Keratin-8 null mice have different gallbladder and liver susceptibility to lithogenic diet-induced injury

Guo, Tao; Toivola, Diana M.; Zhong, Bihui; Michie, Sara A.; Resurreccion, Evelyn Z.; Tamai, Yoshitaka; Taketo, Makoto Mark; Omary, M. Bishr

doi:10.1242/jcs.00782

Cited by 37 publications

(32 citation statements)

References 47 publications

(77 reference statements)

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“…[19][20][21][22] Keratin filament instability or "hyperstability" has also been observed upon transfection of cells with K8 mutations that are found in patients with liver disease, but how keratin filament alterations translate to the ability of a cell to better cope with stress is unknown. 5,17,23 The liver appears to be selectively susceptible to injury as a consequence of K8/K18 mutation or absence as compared with the pancreas 24,25 and gallbladder, 26 which appear to be spared when challenged with tissue-specific insults; this is likely due to compensation by other cytoskeletal and possibly noncytoskeletal proteins. 27 To further address how keratin mutations predispose to liver injury, we used gene profiling and several biochemical tools to assess genetic changes that occur as a consequence of the K18 R89C mutation, which in turn causes keratin filament collapse and increased susceptibility to liver injury.…”

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confidence: 99%

Keratin mutation primes mouse liver to oxidative injury†

Zhou

Chen

et al. 2005

Hepatology

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Mutation of the cytoskeletal intermediate filament proteins keratin 8 and keratin 18 (K8/K18) is associated with cirrhosis in humans, whereas transgenic mice that overexpress K18 Arg893 Cys (R89C) have significant predisposition to liver injury. To study the mechanism of keratinassociated predisposition to liver injury, we used mouse microarrays to examine genetic changes associated with hepatocyte keratin mutation and assessed the consequences of such changes. Liver gene expression was compared in R89C versus nontransgenic or wild-type K18-overexpressing mice. Microarray-defined genetic changes were confirmed by quantitative polymerase chain reaction. Nineteen genes had a more than two-fold altered expression (nine downregulated, 10 upregulated). Upregulated genes in keratin-mutant hepatocytes included the oxidative metabolism genes cytochrome P450, S-adenosylhomocysteine (SAH) hydrolase, cysteine sulfinic acid decarboxylase, and oxidation-reduction pathway genes. Downregulated genes included fatty acid binding protein 5, cyclin D1, and some signaling molecules. Several methionine metabolism-related and glutathione synthetic pathway intermediates, including S-adenosylmethionine (SAMe) and SAH, were modulated in R89C versus control mice. R89C livers had higher lipid and protein oxidation by-products as reflected by increased malondialdehyde and oxidized albumin. In conclusion, K18 point mutation in transgenic mice modulates several hepatocyte oxidative stress-related genes and leads to lipid and protein oxidative by-products. Mutationassociated decreases in SAH and SAMe could compromise needed cysteine availability to generate glutathione during oxidative stress. Hence keratin mutations may prime hepatocytes to oxidative injury, which provides a new potential mechanism for how keratin mutations may predispose patients to cirrhosis. (HEPATOLOGY 2005;41:517-525.)

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confidence: 99%

Keratin mutation primes mouse liver to oxidative injury†

Zhou

Chen

et al. 2005

Hepatology

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“…Keratin hyperphosphorylation also correlates strongly with exposure to a variety of stresses in all tested systems, including cultured cells and mouse models of liver, pancreatic, and gallbladder injury. 3,18,19 In human liver disease, keratin hyperphosphorylation occurs in primary biliary cirrhosis and in association with Mallory bodies in human alcoholic liver disease and in mouse models of such hyaline deposits. 20 -22 Herein we asked whether keratins and their phosphorylation could be used as a potential disease "sensor" and, thus, a marker for human liver disease progression or regression.…”

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Keratin 8 and 18 hyperphosphorylation is a marker of progression of human liver disease

Toivola

Resurreccion

et al. 2004

Hepatology

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Keratin 8 and 18 (K8/18) phosphorylation plays a significant and site-specific role in regulating keratin filament organization, association with binding proteins, and modulation of cell cycle progression. Keratin hyperphosphorylation correlates with exposure to a variety of stresses in cultured cells and in mouse models of liver, pancreatic, and gallbladder injury, and it is found in association with mouse and human Mallory bodies. We asked whether K8/18 phosphorylation correlates with human liver disease progression by analyzing liver explants and biopsies of patients with chronic noncirrhotic hepatitis C virus (HCV) or cirrhosis. We also examined the effect of HCV therapy with interleukin-10 on keratin phosphorylation. Using site-specific antiphosphokeratin antibodies we found keratin hyperphosphorylation on most K8/18 sites in all cirrhotic liver explants tested and in most liver biopsies from patients with chronic HCV infection. Immunofluorescence staining of precirrhotic HCV livers showed focal keratin hyperphosphorylation and limited reorganization of keratin filament networks. In cirrhotic livers, keratin hyperphosphorylation occurred preferentially in hepatic nodule cells adjacent to bridging fibrosis and associated with increased stress kinase activation and apoptosis. Histological and serological improvement after interleukin-10 therapy was accompanied by normalization of keratin hyperphosphorylation on some sites in 7 of 10 patients. In conclusion, site-specific keratin phosphorylation in liver disease is a progression marker when increased and a likely regression marker when decreased. (HEPATOLOGY 2004;40:459 -466.)

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“…Supportive of that only a mild keratin‐related phenotype occurs after a high‐fat regimen, is that K8 +/− and K8 +/+ gall bladders and livers responded similarly to a high‐fat lithogenic gallstone‐inducing diet,19 while HFD induced hepatocellular injury in susceptible K8 −/− mice 30. HFD, which has a systemic metabolic effect on the organism, is likely to primarily reflect liver health and not pancreatic islet health.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, liver fragility is observed in both K8 −/− and K18 −/− as well as in K18 mutant mice, while K8 knockdown disrupts cell morphology and increases apoptosis in the thymus 7, 15. Keratins are upregulated in epithelial cells after organ‐specific stress or disease conditions, as documented in several organs such as colon, liver, kidney, β‐cells and gall bladder 10, 19, 20…”

Section: Introductionmentioning

confidence: 99%

Decreased levels of keratin 8 sensitize mice to streptozotocin‐induced diabetes

et al. 2018

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AimDiabetes is a result of an interplay between genetic, environmental and lifestyle factors. Keratin intermediate filaments are stress proteins in epithelial cells, and keratin mutations predispose to several human diseases. However, the involvement of keratins in diabetes is not well known. K8 and its partner K18 are the main β‐cell keratins, and knockout of K8 (K8−/−) in mice causes mislocalization of glucose transporter 2, mitochondrial defects, reduced insulin content and altered systemic glucose/insulin control. We hypothesize that K8/K18 offer protection during β‐cell stress and that decreased K8 levels contribute to diabetes susceptibility.MethodsK8‐heterozygous knockout (K8+/−) and wild‐type (K8+/+) mice were used to evaluate the influence of keratin levels on endocrine pancreatic function and diabetes development under basal conditions and after T1D streptozotocin (STZ)‐induced β‐cell stress and T2D high‐fat diet (HFD).ResultsMurine K8+/− endocrine islets express ~50% less K8/K18 compared with K8+/+. The decreased keratin levels have little impact on basal systemic glucose/insulin regulation, β‐cell health or insulin levels. Diabetes incidence and blood glucose levels are significantly higher in K8+/− mice after low‐dose/chronic STZ treatment, and STZ causes more β‐cell damage and polyuria in K8+/− compared with K8+/+. K8 appears upregulated 5 weeks after STZ treatment in K8+/+ islets but not in K8+/−. K8+/− mice showed no major susceptibility risk to HFD compared to K8+/+.ConclusionPartial K8 deficiency reduces β‐cell stress tolerance and aggravates diabetes development in response to STZ, while there is no major susceptibility to HFD.

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Keratin-8 null mice have different gallbladder and liver susceptibility to lithogenic diet-induced injury

Cited by 37 publications

References 47 publications

Keratin mutation primes mouse liver to oxidative injury†

Keratin mutation primes mouse liver to oxidative injury†

Keratin 8 and 18 hyperphosphorylation is a marker of progression of human liver disease

Decreased levels of keratin 8 sensitize mice to streptozotocin‐induced diabetes

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