William F. Prigge

Effects of glucagon, epinephrine and insulin on in vitro lipolysis of adipose tissue from mammals and birds

Abstract 1. Glucagon (5·0 μg/ml) stimulated lipolysis in rat, rabbit, goose, duck and owl, but not in dog. 2. Epinephrine (1·0 μg/ml) stimulated lipolysis in rat, dog, goose and owl, but not in duck and rabbit. 3. Insulin (0·1 U/ml) inhibited lipolytic effect of glucagon in rat, but not in goose, duck and rabbit. 4. Nicotinic acid (12·0 μg/ml) inhibited lipolytic effect of glucagon in rat, but not in rabbit, goose, duck and owl.

Effect of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibition on human gut mucosa

Mevalonic acid is an important biochemical intermediate in cholesterol synthesis and other processes involved in cell replication. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is the enzyme which catalyzes mevalonic acid synthesis. To determine whether a potent competitive inhibitor of this enzyme, the drug simvastatin, may have an adverse effect on enterocyte cell replication and cholesterol metabolism, small intestinal biopsies from nine hypercholesterolemic subjects were obtained before and during treatment with simvastatin as a lipid-lowering agent. Histologic review of biopsies in a blinded manner detected no change in ratio of villous length to crypt length or in mitotic index which might indicate altered cell replication. Similarly, no significant change in measured activity of HMG-CoA reductase activity was observed. In spite of the high exposure of jejunal mucosal cells to this potent competitive inhibitor of a key enzyme, no adverse effect on growth could be detected.

Suppression by Hepatectomy of Glucagon-Induced Hypertriglyceridemia in Geese

Summary Continuous infusion of glucagon (1.0 μg/kg/min for 30 min) in normal geese caused an elevation of plasma FFA and blood sugar and a decrease of plasma TGL concentration. Upon discontinuing glucagon infusion, plasma TGL rose significantly to a peak level 2 hr after the end of infusion. Functional hepatectomy suppressed the elevations of plasma TGL and blood sugar observed in normal geese infused with glucagon, and produced a continuous decrease of plasma TGL which was not affected by the administration of glucagon. These results indicate that the elevation of plasma TGL after glucagon infusion is due to increased release of lipoproteins by the liver, induced by the elevation of plasma FFA. The decrease of plasma TGL during the infusion of glucagon and the delay between the elevations of plasma FFA and plasma TGL suggest that glucagon, in addition to its adipokinetic effect, decreases the release of TGL by the liver into the circulation.

Influence of Prostaglandin E1 on the Adipokinetic Effect of Glucagon in Birds

Summary The intravenous administration of PGE1 had adipokinetic and hyperglycemic effects in ducks and geese. No inhibition of the adipokinetic effect of glucagon was demonstrated when PGE1 was injected immediately before glucagon, or during a continuous infusion of glucagon. A significant inhibition of the adipokinetic effect of glucagon in geese was observed, however, when this hormone was injected during a continuous infusion of PGE1. A significant inhibition of glucagon-stimulated lipolysis in vitro, in the adipose tissue of adult ducks, was observed only with the highest dose of PGE1 tested (50.0 μg/ml). Administration of PGE1 in geese caused a prompt fall of arterial pressure and marked elevation of the pulse rate. The skillful technical help of Miss Donna E. Swenson is gratefully acknowledged.

Transport of circulating serum cholesterol by human renal cell carcinoma.

Clear cell renal cancer contains a large quantity of cholesterol ester (300-mg./gm. protein). To determine whether abnormalities in cholesterol transport could account for this sterol accumulation, the uptake, release, and imaging capabilities of intravenously injected 131I-6-iodomethyl-29-norcholesterol, a cholesterol analogue, were studied preoperatively in five patients with clear cell renal cancer. At surgery, samples of the liver, tumor, adrenal, and non-tumor kidney were obtained for analysis. 131I-sterol uptake by the tumor, when normalized for cholesterol content, was less than for adrenal, liver or kidney. In contrast, release of preloaded 131I-sterol from the human tumors was consistently slower than for normal kidney. The reduced release of free cholesterol from renal cancer cells may, in part, be responsible for the accumulation of cholesterol in human renal cancer.

Thyroid hormone is required for dietary fish oil to induce hypersecretion of biliary cholesterol in the rat

In the rat, both fish oil diet and thyroid hormone replacement are reported to augment bile cholesterol secretion out of proportion to bile flow or secretion of other bile lipids. We sought common mechanisms for these effects and evaluated the role of phospholipid fatty acid composition in the process. Methimazole-treated hypothyroid rats were fed low-fat chow or chow supplemented with 10% corn oil or fish oil, and were studied before and after thyroid hormone treatment. Serum, hepatic, and bile lipids were measured, phospholipid fatty acid composition determined, and hepatic 3-hydroxy-3-methylglutaryl CoA reductase activity assayed. Fish oil diet stimulated cholesterol secretion into bile only after thyroid hormone was given, and this action was synergistic with that of thyroid hormone. Reduced serum cholesterol in fish oil-treated rats was associated with increased biliary cholesterol secretion and diminished hepatic cholesterol content. This suggests that augmented biliary cholesterol secretion may contribute to the fish oil-induced reduction of serum cholesterol. No definite relationship between hepatic or biliary phospholipid fatty acid composition and biliary secretion was apparent, although high bile cholesterol secretion was associated with a low percentage of hepatic and bile phospholipid linoleic acid.

Diurnal rhythm of HMG CoA reductase activity in canine intestine is independent of luminal contents.

Activity of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (EC 1.1.1.34) measured in isolated segments of canine intestinal mucosa showed a distinct diurnal rhythm. Total activity changed over a twofold range with a peak occurring during midday, shortly after feeding. Since the isolated segments had no contact with luminal contents, the rhythm was not directly related to food components or bile salts. Humoral or neural influences must mediate the rhythm. The diurnal rhythm persisted for at least 3–5 mo, but was lost by 10 mo following formation of the isolated segment, possibly because of mucosal involution.

ORAL ACETYLSALICYLIC ACID INDUCES BILIARY CHOLESTEROL SECRETION IN THE RAT

Several agents can alter biliary cholesterol secretion, critical for cholesterol excretion and gallstone formation. Although salicylate effects on bile formation and gallstones have been studied, biliary lipid secretion has not been measured during oral aspirin treatment. We examined whether oral acetylsalicylic acid affects bile lipid secretion. Three groups of young rats were fed chow for 3 wk. Two of the groups then received aspirin at either 1.67 or 3.33 g/kg diet for 4 d. Serum, hepatic, and bile lipids were measured, as were enzymes of cholesterol synthesis and esterification. With oral aspirin, bile cholesterol secretion increased by 42% and hepatic cholesteryl ester content decreased by 40%. Serum cholesterol and hepatic free cholesterol did not change. To evaluate mechanisms of the cholesterol hypersecretion, hypothyroid animals fed low-fat or fish oil diets and repleted with triiodothyronine were also studied. Aspirin stimulated cholesterol secretion to a degree similar to triiodothyronine. An additive response was seen in fish oilfed rats. Aspirin did not appear to have a primary action on 3-hydroxy-3-methylglutaryl-CoA reductase or acyl CoA:cholesterol acyltransferase activities, and had no direct effect on esterification of cholesterol by isolated hepatocytes. Aspirin may directly increase cholesterol transport into bile or have cell membrane effects which alter cholesterol transport. It remains to be determined whether the observed alterations in bile cholesterol secretion are specific to the rat or also apply to humans.

Influence of theophylline on the adipokinetic effect of glucagon in vivo.

Summary Injection of theophylline and of aminophylline caused no elevation of plasma FFA, but produced significant elevation of blood sugar concentration in geese, ducks, and owls. Injection of theophylline caused elevations of both plasma FFA and blood sugar in rabbits. The hyperglycemic and adipokinetic effects of glucagon in birds were not potentiated by the administration of theophylline. The adipokinetic and hyperglycemic effects of glucagon in rabbits were greater when the hormone was injected after an injection of theophylline, than when it was injected during an infusion of glucagon producing levels of plasma FFA and blood sugar similar to those produced by the administration of theophylline.