| | Category | BI | L10 | Identifying Novel Mechanisms of Cytochrome P450 2E1 regulation |
| | Abstract | |
| | Cyp2E1 is a vital enzyme involved in the metabolism of many carcinogens |
| | within the liver. Cyp2E1 over expression, seen in many pathophysiological |
| | condition (diabetes, viral hepatitis, obesity, etc.), is known to increase risk |
| | for hepatocellular carcinoma. This study aimed to elucidate mechanisms by |
| | which Cyp2E1 disregulation occurs in diabetics. Specifically, the effects |
| | of insulin and diabetic medication metformin on Cyp2E1 expression were |
| | studied. Primary rat hepatocytes were treated with appropriate |
| | substances at variable concentrations. Gene and miRNA expression was |
| | analyzed through qRT-PCR while protein expression was analyzed with |
| | immunoblots. Inhibitors/activators were used to identify functional elements |
| | of the regulatory pathway. The expression of miRNA’s linked to the |
| | development of cancer was quantified. |
| | Insulin was shown to decrease Cyp2E1 expression while metformin |
| | induced its expression. Insulin mediated regulation was dependant on PI3- |
| | Kinase, Akt, AMPK, and mTOR, with evidence that the FOXO proteins |
| | were involved. miRNA 212 and 132 were both regulated by insulin (up) |
| | and metformin (down). In silico analysis showed significant homology |
| | between the regulatory and coding regions of the human and rat gene, |
| | supporting extrapolation of data to humans. |
| | This study provides the first detailed information of the specific |
| | mechanisms behind insulin mediated Cyp2E1 regulation and was the first |
| | to identify metformin’s effects on Cyp2E1 expression, results with great |
| | potential for furthering our understanding of diabetes and its relation to |
| | cancer. In addition, insulin and metformin were shown to regulate the |
| | expression of miRNA’s related to hepatocellular carcinoma, providing novel |
| | evidence that they are involved in epigenetic regulation. |
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