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Journal of Lipid Research, Vol. 15, 508-516, September 1974
Copyright © 1974 by Lipid Research, Inc.

Effect of alterations of the specific activity of the intracellular acetyl CoA pool on apparent rates of hepatic cholesterogenesis

John M. Dietschy and Michael S. Brown

Gastrointestinal-Liver Unit, Department of Internal Medicine, University of Texas Southwestern Medical School at Dallas, Dallas, Texas 75235

We have previously shown significant dilution of the specific activity of the intracellular acetyl CoA pool when radiolabeled acetate is used as the precursor in liver slice experiments. In the present study, using liver from animals subjected to various manipulations known to alter the rate of cholesterogenesis, the specific activity of the intramitochondrial acetyl CoA pool was 27-49% of the theoretical specific activity expected if no endogenous dilution occurred. Because the cytosolic acetyl CoA pool that gives rise to cholesterol is not in equilibrium with the intramitochondrial pool, these values cannot be used to correct the flux of labeled carbon from [¹⁴C]acetate into cholesterol. However, because [¹⁴C]octanoate is rapidly oxidized intramitochondrially to acetyl CoA, which feeds both the intra- and extramitochondrial metabolic pathways, [¹⁴C]octanoate can be utilized to determine true flux rates of C₂ units into cholesterol and other products. Using this substrate in liver slices from animals subjected to a variety of experimental manipulations, the specific activity of the intracellular acetyl CoA pool was 54-71% of the expected specific activity. After correction for endogenous dilution, the C₂ flux into cholesterol varied from 335 to 459 nmoles.g^-1.hr^-1 in control animals, was suppressed 10-40-fold in animals subjected to fasting and cholesterol feeding, and increased into the range of 1500 nmoles.g^-1.hr^-1 after derepression with cholestyramine feeding or biliary diversion. Data also are presented that show very good agreement between the corrected C₂ flux rate from octanoate into cholesterol and microsomal HMG CoA reductase activity in the same liver under conditions in which the synthetic rates were varied over a 100-fold range.

Supplementary key words substrate dilution • control of cholesterogenesis

Submitted on April 23, 1973
Revised on April 17, 1974
Accepted on May 13, 1974

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