ag-213 and Hyperlipoproteinemias

We studied whether the stimulatory effect of human serum basic protein I (BP I) on the formation of cell triacylglycerols and cholesterol may be mediated through protein tyrosine kinase in normal fibroblasts, and whether there was a deficiency in such a process in cells from subjects with hyperapobetalipoproteinemia (hyperapoB). Genistein, a highly specific inhibitor of tyrosine kinase phosphorylation, was used as a probe. When BP I (428.0 nmol/L) alone was added to F-12 medium without genistein, the mean mass of cell triacylglycerols doubled in six normal cell lines from healthy subjects, an effect that was decreased by 50% in six cell lines from subjects with hyperapoB (P = .007). The addition of genistein with BP I to normal cells decreased the stimulation of triacylglycerol formation by BP I by about 50% (P = .008), whereas genistein had little effect in the BP I-treated hyperapoB cells. The effect of genistein on the stimulation of triglyceride and cholesterol production by BP I was shown to be both time and concentration (92.5 nmol/mL medium nadir) dependent. In normal fibroblasts. BP I stimulated the rate of incorporation of both [14C]acetate (P = .0001) and [3H]mevalonolactone (P = .002) into unesterified cholesterol, an effect that was markedly deficient in the hyperapoB cells (P = .0001 for [14C]acetate and P = .0002 for [3H]mevalonolactone). In normal but not hyper-apoB cells, genistein inhibited the significant stimulation by BP I of the rates of both [14C]acetate (P = .0001) and [3H]mevalonolactone (P = .04) incorporation into unesterified cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Apolipoproteins B; Benzoquinones; Cholesterol; Cholesterol Esters; Fibroblasts; Genistein; Humans; Hyperlipoproteinemias; Isoflavones; Lactams, Macrocyclic; Mevalonic Acid; Nitriles; Phenols; Protein-Tyrosine Kinases; Proteins; Quinones; Rifabutin; Triglycerides; Tyrphostins