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Peroxisome Proliferator-induced Alterations in the Expression and Modification of Rat Hepatocyte Plasma Membrane Proteins¹

Departments of Cell Molecular and Structural Biology [J. R. B., S. K., X. L., L. Z., S. T. I., C. L. N., B. E. F.] and Pathology [J. K. R., M. S. R.], Northwestern University Medical School, Chicago, Illinois 60611

Rats were fed the peroxisome proliferator ciprofibrate (0.025%), and the effects on the expression, modification, and localization of seven domain-specific integral proteins of the rat hepatocyte plasma membrane were assessed using a combination of immunoblotting, -precipitation, and -fluorescence. Ciprofibrate caused the down-regulation of five of the plasma membrane proteins (the epidermal growth factor receptor, the asialoglycoprotein receptor, HA 321, HA 4, and dipeptidylpeptidase IV) and induced the expression of a more basic, lower-M_r isoform of the basolateral plasma membrane protein CE 9. Pulse labeling, chemical deglycosylation, and ¹²⁵I-wheat germ lectin blotting suggested that the ciprofibrate-induced isoform of CE 9 differed in the posttranslational modification of its oligosaccharides and contained more sialic acid. These changes in hepatocyte surface differentiation were first observed between Days 1 and 5 on the ciprofibrate-containing diet, coincident with other aspects of the pleiotropic response of the hepatocyte to peroxisome proliferators, e.g., the induction of the M_r 78,000 peroxisome proliferation-associated protein. The effects were reversed within 2–3 weeks upon removal of ciprofibrate. The three other peroxisome proliferators tested, di(2-ethylhexyl)phthalate, clofibrate, and Wy-14,643, were found to exert most of these same effects on the expression and modification of the hepatocyte plasma membrane proteins, but the compounds differed in relative potency. The ciprofibrate-induced decreases in the concentrations of the epidermal growth factor receptor, the asialoglycoprotein receptor, HA 321, and HA 4 were similar to the selective down-regulation of these proteins observed transiently during the period of hepatocyte proliferation following two-thirds hepatectomy. Other compounds frequently used in studies of liver enzyme induction and carcinogenesis, the antioxidants ethoxyquin and butylated hydroxyanisole and the liver tumor promoter phenobarbital, were not as effective as ciprofibrate or two-thirds hepatectomy at causing the down-regulation of these proteins. The induction of the lower-M_r isoform of the basolateral plasma membrane protein CE 9 was not observed following two-thirds hepatectomy or upon the feeding of the antioxidants or phenobarbital but was specific to the feeding of the peroxisome proliferators.

¹ Supported by Grant BC-676 from the American Cancer Society (to J. R. B.); Grants RR05370 (to J. R. B.), R37 GM23750 (to J. K. R.), and CA36130 (to M. S. R.) from the National Institutes of Health; and a grant from the Northwestern University Research Grants Committee (to J. R. B.).

² To whom correspondence should be addressed, at the Department of Cell Molecular and Structural Biology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611.

Received 5/22/89. Revised 9/29/89. Accepted 10/31/89.

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