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Biomedical subjects

A Angel

Publications and source records attributed to A Angel.

At least 145 records · Page 8Linked to original sources
PubMed1975

Uncoupling of lipolysis from cyclic AMP by procaine: a tool for studying the mechanism of action of antilipolytic agents.

The initial rate of net glycerol release in norepinephrine-stimulated adipose tissue fragments was inhibited (40-78%) by procaine-HCl (1-5mM), whereas basal (unstimulated) lipolysis was unaffected. A dose-related inhibition of norepinephrine-induced lipolysis by procaine-HCl (0.1-1 mM) also occurred in adipocytes. Procaine-induced antilipolysis was associated with an augmented rather than a reduced hormone-stimulated increment in intracellular cyclic AMP. The dissociation of lipolysis from cyclic AMP accumulation has been termed the uncoupling effect of procaine. This effect of procaine was employed to define the precise mechanism of action of the antilipolytic drug clofibrate (Atromid-S) which inhibits lipolysis by reducing cyclic AMP. A reduction in cyclic AMP by clofibrate was demonstrated in norepinephrine-stimulated cells exposed to procaine (uncoupled system). Thus, the inhibitory effect of clofibrate on cyclic AMP could not be attributed to accumulation of products of lipolysis. Because neither procaine-HCl nor clofibrate had any effect on the low Km 3':5'-cyclic-AMP phosphodiesterase (EC 3.1.4.17) activity in hormone stimulated cells, the clofibrate-induced reduction in cyclic AMP was attributed to its direct action on adipocyte adenylate cyclase.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1975

Inhibition of hormone-stimulated lipolysis by clofibrate. A possible mechanism for its hypolipidemic action.

The present study was undertaken to investigate the mechanism of the antilipolytic action of clofibrate (p-chlorophenoxyisobutyrate). Clofibrate, in the dose range of 10-80 mg/199 ml, inhibited the initial rate of norepinephrine-stimulated lipolysis 17-44 percent in isolated rat fat cells. At a dose corresponding to therapeutic levels in vivo (10 mg/100 ml) clofibrate also inhibited hormone-stimulated lipolysis by 20-30 percent in fragments of human subcutaneous fat. Inhibition of lipolysis by clofibrate occurred at all concentrations of norepinephrine and ACTH (0.02-0.1 mug/ml) but did not occur with equilipolytic concentrations of dibutyryl cyclic AMP, suggesting a proximal site of action on the lipolytic sequence. Clofibrate reduced by 60 percent (315plus or minus40 vs. 120plus or minus25 pmol/g lipid; meanplus or minusSEM) the norepinephrine-stimulated initial rise in cyclic AMP, measured 10 min after addition of hormone. Because the antilipolytic effect occurred in the presence of glucose and without altering cellular ATP levels, the reduction in intracellular cyclic AMP levels could not be attributed to uncoupling of oxidative metabolism or to secondary effects of free fatty acid accumulation. In the secondary effects of free fatty acid accumulation. In the presence of procaine-HC1, which blocks hormone-stimulated lipolysis without inhibiting cyclic AMP accumulation, addition of clofibrate prevented the hormone-stimulated rise in cyclic AMP. Clofibrate did not affect the activity of the low-Km 3',5'-cyclic AMP phosphodiesterase in norepinephrine-stimulated adipocytes. These data suggest that the antilipolytic effect of clofibrate is due to its suppression of cyclic AMP production by inhibition of adenylate cyclase. The drug's hypolipidemic action may in part be explained by its antilipolytic effect, which deprives the liver of free fatty acid substrate for lipoprotein synthesis.

Adenosine Triphosphate↗
PubMed1974

Regulation of cholesterol storage in adipose tissue.

Adipose tissue is a major site of cholesterol storage. In an attempt to define mechanisms controlling this process, a variety of nutritional and metabolic alterations were employed and their effects on adipose tissue cholesterol levels were determined by direct chemical analysis. When rats were raised on Purina chow, a linear increase in the cholesterol/DNA ratio in relation to animal weight (from 120 g [5-6 wk] to 700 g [2 yr]) occurred. The rate of cholesterol accumulation was related to the dietary cholesterol load. Cholesterol accumulation by adipose tissue also occurred in rats raised on a cholesterol-free diet and reached levels exceeding those observed in animals fed on a diet containing 0.05 or 0.1% (w/w) cholesterol. In rats maintained on semisynthetic diets containing 0 to 5% (w/w) cholesterol, the serum cholesterol concentration was inversely related to the dietary concentration, suggesting that feedback inhibition of cholesterol formation may be an important determinant of serum cholesterol levels in this species. Early dietary alterations affected adipose tissue levels later in life. Net cholesterol mobilization from adipose tissue also occurred after acute starvation. Comparison of obese mice with nonobese littermate controls showed that the size of the adipose cholesterol pool was proportional to the degree of adipocity because the amount of cholesterol stored per unit glyceride mass was identical. Adipose tissue cholesterol was not affected by animal sex. Thus, adipose tissue cholesterol levels were dependent on animal age, dietary cholesterol load, early nutritional deprivations, and the size of the adipose organ itself.

Adipose Tissue↗
PubMed1973

Bimodal effect of insulin on hormone-stimulated lipolysis: relation to intracellular 3',5'-cyclic adenylic acid and free fatty acid levels.

The present study was undertaken to determine the relationship between the antilipolytic and lipolytic effects of insulin on hormone-stimulated lipolysis and the mechanisms of these reactions. The dose-response curve of norepinephrine-stimulated lipolysis in rat adipocytes was not sigmoidal but biphasic in nature. Intracellular free fatty acid levels were linearly related to lipolytic rate and also described a biphasic profile in response to increments in norepinephrine concentration. Intracellular 3',5'-cyclic AMP levels measured 10 min after addition of increasing concentrations of norepinephrine showed a rise and a plateau followed by a secondary rise. Insulin was antilipolytic at low concentrations of norepinephrine and distinctly lipolytic at high concentrations. The combined antilipolytic and lipolytic effect of insulin is termed the "bimodal" effect of insulin on hormone-stimulated lipolysis. The bimodal effect of insulin correlated positively with changes in peak intracellular 3',5'-cyclic AMP levels. In the presence of glucose, insulin invariably enhanced lipolysis. It is suggested that the antilipolytic effect of insulin is achieved by both inhibition of adenyl cyclase activity and activation of low-K(m) 3',5'-cyclic AMP phosphodiesterase, the net effect being a low accumulation of 3',5'-cyclic AMP. On the other hand, the lipolytic effect of insulin probably reflects enhancement of adenyl cyclase activity to an extent that overrides any activation of low-K(m) 3',5'-cyclic AMP phosphodiesterase activity, resulting in an increase in peak adipocyte 3',5'-cyclic AMP levels.

Adenosine Triphosphate↗
PubMed1973

Studies on the compartmentation of lipid in adipose cells. II. Cholesterol accumulation and distribution in adipose tissue components.

Adipose tissue was shown to contain 0.6-1.6 mg of cholesterol per gram wet weight. When expressed per unit of protein or organ mass, fat tissue contains more cholesterol than most other organs or membranes. The cholesterol content of fat tissue increased with the age and weight of the rat. Over 95% of adipose tissue sterols was cholesterol, and most of it was free. In young (150-165 g) rats two-thirds of fat tissue cholesterol was in collagenase-derived adipocytes while in older rats (450-480 g) 90% of fat tissue cholesterol was in adipocytes and the remainder was in stromal-vascular elements. Age-related differences in subcellular cholesterol distribution were also observed. The cholesterol/phospholipid molar ratios of purified plasma membrane fractions from small and large fat cells were identical (0.22-0.25), thus resembling muscle and liver membranes. 7.5 days after intravenous administration of [4-(14)C]cholesterol the specific activity of adipose cholesterol exceeded that of plasma cholesterol. At 28 days the specific activity of adipose and muscle cholesterol exceeded that of plasma three- to fivefold. The t((1/2)) disappearance of adipose tissue cholesterol was approximately 27 days, which is consistent with its function as a slowly turning over storage pool. Thus, fat tissue is a major cholesterol storage organ. This may well account for the marked expansion of the slowly exchangeable cholesterol pool (pool B) observed in obesity.

Adipocytes↗