gastrins and pirinixic-acid

The three subtypes of peroxisome proliferator activated-receptors (PPARalpha, delta and gamma) control the storage and metabolism of fatty acids. Treatment of rats with the PPARalpha ligand ciprofibrate increases serum gastrin concentrations, and several lines of evidence suggest that non-amidated gastrins act as growth factors for the colonic mucosa. The aim of the present study was to investigate the expression of PPARs and the effect of PPAR ligands on gastrin production and cell proliferation in human colorectal carcinoma (CRC) cell lines. mRNAs for all three PPAR subtypes were detected by PCR in all CRC cell lines tested. The concentrations of progastrin, but not of glycine-extended or amidated gastrin, measured by radioimmunoassay in LIM 1899 conditioned media and cell extracts were significantly increased by treatment with the PPARalpha ligand clofibrate. Similar increases in progastrin were seen following treatment with the PPARalpha ligands ciprofibrate and fenofibrate, but not with bezafibrate, gemfibrozil or Wy 14643. The PPARgamma agonist rosiglitazone had no significant effect on progastrin production. The PPARalpha ligand clofibrate also stimulated proliferation of the LIM 1899 cell line. We conclude that some PPARalpha ligands increase progastrin production by the human CRC cell line LIM 1899, and that clofibrate increases proliferation of LIM 1899 cells. These studies have revealed a relationship between PPARs and gastrin, two regulatory molecules implicated in the pathogenesis of CRC.

Topics: Bezafibrate; Cell Proliferation; Clofibrate; Clofibric Acid; Colorectal Neoplasms; Fenofibrate; Fibric Acids; Gastrins; Gemfibrozil; Humans; Hypolipidemic Agents; Ligands; Peroxisome Proliferator-Activated Receptors; Protein Precursors; Pyrimidines; Radioimmunoassay; RNA, Messenger; Rosiglitazone; Thiazolidinediones; Vasodilator Agents

The peroxisome proliferator (PP) ciprofibrate stimulates gastrin-producing cells (G-cells) in the rat stomach by an unknown mechanism, inducing hypergastrinemia and secondary enterochromaffin-like (ECL) cell hyperplasia. Ciprofibrate is a specific ligand for the nuclear peroxisome proliferator-activated receptor alpha (PPAR alpha). To see whether the effects of ciprofibrate could be imitated, rats were given another PPAR alpha ligand WY-14643 or the PPAR gamma ligand troglitazone by gastric intubations daily for 28 and 56 days. Troglitazone failed to raise gastrin levels. WY-14643 increased gastrin mRNA abundance, G-cell density and induced hypergastrinemia, but to a lesser extent than ciprofibrate. ECL cell parameters increased in proportion with the relative hypergastrinemia. Ciprofibrate and WY-14643 altered the levels of acyl CoA-oxidase mRNA and PPAR alpha mRNA in antrum, but had no effect in corpus. The PPAR alpha receptor was found in at least some G-cells by immunostaining. This study supports the hypothesis that PPAR alpha specific ligands could stimulate the G-cells by acting locally from the stomach lumen through antral PPAR alpha.

Topics: Animals; Chromans; Clofibric Acid; Female; Fibric Acids; Gastric Mucosa; Gastrins; Ligands; Parietal Cells, Gastric; Peroxisome Proliferators; Pyrimidines; Rats; Rats, Inbred F344; Receptors, Cytoplasmic and Nuclear; Thiazoles; Thiazolidinediones; Transcription Factors; Troglitazone