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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:1195-1203.)
© 1995 American Heart Association, Inc.

Articles

Inhibition of Protein Tyrosine Kinase Alters the Effect of Serum Basic Protein I on Triacylglycerols and Cholesterol Differently in Normal and HyperapoB Fibroblasts

Peter O. Kwiterovich, Jr; Mahnaz Motevalli

From the Lipid Research Atherosclerosis Unit, Departments of Pediatrics (M.M.) and Medicine (P.O.K., M.M.), Johns Hopkins University School of Medicine, Baltimore, Md.

Correspondence to Peter Kwiterovich, Johns Hopkins Hospital, CMSC 604, 600 N Wolfe St, Baltimore, MD 21287-3654.

Abstract 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 hyperapoB 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. There was also a significantly greater stimulation by BP I of the rate of [¹⁴C]acetate incorporation into cell esterified cholesterol in normal cells than in hyperapoB cells (P=.003), an effect that was inhibited by genistein in both normal (P=.0009) and hyperapoB (P=.01) cells. BP I also stimulated to a greater extent the mass of total cholesterol (P=.0009) and unesterified cholesterol (P=.015), but to a lesser degree that of esterified cholesterol (P=.44), in normal cells than in hyperapoB cells. Herbimycin A and tyrphostin A47, two other inhibitors of protein tyrosine kinase, also significantly inhibited the effects of BP I on triacylglycerol and cholesterol mass in normal cells but not in hyperapoB cells. The effect of BP I on triacylglycerols and cholesterol formation in normal cells appeared to be mediated through a tyrosine kinase–dependent process that was deficient in hyperapoB cells.

Key Words: coronary artery disease • apolipoprotein B • second messengers • familial combined hyperlipidemia • acylation stimulatory protein

This article has been cited by other articles:

				P. O. Kwiterovich Jr and M. Motevalli Differential Effect of Genistein on the Stimulation of Cholesterol Production by Basic Protein II in Normal and HyperapoB Fibroblasts Arterioscler. Thromb. Vasc. Biol., January 1, 1998; 18(1): 57 - 64. [Abstract] [Full Text] [PDF]

				M. Motevalli, P. J. Goldschmidt-Clermont, D. Virgil, and P. O. Kwiterovich Jr. Abnormal Protein Tyrosine Phosphorylation in Fibroblasts from Hyperapobetalipoproteinemia Subjects J. Biol. Chem., September 26, 1997; 272(39): 24703 - 24709. [Abstract] [Full Text] [PDF]