Inhibitory effect of the pancreatic lipase C-terminal domain on intestinal lipolysis in rats fed a high-fat diet: chronic study.

Objective: Previous in vitro experiments, as well as acute assays in rat showed that the C-terminal domain (CT-domain) of porcine pancreatic lipase behaves as a potent specific noncovalent inhibitor of pancreatic lipase. Nevertheless, the potential use of the CT-domain as a therapeutic tool against obesity in humans requires further investigation and would be best achieved using the human CT-domain. In the present study, we investigated the inhibitory effects of the recombinant human CT-domain, in vivo, upon chronic administration to rats fed a high-fat diet.

The lipase C-terminal domain. A novel unusual inhibitor of pancreatic lipase activity.

In vertebrates, dietary fat digestion mainly results from the combined effect of pancreatic lipase, colipase, and bile. It has been proposed that in vivo lipase adsorption on oil-water emulsion is mediated by a preformed lipase-colipase-mixed micelle complex. The main lipase-colipase binding site is located on the C-terminal domain of the enzyme.

Critical role of micelles in pancreatic lipase activation revealed by small angle neutron scattering.

In the duodenum, pancreatic lipase (PL) develops its activity on triglycerides by binding to the bile-emulsified oil droplets in the presence of its protein cofactor pancreatic colipase (PC). The neutron crystal structure of a PC-PL-micelle complex (Hermoso, J., Pignol, D.

Ion pairing between lipase and colipase plays a critical role in catalysis.

Among the polar interactions occurring in pancreatic lipase/colipase binding, only one ion pair involving lysine 400 on lipase and glutamic acid 45 on colipase has been described. These residues are strictly conserved among species, suggesting that the ion pair is likely to play an important role. Therefore, in order to prevent this interaction, mutations intended to neutralize or inverse the charge of these residues have been introduced in the cDNAs encoding horse lipase and colipase.

Recombinant C-terminal domain of pancreatic lipase retains full ability to bind colipase.

The organization of the pancreatic lipase in two well defined domains has been correlated to a specific function for each domain, catalytic activity for the N-terminal domain and colipase binding for the C-terminal domain. In order to see if such an organization implies that the two domains can behave as separate entities, we expressed the N- and C-terminal domains in insect cells. The recombinant proteins secreted in the cell supernatants present the expected molecular properties.

Extrapulmonary manifestations of tumors of the lung.

Lung tumors, among other, secrete substances which are identical to or which mimic the activities of conventional hormones. These ectopic tumor secretions appear to be anarchistic and beyond the control of mechanisms regulating normal endocrine physiology. Despite the relative inefficiency of these tumors as endocrine organs, production of sufficient quantities of the substance, exceeding those from normal sources, results in recognizable ectopic endocrinopathies.

Ectopic production of big ACTH in carcinoma of the lung. Its clinical usefulness as a biologic marker.

This report considers the potential usefulness of adrenocorticotropic hormone (ACTH) determinations in diagnosis and in prognosis for therapy of patients with carcinoma of the lung but without clinical Cushing's syndrome. The report is based on radioimmunoassay data from 129 patients, including 62 with lung cancers and 67 with nonmalignant pulmonary conditions. Elevated plasma ACTH was found in 21 of 24 patients with untreated cancer and the hormone was detected in tumor extracts and/or bronchial washings from the remaining 3.