Effects of bile salts on rat hepatic acyl CoA:cholesterol acyltransferase.

Acyl CoA:cholesterol acyltransferase (EC2.3.1.26, ACAT), responsible for intracellular esterification of cholesterol, may play an important role in cholesterol trafficking within the cell, and thus, in maintenance of cellular cholesterol homeostasis. Bile acids are potential regulators of cholesterol trafficking in the liver. Therefore, the effect of bile salts on hepatic ACAT activity was studied in the perfused rat liver. ACAT activity was increased after liver perfusion with either taurocholate or taurochenodeoxycholate. However, addition of these bile salts at physiological concentrations in vitro had little effect on microsomal ACAT activity. The increase in hepatic ACAT activity due to perfusion with bile salts was accompanied by reduced accumulation of very low density lipoprotein cholesterol in the perfusate, but there was no effect on 3-hydroxy-3-methylglutaryl-CoA reductase activity. Hepatic ACAT activity was decreased after bile diversion for four hours in the intact animal. This treatment had no statistically significant effect on 3-hydroxy-3-methylglutaryl-CoA reductase activity. These data suggest that bile salts induce changes in hepatic compartmentation and traffic of cholesterol within the hepatocyte accompanied by response of ACAT activity to maintain cellular cholesterol homeostasis.

Brunner's gland adenoma.

We have reported a case of Brunner's gland adenoma. Proliferative lesions of these duodenal glands are rare; they are occasionally associated with gastric hyperchlorhydria or chronic pancreatitis. The clinical presentation can vary from vague upper abdominal symptoms with dyspepsia and nausea to diarrhea, jaundice, obstruction, and gastrointestinal bleeding. The diagnosis is usually made by radiologic studies followed by upper endoscopy, which can also provide definitive treatment. As in our case, surgery may be necessary for adequate removal of these lesions.

Regulation of rat hepatic cholesterol metabolism. Effects of lipoprotein composition on acyl coenzyme A:cholesterol acyltransferase in vivo and in the perfused liver and on hepatic cholesterol secretion.

Lipoproteins that are removed from the circulation by the liver can deliver both cholesterol and triglycerides to the hepatocyte. Relative proportions of these lipids may vary in lipoproteins and, thus, their uptake may have differing effects on cholesterol homeostasis. To study this, lipoproteins containing the same amounts of cholesterol but different amounts of triglyceride were administered to intact rats or to an isolated perfused rat liver. The responses of acyl coenzyme A:cholesterol acyltransferase (ACAT), very low density lipoprotein (VLDL) triglyceride and cholesterol secretion, and biliary cholesterol content were examined after 2 hr. Administration of triglyceride-rich chylomicrons (average triglyceride:cholesterol = 136.5 by mass) in vivo or their remnants (average triglyceride:cholesterol = 32.7 by mass) to the perfused liver resulted in an 80% decrease in ACAT activity. In the perfused liver system, VLDL cholesterol and triglyceride secretion was increased while biliary cholesterol content decreased. Administration of standard chylomicrons (average triglyceride:cholesterol = 33.9 by mass) or their remnants (average triglyceride:cholesterol = 11.4 by mass) lowered ACAT activity by 24% in vivo, but had no significant effect on any of the parameters measured in the perfused liver system. Administration of cholesterol-rich VLDL (average triglyceride:cholesterol = 0.47 by mass) in vivo increased ACAT activity 1.4-fold, but administration of their remnants (average triglyceride:cholesterol = 0.17 by mass) had little effect on any of the parameters measured in the perfused liver. Thus, the lipid composition of lipoproteins removed by the liver elicited acute responses by parameters important in the maintenance of hepatic cholesterol homeostasis. These responses reflected the net effects of both the cholesterol and the triglyceride contents of the particles.

Effect of removal of lipoproteins of different composition on hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and hepatic very low density lipoprotein secretion.

The effect of remnant lipoproteins on hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and hepatic very low density lipoprotein (VLDL) secretion was studied in the perfused rat liver and in vivo. As had been observed previously, when the liver was perfused with a lipid-free medium, HMG-CoA reductase activity increased about twofold after 150 min, and this increase could be prevented by the addition of chylomicron remnants to the medium. However, suppression below base line activity did not occur even with increasing amounts of remnant cholesterol. When chylomicron remnants prepared from triglyceride-rich particles were included in the medium, reductase activity was increased even above that in the control perfusions despite the fact that approximately the same amount of cholesterol was removed from these particles as from standard particles. In contrast, particles that were low in triglycerides and rich in cholesterol not only prevented the rise in reductase activity but inhibited it significantly below base line activity. Again, the total amount of cholesterol removed was the same as with the other types of particles. These results suggested that both the triglycerides and cholesterol exerted an effect on HMG-CoA reductase. Consistent with this hypothesis, a significant correlation was found between reductase activity and the ratio of triglycerides to cholesterol removed, but not to either alone. To explore the role of triglycerides further, the effect of these lipoprotein particles on VLDL secretion was determined. VLDL secretion was stimulated by both standard and triglyceride-rich remnants but not by triglyceride-poor remnants. The degree of stimulation with standard chylomicron was comparable to that induced by infusion of a comparable fatty acid load as oleic acid bound to albumin. In vivo a similar effect of these lipoproteins on HMG-CoA reductase activity was observed. Rats were injected with a lipoprotein bolus containing 7 mg of cholesterol, and reductase activity in the liver was measured 2 hr later. Standard chylomicrons and triglyceride-rich chylomicrons stimulated reductase to 157% and 187% of control activity, respectively, whereas cholesterol-rich VLDL suppressed reductase activity to 30% of control activity. These observations support the hypothesis that remnant lipoproteins have a dual effect on hepatic HMG-CoA reductase activity; the cholesterol in these lipoproteins suppresses hepatic reductase activity while the triglycerides concommitantly delivered stimulate reductase activity at least in part because they stimulate hepatic VLDL secretion. Therefore, the net response of hepatic HMG-CoA reductase to a particular dietary lipoprotein will depend upon the balance between the cholesterol and triglycerides carried to the liver.-Van Zuiden, P. E. A., S. K. Erickson, and A. D. Cooper. Effect of removal of lipoproteins of different composition on hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and hepatic very low density lipoprotein secretion.

Progressive enlargement of an hepatic cell adenoma.

Over a 5-mo period, an hepatic cell adenoma was noted to increase considerably in size, despite discontinuation of oral contraceptives. Progressive tumor enlargement was documented by hepatic angiography, computed tomographic scan (CT scan) of the liver and 99mTc liver scan. The repeat hepatic angiogram also revealed that the tumor had become more vascular. Multiple adenomas were in fact seen by all three techniques mentioned above. At surgery, seven hepatic cell adenomas were demonstrated, of which four were resected.