PCB, diabète de type 2 et obésité: Approches cellulaire, moléculaire et expérimentale de l’effet des polychlorobiphényles (PCB) sur la biologie de l’adipocyte : implications dans le diabète et l’obésité

Les polluants organiques persistants (POP) sont des substances qui sont difficilement détruites dans l’environnement et qui s’y stockent. Ils contaminent aussi les organismes vivants et s’accumulent tout au long de la chaîne alimentaire. Les polychlorobiphényles (PCB) sont l’exemple type de ces POP auxquels nous sommes tous exposés à des degrés divers. Cependant les mécanismes biologiques qui seraient à l’origine de l’effet des PCB demeurent méconnus. L’étude met en œuvre deux approches complémentaires : la première entreprise chez la souris et la seconde réalisée in vitro au moyen de cultures cellulaires d’adipocytes humains

MRP8/ABCC11 expression is regulated by dexamethasone in breast cancer cells and is associated to progesterone receptor status in breast tumors

International audienceThe ATP-binding cassette multidrug resistance protein 8 (MRP8/ABCC11) mediates the excretion of anticancer drugs. ABCC11 mRNA and protein levels were enhanced by DEX (dexamethasone) and by PROG (progesterone) in MCF7 (progesterone receptor-(PR-) positive) but not in MDA-MB-231 (PR-negative) breast cancer cells. This suggested a PR-signaling pathway involvement in ABCC11 regulation. Nevertheless, pregnenolone-16α-carbonitrile (GR antagonist) and clotrimazole strongly and moderately decreased ABCC11 expression levels in Glucocortocoid Receptor-(GR-) and Pregnane X Receptor (PXR)-positive MCF7 cells but not in MDA-MB-231 cells (GR- and PXR-positive). Thus, GR-signaling pathway involvement could not be excluded in ABCC11 regulation in MCF7 cells. Furthermore, ABCC11 levels were positively correlated with the PR status of postmenopausal patient breast tumors from two independent cohorts. Thus, in the subclass of breast tumors (Estrogen Receptor-(ER-) negative/PR-positive), the elevated expression level of ABCC11 may alter the sensitivity to ABCC11 anticancer substrates, especially under treatment combinations with DEX

Losartan, an angiotensin II type 1 receptor blocker, protects human islets from glucotoxicity through the phospholipase C pathway

As shown in a large clinical prospective trial, inhibition of the renin-angiotensin system (RAS) can delay the onset of type 2 diabetes in high-risk individuals. We evaluated the beneficial effects of RAS inhibition on β-cell function under glucotoxic conditions. Human islets from 13 donors were cultured in 5.5 mM (controls) or 16.7 mM glucose [high glucose (HG)] for 4 d with or without losartan (5 μM), a selective AT1R blocker, and/or U73122 (2 μM), a selective PLC inhibitor, during the last 2 d. HG induced RAS activation with overexpression of AT1R (P<0.05) and angiotensinogen (P<0.001) mRNAs. HG increased endoplasmic reticulum (ER) stress markers (P<0.001) such as GRP78, sXBP1, and ATF4 mRNAs and Grp78 protein levels (P<0.01). HG also decreased reticular calcium concentration (P<0.0001) and modified protein expressions of ER calcium pumps with reduction of SERCA2b (P<0.01) and increase of IP3R2 (P<0.05). Losartan prevented these deleterious effects and was associated with improved insulin secretion despite HG exposure. AT1R activation triggers the PLC-IP3-calcium pathway. Losartan prevented the increase of PLC β1 and γ1 protein levels induced by HG (P<0.05). U73122 reproduced all the protective effects of losartan. AT1R blockade protects human islets from the deleterious effects of glucose through inhibition of the PLC-IP3-calcium pathway

The Transcriptional Effects of PCB118 and PCB153 on the Liver, Adipose Tissue, Muscle and Colon of Mice: Highlighting of Glut4 and Lipin1 as Main Target Genes for PCB Induced Metabolic Disorders.

Epidemiological studies have associated environmental exposure to polychlorinated biphenyls (PCBs) with an increased risk of type 2 diabetes; however, little is known about the underlying mechanisms involved in the metabolic side-effects of PCB. Our study evaluated the transcriptional effects of a subchronic exposure (gavage at Day 0 and Day 15 with 10 or 100 μmol/Kg bw) to PCB118 (dioxin-like PCB), PCB153 (non-dioxin-like PCB), or an equimolar mixture of PCB118 and PCB153 on various tissues (liver, visceral adipose tissue, muscle, and colon) in mice. Our results showed that a short-term exposure to PCB118 and/or PCB153 enhanced circulating triglyceride levels but did not affect glycemia. Among the studied tissues, we did not observe any modification of the expression of inflammation-related genes, such as cytokines or chemokines. The main transcriptional effects were observed in visceral adipose and liver tissues. We found a downregulation of lipin1 and glut4 expression in these two target organs. In adipose tissue, we also showed a downregulation of Agpat2, Slc25a1, and Fasn. All of these genes are involved in lipid metabolism and insulin resistance. In muscles, we observed an induction of CnR1 and Foxo3 expression, which may be partly involved in PCB metabolic effects. In summary, our results suggest that lipin1 and glut4, notably in adipose tissue, are the main targeted genes in PCB-induced metabolic disorders, however, further studies are required to fully elucidate the mechanisms involved

Real-time RT-PCR validation of genes selected within the muscles after microarray analyses (*p < 0.05).

<p>Real-time RT-PCR validation of genes selected within the muscles after microarray analyses (*p < 0.05).</p

Genes involved in lipid homeostasis based on microarray analyses.

<p>Genes involved in lipid homeostasis based on microarray analyses.</p

Genes involved in the metabolism of xenobiotics based on microarray analyses.

<p>Genes involved in the metabolism of xenobiotics based on microarray analyses.</p

Real-time RT-PCR validation of genes selected within the visceral adipose tissue after microarray analyses (*p < 0.05).

<p>Real-time RT-PCR validation of genes selected within the visceral adipose tissue after microarray analyses (*p < 0.05).</p