated pre-beta-lipoprotein cholesterol. PCB-treated rats had more apolipoprotein A-I in the lipoprotein fraction than control and cholesterol-fed rats. The data demonstrated that hyperlipoproteinemia induced by PCB is a novel alpha-lipoproteinemia and a useful model for investigating metabolism of high density lipoprotein.

Predicted reductions in the risk of coronary heart disease by antihypertensive therapy: the confounding effect of lipids.

The treatment of arterial hypertension confers several important benefits, e.g. reducing hypertension-induced cardiovascular morbidity and mortality. However, the preventive effect for coronary heart disease is considerably smaller than the effect of treatment on the incidence of strokes. Several factors may explain this discrepancy, but it appears likely that drug-induced increases in serum lipoproteins may, to some extent, offset the risk reduction obtained through the lowering of blood pressure. It appears that more emphasis should be put on therapeutic intervention in other risk factors in addition to the treatment of hypertension. An appropriate therapeutic aim of the treatment of hypertension should be to lower blood pressure to 'normotensive' levels, by using drugs which do not themselves increase cardiovascular risks, e.g. do not increase serum lipoproteins, and to actively intervene against other co-existing risk factors, such as hyperlipidaemia. By using this approach, it seems likely that the risk of coronary heart disease can be reduced.

[The HDL cholesterol level in patients treated with antiepileptic drugs]. / Cholesterol HDL (lipoprotein wysokiej gestosci) u pacjentów leczonych lekami przeciwpadaczkowymi.

Total cholesterol, HDL cholesterol, and HDL2 and HDL3 cholesterol were estimated in individuals undergoing anticonvulsant therapy. Significantly higher, than in the corresponding control groups HDL concentration, concerning mainly HDL2 subfraction was found in female epileptic and in male alcoholic epileptic patients. It was observed that higher drug levels were accompanied by higher HDL cholesterol values. In alcohol addicted subjects undergoing anticonvulsant therapy low-nontherapeutic serum drug concentration was often observed. In spite of this, HDL levels were high. This could result from an additional induction of cytochrome P-450 caused by alcohol and an accelerated oxidation of the drugs. This observation indicates that frequent control of drug concentration in these patients is desirable.

[Modification of lipoprotein metabolism by antihypertensive therapy]. / Zur Beeinflussung des Lipoproteinmetabolismus bei antihypertensiver Therapie.

Of various antihypertensive drugs, particularly the unselective as well as the selective beta-receptor blockers but also diuretic drugs unfavourable effects on the lipid metabolism are reported, which above all consist of increases of triglycerides and decreases of HDL-cholesterol. The more modern antihypertensive drugs such as calcium antagonists, alpha 1-receptor blockers or angiotensin converting enzyme inhibitors according to the hitherto existing studies have no significant influence on the serum lipids. The final classification of the antihypertensive drugs regarding their influence on the atherogenic risk by negative changes in the lipoprotein metabolism is, however, at present not yet possible on account of insufficient long-term studies. For the reduction of adequate endangerings dietetic measures, reduction of overweight, physical training and when occasion arises change of the medication are recommended.