Overexpression of Hepatic Pancreatic Polypeptide Receptors in Chronic Pancreatitis

Abstract

Pancreatic polypeptide (PP) receptors have recently been demonstrated on liver microsomal membranes although the mechanisms of PP action on hepatocytes remain uncertain. The binding characteristics of these high affinity receptors under pathophysiologic conditions were studied in rats with oleic acid-induced chronic pancreatitis (CP), a state associated with diminished pancreatic PP content. Sixteen pancreatitic and 11 sham-operated control animals either were 16-h fasted or were given free access to food prior to organ removal. Competitive binding studies were performed by incubating hepatocyte microsomal preparation with125I-labeled PP (20–40 pM) and increasing concentrations of nonlabeled PP (1 × 10−10to 1 × 10−6M). After total and nonspecific binding was quantified by gamma counting, coefficients of dissociation (Kd) and maximal binding sites (Bmax) were determined by Scatchard analysis of specifically bound radioactivity. Binding data were normalized to membrane protein content and expressed as means ± standard error.Bmaxwas significantly greater in tissue from fed control animals than from fasted controls (4.46 ± 0.36 versus 2.83 ± 0.25,P< 0.05).Bmaxwas significantly greater under fasted conditions in tissue from CP animals than from controls (5.25 ± 0.94 versus 2.83 ± 0.25,P< 0.01). Under fed conditions, this difference was abolished by the increase in maximal binding in the control group. The fasting-associated decrease in maximal binding sites observed in controls did not occur in CP specimens. IncreasedBmaxin fed versus fasted control, as well as fasted CP versus fasted control, were associated with slight reciprocal decreases in receptor affinity. These data indicate that hepatic PP receptor concentration is upregulated in this model of chronic pancreatitis, most likely due to diminished exposure to ligand. Furthermore, normal PP receptor responses to the fed/fasted state are blunted in this condition. Regulatable PP receptor changes may play a role in altered hepatic metabolism previously observed in chronic pancreatitis.