Effect of cholesterol feeding and biliary obstruction on hepatic cholesterol biosynthesis in the rat

Harry, David; Dini, Marco; McIntyre, Neil

doi:10.1016/0005-2760(73)90061-1

Cited by 74 publications

(14 citation statements)

References 14 publications

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“…The finding that small changes in hepatic cholesterol content occur reciprocally with change in cholesterol synthesis suggests that these changes (49) or perhaps the cholesterol content of some intracellular compartment (50) may ultimately mediate the bile salt effect. That this was not noted in all studies of bile salt feeding ( 12) may be due to the fact that a large number of animals must be studied before such small changes become statistically significant.…”

Section: A D Coopermentioning

confidence: 99%

The regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the isolated perfused rat liver.

Cooper¹

1976

J. Clin. Invest.

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A B S T R A C T The effect of perfusion of an isolated rat liver on hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase was studied. In liver removed during the basal period of the diurnal cycle of enzyme activity, a 227±41% increase in enzyme activity occurred after 3 h of a l)lasna-free perfusion. This could be prevented by the addition of cycloheximide or pure cholesterol (dispersed with lecithin) to the perfusate. In contrast, the continuous addition of taurocholate or taurochenodeoxycholate, alone or in combination, at a variety of rates did not prevent the increase in enzyme activity. The added bile salts were efficiently extracted from the perfusate and excreted in the bile. The addition of these bile salts to a cholesterol-enriched perfusate did not alter the effect obtained with cholesterol alone.If the perfusate contained whole serum, the increase induced by perfusion in the basal period was smaller (88±27%) than with plasma-free perfusate. Again, the major bile salts of the rat failed to prevent the increase in enzyme activity induced by liver perfusion.If livers were removed and perfused at the height of the diurnal cycle of enzyme activity, the enzyme activity remained high (2+10% increase) rather than decreasing, as occurs in vivo. If cholesterol was added to these perfusions, a 52-+-4% decrease was induced. Bile salt addition induced no decrease. From these results it is concluded that the major bile salts are not direct regulators of hepatic cholesterol synthesis, but pure cholesterol, in the absence of bile salt or lipoprotein, is able to initiate the mechanism that represses hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase.

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Section: A D Coopermentioning

confidence: 99%

The regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the isolated perfused rat liver.

Cooper¹

1976

J. Clin. Invest.

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“…The total amount of cholesterol in the hepatic cell changes in response to changes in dietary cholesterol content and to other manipulations that affect the rate of endogenous cholesterol biosynthesis. However, the concentration of unesterified cholesterol present in the liver remains within a relatively narrow range, whereas the amount of esterified cholesterol can be remarkably increased (6)(7)(8). This effect is also clearly seen in hepatocytes from rats that have been fed fat and cholesterol (5), as well as in hepatocytes exposed to high concentrations of the sterol precursor mevalonic acid (9, 10).…”

mentioning

confidence: 99%

Evidence for phosphorylation/dephosphorylation of rat liver acyl-CoA:cholesterol acyltransferase.

Gavey¹,

Trujillo²,

Scallen³

1983

Proc. Natl. Acad. Sci. U.S.A.

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Acyl-coenzyme A: cholesterol O-acyltransferase (ACATase; EC 2.3.1.26) is a membrane-bound microsomal enzyme that catalyzes the formation of long-chain fatty-acyl cholesterol esters in rat liver and other tissues. This enzyme is important in regulating the concentration of unesterified cholesterol in the cell. Having recently demonstrated that rat liver 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase; EC 1.1.1.34), the major regulatory enzyme in cholesterol biosynthesis, undergoes in vivo phosphorylation and inactivation after a single cholesterol meal, we decided to test the hypothesis that the enzyme ACATase, important in cholesterol utilization and storage, is also subject to regulation by phosphorylation/dephosphorylation. The results show that rat liver ACATase can be reversibly inactivated/activated, in vitro, by incubation conditions that favor dephosphorylation/phosphorylation. Activation was also achieved by using a partially purified protein kinase extracted from microsomes. It is significant that HMG-CoA reductase is inactivated by phosphorylation whereas ACATase is activated by phosphorylation. ACATase is, therefore, regulated by phosphorylation in a manner exactly opposite to that of HMG-CoA reductase. We propose that the coordinate regulation of ACATase and HMG-CoA reductase by phosphorylation/dephosphorylation provides a mechanism for short-term intracellular cholesterol homeostasis.Acyl-coenzyme A:cholesterol 0-acyltransferase (ACATase) is a membrane bound microsomal enzyme that catalyzes the formation of long-chain fatty-acyl cholesterol esters in rat liver and in other tissues. It has been proposed that esterification is a mechanism for the removal of a potentially harmful excess of unesterified cholesterol by conversion to a form that can be stored intracellularly without deleterious effects to the cell (1, 2).Alternatively, at least for liver, esterified cholesterol may be utilized in the formation of lipoproteins, which are secreted from the liver and pass into the circulation (3-5). The total amount of cholesterol in the hepatic cell changes in response to changes in dietary cholesterol content and to other manipulations that affect the rate of endogenous cholesterol biosynthesis. However, the concentration of unesterified cholesterol present in the liver remains within a relatively narrow range, whereas the amount of esterified cholesterol can be remarkably increased (6)(7)(8). This effect is also clearly seen in hepatocytes from rats that have been fed fat and cholesterol (5), as well as in hepatocytes exposed to high concentrations of the sterol precursor mevalonic acid (9, 10).The activity of microsomal ACATase has been found to be greater when the amount of total cholesterol in the cell is increased (8,11). Thus ACATase appears to be important in regulating the amount of unesterified cholesterol in the cell. Previously, we have demonstrated the in vivo relevance of the phosphorylation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) as a...

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“…This hormone has been suggested to act by lowering the blood cholesterol, and consequently the amount of cholesterol in the liver, thus relieving the inhibition due to cholesterol (Ness et al, 1973), but available evidence does not support this view. First, although the amount of cholesterol does rise in the livers and circulation of rats fed on cholesterol-rich diets (Shapiro & Rodwell, 1971;Harry et al, 1973;Edwards & Gould, 1974), there is no evidence that this rise must occur if the activity of liver 3-hydroxy-3-methylglutaryl-CoA reductase is to be lowered. It cannot therefore be taken for granted that a stimulus which lowers liver cholesterol will also increase the activity ofthis enzyme.…”

Section: Resultsmentioning

confidence: 99%

Specificity of the effect of dietary cholesterol on rat liver microsomal 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity (Short Communication)

Gregory

Booth

1975

Biochemical Journal

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Effect of cholesterol feeding and biliary obstruction on hepatic cholesterol biosynthesis in the rat

Cited by 74 publications

References 14 publications

The regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the isolated perfused rat liver.

The regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the isolated perfused rat liver.

Evidence for phosphorylation/dephosphorylation of rat liver acyl-CoA:cholesterol acyltransferase.

Specificity of the effect of dietary cholesterol on rat liver microsomal 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity (Short Communication)

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