The role of keratins in the liver
Final Report Abstract
Background: Keratins (K) 7, 8 and 18-20/23 are the intermediate filaments of digestive epithelia displaying an important cytoprotective function. In the liver, hepatocytes express only K8/K18 while biliary and progenitor cells also harbour K7/K19. Given the multiplicity of keratin genes in the human genome, the aim of the proposal was to study the biological role of individual keratins as well as the associated proteins in the digestive system. Moreover, since K18/K19 fragments constitute well-known cellular injury markers, we assessed their predictive relevance in several specific disorders. Results: Our work identified K23 as a virus-inducible hepatic gene. Cross-breeding of K7/K19-deficient animals with Mdr2 knockouts as a well-established cholestatic liver injury model did not detect a significant relevance of K7/K19 in this context. In contrast, K7/K19 are essential for intestine. While the loss of both keratins can be compensated under basal conditions, it promotes the intestinal injury induced by administration of dextran sodium sulfate (DSS). Similar observations were made in mice with an intestine-specific deletion of desmoplakin (Dsp), a protein connecting keratin network to the desmosome intercellular junction. Dsp knockouts displayed a retraction of keratin network under basal conditions. Moreover, the epithelial cells were susceptible to mechanical stress as well as DSS-induced colitis. In subjects with severe alcoholic hepatitis (sAH), the K18-based serum fragments M30/M65 reflected the extent of acute liver damage and high M30 levels predicted a response to prednisolone, a double-edged antianflammatory drug. While CYFRA21-1 (K19-based fragment) did not significantly predicted the response to prednisolone, increased CYFRA21-1 levels indicated a dismal prognosis, i.e. an increased death or a need for liver transplantation. Conclusions: The role of K7/K19 in the cholestatic liver injury is limited, however, both proteins seem to act as protective stress buffers in the intestine and the latter is also true for the keratin-desmosome connector Dsp. K18- and K19-serum fragments are attractive indicator of liver injury, but further work is needed to prove their relevance in the clinical routine.
Publications
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(2019) Identification of Keratin 23 as a Hepatitis C Virus-Induced Host Factor in the Human Liver. Cells 8:E610
Kinast V, Leber SL, Brown RJP, Vieyres G, Behrendt P, Eßbach C, Strnad P, Vondran FWR, Cornberg M, Wex C, Pietschmann T, Haybaeck J, Todt D, Steinmann E
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(2020) In Severe Alcoholic Hepatitis, Serum Keratin-18 Fragments Are Diagnostic, Prognostic, and Theragnostic Biomarkers. Am J Gastroenterol 115:1857-1868
Atkinson SR, Grove JI, Liebig S, Astbury S, Vergis N, Goldin R, Quaglia A, Bantel H, Guha IN, Thursz MR, Newcombe P, Strnad P, Aithal GP
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(2020) Serum keratin 19 (CYFRA21-1) links ductular reaction with portal hypertension and outcome of various advanced liver diseases. BMC Med 18:336
Hamesch K, Guldiken N, Aly M, Hüser N, Hartmann D, Rufat P, Ziol M, Remih K, Lurje G, Scheiner B, Trautwein C, Mandorfer M, Reiberger T, Mueller S, Bruns T, Nahon P, Strnad P
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(2022) Desmoplakin Maintains Transcellular Keratin Scaffolding and Protects From Intestinal Injury. Cell Mol Gastroenterol Hepatol 13:1181-1200
Gross A, Zhou B, Bewersdorf L, Schwarz N, Schacht GM, Boor P, Hoeft K, Hoffmann B, Fuchs E, Kramann R, Merkel R, Leube RE, Strnad P
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(2022) Serum keratin 19 (CYFRA21-1) is a prognostic biomarker in severe alcoholic hepatitis. Liver Int. 42:1049-1057
Atkinson SR, Aly M, Remih K, Tyson LD, Guldiken N, Goldin R, Quaglia A, Thursz M, Strnad P
