Histochem Cell Biol (2008) 129:735–749 DOI 10.1007/s00418-008-0431-x R E V I E W Intermediate Wlament cytoskeleton of the liver in health and disease P. Strnad · C. Stumptner · K. Zatloukal · H. Denk Accepted: 14 April 2008 / Published online: 29 April 2008 © Springer-Verlag 2008 Abstract Intermediate Wlaments (IFs) represent the largest cytoskeletal gene family comprising »70 genes expressed in tissue speciWc manner. In addition to scaVolding func- tion, they form complex signaling platforms and interact with various kinases, adaptor, and apoptotic proteins. IFs are established cytoprotectants and IF variants are associ- ated with >30 human diseases. Furthermore, IF-containing inclusion bodies are characteristic features of several neurodegenerative, muscular, and other disorders. Acidic (type I) and basic keratins (type II) build obligatory type I and type II heteropolymers and are expressed in epithelial cells. Adult hepatocytes contain K8 and K18 as their only cytoplasmic IF pair, whereas cholangiocytes express K7 and K19 in addition. K8/K18-deWcient animals exhibit a marked susceptibility to various toxic agents and Fas- induced apoptosis. In humans, K8/K18 variants predispose to development of end-stage liver disease and acute liver failure (ALF). K8/K18 variants also associate with devel- opment of liver Wbrosis in patients with chronic hepatitis C. Mallory-Denk bodies (MDBs) are protein aggregates con- sisting of ubiquitinated K8/K18, chaperones and sequesto- some1/p62 (p62) as their major constituents. MDBs are found in various liver diseases including alcoholic and non- alcoholic steatohepatitis and can be formed in mice by feeding hepatotoxic substances griseofulvin and 3,5-dieth- oxycarbonyl-1,4-dihydrocollidine (DDC). MDBs also arise C. Stumptner · K. Zatloukal · H. Denk (&) Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, 8036 Graz, Austria e-mail: helmut.denk@meduni-graz.at P. Strnad Department of Internal Medicine I, University of Ulm, Robert-Koch-Straße 8, 89081 Ulm, Germany e-mail: Strnad@stanford.edu in cell culture after transfection with K8/K18, ubiquitin, and p62. Major factors that determine MDB formation in vivo are the type of stress (with oxidative stress as a major player), the extent of stress-induced protein misfolding and resulting chaperone, proteasome and autophagy overload, keratin 8 excess, transglutaminase activation with transami- dation of keratin 8 and p62 upregulation. Keywords Keratin · Mallory-Denk body · Aggregate · Inclusion · Variant · p62 · Ubiquitin · Oxidative stress · Steatohepatitis Intermediate Wlaments in health and disease Together with the actin microWlaments and the micro- tubules, intermediate Wlaments (IFs) are the components of the cytoskeleton of eukaryotic cells, which is involved in the maintenance of cell shape, locomotion, intracellular organization, and transport (Bershadsky and Vasiliev 1988; Ku et al. 1999). IF proteins comprise a large family, which includes »70 diVerent genes (Omary et al. 2004; Kim and Coulombe 2007; Herrmann et al. 2007; Goldman et al. 2008). They are further divided into six subtypes (Table 1), which are, at least in part, expressed in a cell type (and diVerentiation)-dependent manner (Omary et al. 2004; Kim and Coulombe 2007; Goldman et al. 2008). Accordingly, IFs serve as cell type markers and antibodies to IF proteins are widely used today in diagnostic pathology (Wick 2000; Barak et al. 2004). Individual IF proteins consist of a con- served central coiled-coil -helical rod domain (interrupted by linkers) which is Xanked by N-terminal (head) and C-terminal (tail) domains (Omary et al. 2006; Godsel et al. 2008; Kim and Coulombe 2007; Herrmann et al. 2007; Goldman et al. 2008). The N- and C-terminal domains 123