| セッション情報 | 特別講演7 |
|---|---|
| タイトル | SL-7：Role of the keratin cytoskeleton in digestive health and disease |
| 演者 | Omary M Bishr（Department of Molecular ＆ Integrative Physiology, University of Michigan, USA） |
| 共同演者 | |
| 抄録 | Intermediate filaments（IFs）make up a large family of tissue and cell specific cytoplasmic and nuclear proteins that are involved in more than 70 human diseases. Keratins are epithelial-specific IFs and in digestive simpletype epithelia the major IFs are keratins 8 and 18（K8/K18）with variable levels of K7/K19/K20 depending on the cell type. K8/K18 protect hepatocytes from mechanical and non-mechanical stress as demonstrated using transgenic mouse models. Notably, human mutations in K8/K18/K19 predispose their carriers to acute or chronic liver disease progression via several mechanisms including the promotion of hepatocyte apoptosis. The role of pancreatic keratins is less understood due to the ability of the exocrine pancreas to cope with keratin mutation via compensatory mechanisms. In the colon, K8-null mice develop spontaneous colitis and diarrhea that is likely related to mistargeting of ion transporters from their usual cellular compartments. In contrast to liver, keratins have a paradoxical proapoptotic microflora-dependent role in the colon. K8/K18 are also the major constituents of Mallory-Denk bodies（MDBs）, that are found in association with alcoholic and nonalcoholic steatohepatitis. Factors that lead to MDB formation include keratin upregulation in response to oxidative stress, a K8＞K18 state, K8 transamidation and phosphorylation, chaperone and proteasome dysfunction, gender and the genetic background；while autophagy induction prevents MDB formation. In patients, the presence of MDBs is a marker for liver disease progression. Therefore, keratins serve as liver disease genetic modifiers via their role in hepatocyte cytoprotection, and are essential for MDB formation. |
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