Apolipoprotein E is a putative autocrine regulator of the rat ovarian theca cell compartment.

Apolipoprotein (apo) E inhibits androgen production by ovarian theca cells. We found that apo E, as a synthetic peptide mimicked the full-size protein, induced theca and interstitial cell (TIC) apoptosis indicated by pyknotic cell morphology, increased DNA end-labeling (TUNEL), and DNA ladders. None of the low-density lipoprotein (LDL) receptor superfamily members were involved because the universal antagonist of these receptors, receptor-associated protein (RAP), did not block apo E-induced apoptosis. Furthermore, several apo E synthetic peptides that do not bind the LDL receptor did induce TIC apoptosis. Similar to apo E, apoptogenic agents such as ceramide and LY 294002, a phosphatidylinositol (PI) 3-kinase inhibitor, induced apoptosis and suppressed androstenedione production. However, apoptosis alone was not responsible for apo E suppression of androstenedione production because both insulin and IGF-I prevented apo E-induced apoptosis, but neither restored androstenedione production. Theca cells of atretic follicles express the greatest apo E mRNA, and here we show that cultured TIC produce apo E. When considered with the observation of TUNEL-positive theca cells in atretic follicles these results support our hypothesis that intraovarian apo E controls theca cell production of androgen as well as limiting the size of the theca cell compartment.

Apolipoprotein E peptide stimulation of rat ovarian theca cell androgen synthesis is mediated by members of the low density lipoprotein receptor superfamily.

Ovarian androgen production is rate limiting for follicular maturation and can induce follicular atresia. Thus, it is important to define the actions of the intraovarian agents, such as apolipoprotein (apo) E, that modulate theca cell androgen production. Theca cell androgen production is stimulated at low concentrations and inhibited at higher concentrations of native apo E. The apo E peptide, acetyl-Y(LRKLRKRLLRDADDL)(2)C or acetyl-Y(141-155)(2)C, has low density lipoprotein (LDL) receptor and LDL receptor-related protein-binding activity, and it mimics the activity of native apo E in the theca-interstitial cell system. To define the role of members of the LDL receptor superfamily in the apo E peptide-mediated responses, we found that receptor-associated protein prevented the stimulation without altering the inhibition of androstenedione production. The apo E peptide (129-162), which has no LDL receptor-binding activity, did not stimulate androstenedione production. The apo E peptide acetyl-Y(141-155)(2)C did not stimulate androstenedione production when cell surface heparan sulfate proteoglycans were degraded with heparinase. The apo E peptide acetyl-Y(141-155)(2)C bound to heparin, a property of LDL receptor ligands, and in this complex the peptide had no effect on androstenedione production. These observations support the conclusion that apo E-mediated stimulation, but not inhibition, of ovarian theca cell androstenedione production was mediated by members of the LDL receptor superfamily.

Physiological constraints in the aerobic performance of hummingbirds

Hovering flight has been described as the most energetically expensive form of locomotion. Among the vertebrates, hummingbirds weighing only 1.5-20 g are the elite practitioners of this aerial art. Their flight muscles are, therefore, the most oxygen demanding locomotor muscles per unit tissue mass of all vertebrates. Tissue level functional and structural adaptations for oxygen transport are compared between hummingbirds and mammals in this paper. Hummingbirds present extreme structural adaptations in their flight muscles. Mitochondrial densities greater than 30 per cent are observed in their pectoral muscles, and the surface area of the inner membrane of their mitochondria is tvace that of mammals. This doubling of their mitochondrial oxidative capacity is accompanied by a proportional increase in the specific activity (per g tissue) of the mitochondrial manganese superoxide dismutase (SOD-Mn) in their flight muscles, thus indicating that oxygen toxicity is not a constraint in the aerobic performance of hummingbirds during hovering flight. Finally, the liver appears to play a major role in providing the necessary substrates for their high aerobic performance, and also in eliminating the oxygen free radicals formed during oxidative phosphorylation.

Physiological constraints in the aerobic performance of hummingbirds.

Hovering flight has been described as the most energetically expensive form of locomotion. Among the vertebrates, hummingbirds weighing only 1.5-20 g are the elite practitioners of this aerial art. Their flight muscles are, therefore, the most oxygen demanding locomotor muscles per unit tissue mass of all vertebrates. Tissue level functional and structural adaptations for oxygen transport are compared between hummingbirds and mammals in this paper. Hummingbirds present extreme structural adaptations in their flight muscles. Mitochondrial densities greater than 30% are observed in their pectoral muscles, and the surface area of the inner membrane of their mitochondria is twice that of mammals. This doubling of their mitochondrial oxidative capacity is accompanied by a proportional increase in the specific activity (per g tissue) of the mitochondrial manganese superoxide dismutase (SOD-Mn) in their flight muscles, thus indicating that oxygen toxicity is not a constraint in the aerobic performance of hummingbirds during hovering flight. Finally, the liver appears to play a major role in providing the necessary substrates for their high aerobic performance, and also in eliminating the oxygen free radicals formed during oxidative phosphorylation.

Independent regulation of chylomicron lipolysis and particle removal rates: effects of insulin and thyroid hormones on the metabolism of artificial chylomicrons.

The processes of chylomicron lipolysis and removal from plasma were investigated by the intra-arterial infusion of doubly labeled artificial chylomicrons in rats. The rate of lipolysis was measured as a delipidation index (DI), which is the glyceryl-tri-9,10(N)-3H oleate (3H-TO) fraction removed from the particle as fatty acids, whereas the cholesteryl(1-14C) oleate (14C-CO) plasma disappearance rate measures the splanchnic organ particle uptake. In the alloxan-diabetic rats, despite a normal DI, the 14C-CO plasma residence time (RT) was longer than in control animals and remained longer after stimulation of the lipoprotein lipase by heparin. DI and 14C-CO removal rate were not significantly altered by insulin administration to glucose-supplemented control rats. Lipolysis was remarkable in propylthiouracil (PTU)-induced hypothyroidism, and yet the 14C-CO removal rate was retarded. In hypothyroidism, heparin enhanced the 14C-CO removal more than in the control group; however, after heparin, the 14C-CO RT still remained higher in the hypothyroid animals as compared with the control group. Hyperthyroidism lowered the DI; nevertheless, the 14C-CO disappearance rate was faster than in controls. In summary, lack or excess of thyroid hormone influences both the chylomicron lipolysis and removal systems, whereas lack of insulin impairs mostly the particle removal from plasma, and excess of insulin has no effect on the chylomicron metabolism.

[Effects of lovastatin in primary hypercholesterolemia]. / Efeitos da lovastatina na hipercolesterolemia primária.

Lovastatin, a potent inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme-A-reductase, was investigated in a placebo-controlled trial of 26 primary hypercholesterolemic subjects. Drug dosage varied from 20 to 40 mg/d in a single dose on a 12 weeks treatment period. Average plasma cholesterol reduction levels were 17 and 31%, and LDL-cholesterol 24 and 41% on 20 and 40 mg/d respectively. High-density lipoprotein and triglycerides levels did not change significantly. Similar mean decreases in total plasma cholesterol and LDL-cholesterol levels were observed in hypercholesterolemics irrespectively of being of familial origin or not. No serious clinical and laboratory abnormalities were observed. In this study, lovastatin was a well tolerated and effective agent for the treatment of non familial and heterozygous familial hypercholesterolemia.