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J Seager

Publications and source records attributed to J Seager.

23 records · Page 2Linked to original sources
PubMed1977

Mechanism of induction of 3-hydroxy-3-methylglutaryl coenzyme A reductase in human leukocytes.

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 Popják, 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.

Adolescent↗
PubMed1975

IgA deficiency, epilepsy, and phenytoin treatment.

In a prospective study of thirty-two children with seizures treated with phenytoin (diphenylhydantoin), five had low levels of serum-IgA before treatment. All of these were among the fifteen who had had febrile convulsions in infancy. IgA levels fell significantly during 6 months treatment in the fourteen patients studied sequentially. Treated children with low serum-IgA had normal numbers of lymphocytes with surface IgA. This suggests that phenytoin causes failure of terminal differentiation of B lymphocytes, and is the first known cause of this, the commonest mechanism of immunoglobulin deficiency.

Adolescent↗
PubMed1975

Abnormal induction of 3-hydroxy-3-methylglutaryl coenzyme A reductase in leukocytes from subjects with heterozygous familial hypercholesterolemia.

Human leukocytes isolated from fresh defibinated blood were shown to utilize acetate and mevalonate for sterol synthesis. The capacity of the leukocytes to synthesize sterols is limited severely as compared to their ability to convert mevalonate into farnesyl pyrophosphate (which they hydrolyze rapidly to free farnesol) and into squalene. When leukocytes are incubated in a medium containing lipid-free serum, synthesis of sterols from acetate, but not from mevalonate, is much enhanced. It was shown that this increased synthesis resulted from increased levels of 3-hydroxy-3-methylglutaryl-CoA reductase activity in the cells. A comparison was made of the activation of sterol synthesis from acetate in leukocytes of normal individuals and of heterozygous familial hypercholesterolemics. The latter group responded to incubation in lipid-free sera with a significantly higher activation than the cells of normocholesterolemics. This activation was shown to be well correlated with a higher induction of 3-hydroxy-3-methylglutaryl-CoA reductase in the heterozygous cells than in the normals. The leukocytes of a heterozygous familial hypercholesterolemic individual were found to release, into a lipid-free incubation medium, more endogenously synthesized [3H]sterol (but not [3H]squalene) than the cells of a normal person. It is suggested that the genetic abnormality in heterozygous familial hypercholesterolemia could be accounted for by a mutation resulting in a weaker binding of a sterol repressor by heterozygous cells than by normal cells.

Acetates↗