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Regulation of the Rate of Sterol Synthesis and the Level of ß-Hydroxy-ß-methylglutaryl Coenzyme A Reductase Activity in Mouse Liver and Hepatomas¹

The Jackson Laboratory, Bar Harbor, Maine 04609

Studies were carried out to determine whether feedback regulation of sterol synthesis is altered in the livers of mice with a high incidence of spontaneous hepatomas, to compare some properties of ß-hydroxy-ß-methylglutaryl-CoA (HMG-CoA) reductase from liver and hepatomas and to determine the extent to which this enzyme activity is altered in hepatomas by a variety of dietary steroids and other factors. The rate of hepatic sterol synthesis from acetate and the level of HMG-CoA reductase activity were depressed by the addition of cholesterol to the diets of mice genetically disposed to a high incidence of hepatomas (CE x DBA/2WyDi F₁ and C3H-A^y mice); this is a normal regulatory response to the sterol. The level of HMG-CoA reductase activity was high in spontaneous hepatomas and in 2 transplanted hepatomas and was relatively unaffected by dietary cholesterol, food deprivation, or injected Triton WR 1339. Rates of sterol synthesis from both mevalonate and acetate were elevated in spontaneous hepatomas indicating that the rate was also elevated over that portion of the pathway subsequent to HMG-CoA reductase. The rate of sterol synthesis from acetate in hepatoma BW-7756 was unaffected by several steroids other than cholesterol that altered the rate in liver. Analyses of K_m values and heat liability for HMG-CoA reductase from liver and hepatomas did not indicate any variation in these properties.

¹ This research was supported in part by NIH Research Grant CA-02758 from the National Cancer Institute, by grants from the Eloise and Richard Webber Foundation and the Elsa U. Pardee Foundation, and by an allocation from General Research Support Grant RR-05545 from the Division of Research Resources to The Jackson Laboratory.

² Present address: Division of Medical Biochemistry, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.

Received 3/23/71. Accepted 5/20/71.

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