Keratins 8 and 18 (K8/K18) are heteropolymeric intermediate filament (IF) phospho-glycoproteins in simple-type epithelia. K8/K18 protect hepatocytes from apoptosis and their mutations predispose to liver disease. We previously reported the disease association of K8/K18. This work was based on our findings in transgenic mice which overexpressed a dominant-negative mutant of human K18. The mice developed chronic hepatitis, fragile hepatocytes with disrupted filament and increased susceptibility to drug-induced liver injury. This result led us to hypothesize that some cases of human hepatitis may be associated with K8 and/or K18 mutations. We tested and confirmed this hypothesis with findings that have been described in several publications. Our findings to date indicate that K8 or K18 mutations pose a risk factor for developing liver disease. Such mutations are found in 12% of all patients with liver disease. Another area of research focuses on studying the in vivo function of K18 glycosylation. K18 undergoes dynamic single O-linked N-acetylglucosamine(O-GlcNAc)-type glycosylation at Ser29/30/48. Although experimental animal models treated with the O-GlcNAcase inhibitor streptozotocin (STZ) accumulate O-GlcNAc-modified proteins and develop diabetes and neurodegeneration, and cultured adipocytes treated with O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc), another O-GlcNAcase inhibitor, increase O-GlcNAc level and become insulin resistance, no reported studies test the function of site-specific glycosylation in animal models. We addressed the function of K18 glycosylation by generating transgenic mice that overexpress K18 Ser29/30/48Ala (K18-Gly-), and compared their susceptibility to STZ- or PUGNAc/Fas-mediated injury using non-transgenic mice or mice that overexpress wild-type K18. K18-Gly- mice are significantly more susceptible to STZ- or PUGNAc/Fas-induced injury and lethality as compared with the other tested mouse lines. Insulin production is reduced and islet injury is increased in K18-Gly- mice, coupled with prominent hepatocyte apoptosis which is specific to STZ or PUGNAc since Fas-ligand alone induces apoptosis similarly in K18-Gly- and control mice. The enhanced apoptosis in K18-Gly- mice involves Akt inactivation due to site-specific hypophosphorylation at or near potential glycosylation site. Therefore, K18 glycosylation protects from unique forms of epithelial injury likely by promoting hyperphophorylation/activation of cell survival kinases possibly via shunting their glycosylation towards keratins.