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Alterations in Hepatocyte Insulin Receptors in Rats Fed a Choline-deficient Diet¹

Department of Pathology, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania 15213

Specific insulin binding and glycogen synthesis were studied in control hepatocytes, hepatocytes from rats fed a choline-deficient (CD) diet for 7 to 14 days, and hepatoma cells induced with a CD diet and DL-ethionine in culture. Both the binding affinity and the number of receptors were affected in hepatocytes by the CD diet. The number of receptor sites was 26,000/cell and the dissociation constant (K_d) for the high affinity binding site was 2.6 nM at 30°C, in contrast to the control values of 205,000 sites/cell and 23.2 nM, respectively. In the hepatoma cells, receptor cell number and K_d were further diminished to 6,400 sites/cell and K_d = 1.1 nM.

The basal level of glycogen synthesis in control hepatocytes and in CD hepatocytes was similar; however, the basal rate of glycogen synthesis in hepatoma cells was only 16% of that in the control cells. The glycogen synthesis in hepatoma cells was stimulated by insulin, but at a 3-log higher concentration compared to the control cells. This loss of sensitivity to insulin is consistent with the marked decrease in insulin receptors. CD hepatocytes had a decrease in insulin receptors with a concurrent decrease in K_d (increase in binding affinity), such that, sensitivity to insulin did not differ significantly from that of control hepatocytes. However, the maximal stimulation of glycogen synthesis was only 27% that of the control cells. The changes in receptor number and K_d of hepatocytes from rats fed a CD diet may be due to alterations in cell membrane lipid composition and this alteration may be responsible for the enhanced sensitivity of hepatocytes to chemical carcinogens and for the tumor promoting effect of the diet.

¹ This work was supported in part by Grants 1R23 AM27306 and CA 26556 awarded by the NIH, Department of Health and Human Services.

² To whom requests for reprints should be addressed, at Division of Clinical Chemistry, Department of Pathology, 1 Children's Place, Fifth Ave., Pittsburgh, PA 15213.

Received 8/19/85. Revised 1/15/86. Revised 5/12/86. Accepted 5/15/86.