Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.21 (CPT)
 4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fatty acids may promote type 2 diabetes by altering insulin secretion from pancreatic beta cells, a process known as lipotoxicity. The underlying mechanisms are poorly understood. To test the hypothesis that peroxisome proliferator-activated receptor alpha (PPARalpha) has a direct effect on islet function, we treated INS-1 cells, an insulinoma cell line, with a PPARalpha adenovirus (AdPPARalpha) as well as the PPARalpha agonist clofibric acid. AdPPARalpha-infected INS-1 cells showed PPARalpha agonist- and fatty acid-dependent transactivation of a PPARalpha reporter gene. Treatment with either AdPPARalpha or clofibric acid increased both catalase activity (a marker of peroxisomal proliferation) and palmitate oxidation. AdPPARalpha induced carnitine-palmitoyl transferase-I (CPT-I) mRNA, but had no effect on insulin gene expression. AdPPARalpha treatment increased cellular triglyceride content but clofibric acid did not. Both AdPPARalpha and clofibric acid decreased basal and glucose-stimulated insulin secretion. Despite increasing fatty acid oxidation, AdPPARalpha did not increase cellular ATP content suggesting the stimulation of uncoupled respiration. Consistent with these observations, UCP2 expression doubled in PPARalpha-treated cells. Clofibric acid-induced suppression of glucose-simulated insulin secretion was prevented by the CPT-I inhibitor etomoxir. These data suggest that PPARalpha-stimulated fatty acid oxidation can impair beta cell function.
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PMID:PPARalpha suppresses insulin secretion and induces UCP2 in insulinoma cells. 1203 69

Free fatty acids (FFA) have generally been proposed to regulate pancreatic insulin release by an intracellular mechanism involving inhibition of CPT-1. The recently de-orphanized G-protein coupled receptor, FFA(1)R/GPR40, has been shown to be essential for fatty-acid-stimulated insulin release in MIN6 mouse insulinoma cells. The CPT-1 inhibitor, 2-bromo palmitate (2BrP), was investigated for its ability to interact with mouse FFA(1)R/GPR40. It was found to inhibit phosphatidyl inositol hydrolysis induced by linoleic acid (LA) (100 muM in all experiments) in HEK293 cells transfected with FFA(1)R/GPR40 and in the MIN6 subclone, MIN6c4. 2BrP also inhibited LA-stimulated insulin release from mouse pancreatic islets. Mouse islets were subjected to antisense intervention by treatment with a FFA(1)R/GPR40-specific morpholino oligonucleotide for 48 h. Antisense treatment of islets suppressed LA-stimulated insulin release by 50% and by almost 100% when islets were pretreated with LA for 30 min before applying the antisense. Antisense treatment had no effect on tolbutamide-stimulated insulin release. Confocal microscopy using an FFA(1)R/GPR40-specific antibody revealed receptor expression largely localized to the plasma membrane of insulin-producing cells. Pretreating the islets with LA for 30 min followed by antisense oligonucleotide treatment for 48 h reduced the FFA(1)R/GPR40 immunoreactivity to background levels. The results demonstrate that FFA(1)R/GPR40 is inhibited by the CPT-1 inhibitor, 2BrP, and confirm that FFA(1)R/GPR40 is indeed necessary, at least in part, for fatty-acid-stimulated insulin release.
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PMID:Free fatty acid receptor 1 (FFA(1)R/GPR40) and its involvement in fatty-acid-stimulated insulin secretion. 1604 21

Carbohydrate metabolism in pregnancy reflects the balance between counterregulatory hormones, which induce insulin resistance, and lactogenic hormones, which stimulate beta-cell proliferation and insulin production. Here we explored the interactions of prolactin (PRL) and glucocorticoids in the regulation of beta-cell gene expression, fatty acid oxidation, and glucose-stimulated insulin secretion (GSIS). In rat insulinoma cells, rat PRL caused 30-50% (P < 0.001) reductions in Forkhead box O (FoxO)-1, peroxisome proliferator activator receptor (PPAR)-gamma coactivator-1alpha (PGC-1alpha), PPARalpha, and carnitine palmitoyltransferase 1 (CPT-1) mRNAs and increased Glut-2 mRNA and GSIS; conversely, dexamethasone (DEX) up-regulated FoxO1, PGC1alpha, PPARalpha, CPT-1, and uncoupling protein 2 (UCP-2) mRNAs in insulinoma cells and inhibited GSIS. Hydrocortisone had similar effects. The effects of DEX were attenuated by coincubation of cells with PRL. In primary rat islets, PRL reduced FoxO1, PPARalpha, and CPT-1 mRNAs, whereas DEX increased FoxO1, PGC1alpha, and UCP-2 mRNAs. The effects of PRL on gene expression were mimicked by constitutive overexpression of signal transducer and activator of transcription-5b. PRL induced signal transducer and activator of transcription-5 binding to a consensus sequence in the rat FoxO1 promoter, reduced nuclear FoxO1 protein levels, and induced its phosphorylation and cytoplasmic redistribution. DEX increased beta-cell fatty acid oxidation and reduced fatty acid esterification; these effects were attenuated by PRL. Thus, lactogens and glucocorticoids have opposing effects on a number of beta-cell genes including FoxO1, PGC1alpha, PPARalpha, CPT-1, and UCP-2 and differentially regulate beta-cell Glut-2 expression, fatty acid oxidation, and GSIS. These observations suggest new mechanisms by which lactogens may preserve beta-cell mass and function and maternal glucose tolerance despite the doubling of maternal cortisol concentrations in late gestation.
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PMID:The interplay of prolactin and the glucocorticoids in the regulation of beta-cell gene expression, fatty acid oxidation, and glucose-stimulated insulin secretion: implications for carbohydrate metabolism in pregnancy. 1859 50