JBC, Vol. 252, Issue 2, 644-651, Jan, 1977
Mechanism of induction of 3-hydroxy-3-methylglutaryl coenzyme A reductase in human leukocytes
A. M. Fogelman, J. Seager, P. A. Edwards and G. Popjak
Incubation of leukocytes in buffer alone devoid of lipoproteins does not
lead to the induction of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)
reductase, but incubation of these cells in lipid-depleted serum,
abetaliprproteinemic serum, or lipoprotein-deficient serum (d greater than
1.21) leads to sterol loss from the cells and the activation of sterol
synthesis from acetate. The latter was shown previously to be proportional
to the HMG-CoA reductase levels in the cells (Fogelman, A. M., Edmond, J.,
Seager, J., and Popjak, G. (1975)J. Biol. Chem. 250, 2045-2055). Sterol
loss occurs from normal and heterozygous familial hypercholesterolemic
leukocytes within 15 min in lipid-depleted serum. Since induction of
HMG-CoA reductase activity is not detectable until after the leukocytes
have been incubated in the lipid-depleted serum for at least 3 h (Fogelman
et al., see above), sterol loss clearly precedes the induction of the
enzyme. In six out of six experiments, the nonisotopic sterol content of
leukocytes incubated in lipid-depleted serum was equal to or lower than
that of the same leukocytes incubated in full serum. This occurred at a
time when the leukocytes in the lipid-depleted serum were incorporating 4
to 5 times more [14C]acetate into sterols than the same leukocytes in full
serum. This strongly suggests that the induction of the reductase was a
compensatory mechanism for sterol loss. Incubation of leukocytes in buffer,
or buffer plus lecithin dispersions, or buffer plus albumin did not lead to
sterol loss or induction of the reductase, but incubation in buffer and
albumin together with lecithin dispersions caused sterol loss into the
medium and the activation of sterol synthesis from acetate. It is concluded
that a phospholipid-protein-cell interaction, which produces sterol loss,
is necessary to induce the reductase in leukocytes. A close correlation
between sterol loss and total sterol synthesis (a function of HMG-CoA
reductase activity) was demonstrated in normal and heterozygous leukocytes
incubated in a variety of incubation media (r = 0.95; p less than 0.005).
Heterozygous leukocytes taken fresh from the blood contained no more
cholesterol than the leukocytes of their age and sex-matched controls,
despite the marked difference in their serum cholesterol concentrations. It
is proposed that the abnormality in familial hypercholesterolemia can be
accounted for by an abnormal efflux of cholesterol from heterozygous cells.
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