Integrins are transmembrane glycoproteins, composed of noncovalently associated ␣ and  subunits, that are involved in cell-extracellular matrix (ECM) 1 and cell-cell interactions (1). Many integrin ␣ chains undergo a post-translational endoproteolytic cleavage. The ␣ 3 , ␣ 5 , ␣ 6 , ␣ 7 , ␣ 8 , ␣ 9 , ␣ v , and ␣ IIb subunits are cleaved in the membrane-proximal extracellular region, resulting in a heavy chain that is disulfide-linked to a membrane spanning light chain (2). The ␣ 4 and ␣ E subunits can also be cleaved, but at unusual positions, near the middle and in the N-terminal region of the molecule, respectively (3, 4). Endoproteolytic cleavage of integrin ␣ subunits occurs at specific sites comprising pairs of basic amino acids.Post-translational proteolysis is a common mechanism required for the synthesis of biologically active proteins in bacteria, fungi, yeast, invertebrates, and mammals (5). However, the role of endoproteolytic cleavage of integrin ␣ subunits is not clear. The cleavage is conserved, not only in different ␣ chains but also across species, suggesting that it might be of functional importance. It has been established, by site-directed mutagenesis of cleavage sites, that uncleaved ␣ IIb  3 and ␣ 4
We demonstrate that intestinal inflammation caused by high-fat diet is increased by the environmental contaminant benzo[a]pyrene. Our in vivo results indicate that a high-fat diet (HFD) induces a pre-diabetic state in mice compared with animals fed normal chow. HFD increased IL-1betamRNA concentration in the jejunum, colon, and liver, and TNFalpha was increased in the colon and strongly increased in the liver. HFD also increased the expression of other genes related to type 2 diabetes, such as the uncoupling protein UCP2, throughout the bowel and liver, but not in the colon. The treatment of HFD with BaP enhanced the expression of IL-1beta in the liver and TNFalpha throughout the bowel and in the liver. Adding BaP to the diet also caused a significant decrease in the expression of the incretin glucagon-like peptide 1, which plays an important role in insulin secretion. Our results suggest that intestinal inflammation may be involved in the onset of type 2 diabetes and that chronic exposure to environmental polycyclic aromatic hydrocarbons can increase the risk of type 2 diabetes by inducing pro-inflammatory cytokine production.
BackgroundWe previously showed that blood serum induced cytochrome P450 1A1 (CYP1A1) monooxygenase expression in vitro.ObjectiveOur purpose was (i) to identify the molecular mechanism involved and (ii) to characterize the inducer compound(s) in serum involved at least in part.MethodsSerum was fractionated on hydrophobic columns. PPARα involvement was demonstrated by gene reporter assays, DNA mutagenesis and EMSA. Gene expression was evaluated by qRT-PCR. Serum samples were analyzed using HS-SPME-GC-MS.ResultsThe inductive effect of serum did not depend on the AhR pathway and was enhanced by cotransfection of PPARα cDNA. Mutations in the PPAR response elements of the CYP1A1 gene promoter suppressed this effect. One of the PPRE sites appeared highly specific for human PPARα, an unreported PPRE property. A link was found between CYP1A1 inducibility and serum hydrophobic compounds. Characterization of sera showed that hexanal, a metabolite produced by peroxidation of linoleic acid, was involved in CYP1A1 induction by serum, possibly along with other serum entities.ConclusionWe demonstrate that serum induces CYP1A1 via the PPARα pathway and that hexanal is one of the serum inducers. The two PPRE sites within the CYP1A1 promoter are functional and one of them is specific for PPARα.
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