Keratin-18: Diagnostic, Prognostic, and Theragnostic for Alcohol-Associated Hepatitis

Although hepatocellular carcinoma (HCC) is developed with various etiologies, protection of hepatocytes seems basically essential to prevent the incidence of HCC. Keratin 8 and keratin 18 (K8/K18) are cytoskeletal intermediate filament proteins that are expressed in hepatocytes. They maintain the cell shape and protect cells under stress conditions. Their protective roles in liver damage have been described in studies of mouse models, and K8/K18 mutation frequency in liver patients. Interestingly, K8/K18 bind to signaling proteins such as transcription factors and protein kinases involved in HCC development. Since K8/K18 are abundant cytoskeletal proteins, K8/K18 binding with the signaling factors can alter the availability of the factors. Herein, we discuss the potential roles of K8/K18 in HCC development.

Download Full-text

Caspase-Cleaved Keratin 18 Measurements Identified Ongoing Liver Injury after Bariatric Surgery

Journal of Clinical Medicine ◽

10.3390/jcm10061233 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1233

Author(s):

Felix Hempel ◽

Martin Roderfeld ◽

Lucas John Müntnich ◽

Jens Albrecht ◽

Ziya Oruc ◽

...

Keyword(s):

Bariatric Surgery ◽

Liver Disease ◽

Liver Injury ◽

Response To Treatment ◽

Morbidly Obese ◽

Alcoholic Fatty Liver ◽

Laboratory Parameters ◽

Nafld Fibrosis Score ◽

Keratin 18 ◽

One Year

Bariatric surgery has emerged as an effective treatment option in morbidly obese patients with non-alcoholic fatty liver disease (NAFLD). However, worsening or new onset of non-alcoholic steatohepatitis (NASH) and fibrosis have been observed. Caspase-cleaved keratin 18 (ccK18) has been established as a marker of hepatocyte apoptosis, a key event in NASH development. Thus, ccK18 measurements might be feasible to monitor bariatric surgery patients. Clinical data and laboratory parameters were collected from 39 patients undergoing laparoscopic Roux-en-Y gastric bypass at six timepoints, prior to surgery until one year after the procedure. ccK18 levels were measured and a high-throughput analysis of serum adipokines and cytokines was carried out. Half of the cohort’s patients (20/39) presented with ccK18 levels indicative of progressed liver disease. 21% had a NAFLD-fibrosis score greater than 0.676, suggesting significant fibrosis. One year after surgery, a mean weight loss of 36.87% was achieved. Six and twelve months after surgery, ccK18 fragments were significantly reduced compared to preoperative levels (p < 0.001). Yet nine patients did not show a decline in ccK18 levels ≥ 10% within one year postoperatively, which was considered a response to treatment. While no significant differences in laboratory parameters or ccK18 could be observed, they presented with a greater expression of leptin and fibrinogen before surgery. Consecutive ccK18 measurements monitored the resolution of NAFLD and identified non-responders to bariatric surgery with ongoing liver injury. Further studies are needed to elicit the pathological mechanisms in non-responders and study the potential of adipokines as prognostic markers.

Download Full-text

Localization of the gene for human simple epithelial keratin 18 to chromosome 12 using polymerase chain reaction

Genomics ◽

10.1016/0888-7543(90)90540-b ◽

1990 ◽

Vol 7 (2) ◽

pp. 188-194 ◽

Cited By ~ 23

Author(s):

Ahmad Waseem ◽

Alan C. Gough ◽

Nigel K. Spurr ◽

E.Birgitte Lane

Keyword(s):

Polymerase Chain Reaction ◽

Chromosome 12 ◽

Chain Reaction ◽

Polymerase Chain ◽

Keratin 18

Download Full-text

Transcriptional insulation of the human keratin 18 gene in transgenic mice

Molecular and Cellular Biology ◽

10.1128/mcb.13.4.2214-2223.1993 ◽

1993 ◽

Vol 13 (4) ◽

pp. 2214-2223

Author(s):

N Neznanov ◽

I S Thorey ◽

G Ceceña ◽

R G Oshima

Keyword(s):

Transgenic Mice ◽

Thymidine Kinase ◽

Copy Number ◽

Thymidine Kinase Gene ◽

Flanking Sequence ◽

Kinase Gene ◽

Tissue Specific ◽

Dependent Behavior ◽

Flanking Sequences ◽

Keratin 18

Expression of the 10-kb human keratin 18 (K18) gene in transgenic mice results in efficient and appropriate tissue-specific expression in a variety of internal epithelial organs, including liver, lung, intestine, kidney, and the ependymal epithelium of brain, but not in spleen, heart, or skeletal muscle. Expression at the RNA level is directly proportional to the number of integrated K18 transgenes. These results indicate that the K18 gene is able to insulate itself both from the commonly observed cis-acting effects of the sites of integration and from the potential complications of duplicated copies of the gene arranged in head-to-tail fashion. To begin to identify the K18 gene sequences responsible for this property of transcriptional insulation, additional transgenic mouse lines containing deletions of either the 5' or 3' distal end of the K18 gene have been characterized. Deletion of 1.5 kb of the distal 5' flanking sequence has no effect upon either the tissue specificity or the copy number-dependent behavior of the transgene. In contrast, deletion of the 3.5-kb 3' flanking sequence of the gene results in the loss of the copy number-dependent behavior of the gene in liver and intestine. However, expression in kidney, lung, and brain remains efficient and copy number dependent in these transgenic mice. Furthermore, herpes simplex virus thymidine kinase gene expression is copy number dependent in transgenic mice when the gene is located between the distal 5'- and 3'-flanking sequences of the K18 gene. Each adult transgenic male expressed the thymidine kinase gene in testes and brain and proportionally to the number of integrated transgenes. We conclude that the characteristic of copy number-dependent expression of the K18 gene is tissue specific because the sequence requirements for transcriptional insulation in adult liver and intestine are different from those for lung and kidney. In addition, the behavior of the transgenic thymidine kinase gene in testes and brain suggests that the property of transcriptional insulation of the K18 gene may be conferred by the distal flanking sequences of the K18 gene and, additionally, may function for other genes.

Download Full-text

RETRACTED: Molecular forms of HMGB1 and keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity

Journal of Hepatology ◽

10.1016/j.jhep.2011.12.019 ◽

2012 ◽

Vol 56 (5) ◽

pp. 1070-1079 ◽

Cited By ~ 239

Author(s):

Daniel J. Antoine ◽

Rosalind E. Jenkins ◽

James W. Dear ◽

Dominic P. Williams ◽

Mitchell R. McGill ◽

...

Keyword(s):

Cell Death ◽

Molecular Forms ◽

Keratin 18 ◽

Acetaminophen Hepatotoxicity

Download Full-text

Formation of Mallory Body-like Inclusions and Cell Death Induced by Deregulated Expression of Keratin 18

Molecular Biology of the Cell ◽

10.1091/mbc.01-10-0510 ◽

2002 ◽

Vol 13 (10) ◽

pp. 3441-3451 ◽

Cited By ~ 23

Author(s):

Ikuo Nakamichi ◽

Shigetsugu Hatakeyama ◽

Keiichi I. Nakayama

Keyword(s):

Cell Death ◽

Important Determinant ◽

Cellular Model ◽

Microtubule Network ◽

Cytoplasmic Inclusions ◽

Mallory Bodies ◽

Keratin 18 ◽

Intracellular Aggregates

Mallory bodies (MBs) are cytoplasmic inclusions that contain keratin 8 (K8) and K18 and are present in hepatocytes of individuals with alcoholic liver disease, nonalcoholic steatohepatitis, or benign or malignant hepatocellular neoplasia. Mice fed long term with griseofulvin are an animal model of MB formation. However, the lack of a cellular model has impeded understanding of the molecular mechanism of this process. Culture of HepG2 cells with griseofulvin has now been shown to induce both the formation of intracellular aggregates containing K18 as well as an increase in the abundance of K18 mRNA. Overexpression of K18 in HepG2, HeLa, or COS-7 cells also induced the formation of intracellular aggregates that stained with antibodies to ubiquitin and with rhodamine B (characteristics of MBs formed in vivo), eventually leading to cell death. The MB-like aggregates were deposited around centrosomes and disrupted the microtubular array. Coexpression of K8 with K18 restored the normal fibrous pattern of keratin distribution and reduced the toxicity of K18. In contrast, an NH2-terminal deletion mutant of K8 promoted the formation of intracellular aggregates even in the absence of K18 overexpression. Deregulated expression of K18, or an imbalance between K8 and K18, may thus be an important determinant of MB formation, which compromises the function of centrosomes and the microtubule network and leads to cell death.

Download Full-text

Keratin 18 Is a Diagnostic and Prognostic Factor for Acute Alcoholic Hepatitis

Clinical Gastroenterology and Hepatology ◽

10.1016/j.cgh.2019.11.050 ◽

2020 ◽

Vol 18 (9) ◽

pp. 2046-2054 ◽

Cited By ~ 8

Author(s):

Vatsalya Vatsalya ◽

Matthew C. Cave ◽

Maiying Kong ◽

Leila Gobejishvili ◽

K. Cameron Falkner ◽

...

Keyword(s):

Prognostic Factor ◽

Alcoholic Hepatitis ◽

Acute Alcoholic Hepatitis ◽

Keratin 18

Download Full-text

Keratin 18 is an integral part of the intermediate filament network in murine skeletal muscle

AJP Cell Physiology ◽

10.1152/ajpcell.00279.2019 ◽

2020 ◽

Vol 318 (1) ◽

pp. C215-C224 ◽

Cited By ~ 1

Author(s):

Joaquin M. Muriel ◽

Andrea O’Neill ◽

Jaclyn P. Kerr ◽

Emily Kleinhans-Welte ◽

Richard M. Lovering ◽

...

Keyword(s):

Skeletal Muscle ◽

Isometric Force ◽

Dominant Negative ◽

Dominant Negative Mutant ◽

Type I ◽

Mrna Levels ◽

Force Transmission ◽

Keratin 18 ◽

Murine Skeletal Muscle

Intermediate filaments (IFs) contribute to force transmission, cellular integrity, and signaling in skeletal muscle. We previously identified keratin 19 (Krt19) as a muscle IF protein. We now report the presence of a second type I muscle keratin, Krt18. Krt18 mRNA levels are about half those for Krt19 and only 1:1,000th those for desmin; the protein was nevertheless detectable in immunoblots. Muscle function, measured by maximal isometric force in vivo, was moderately compromised in Krt18-knockout ( Krt18-KO) or dominant-negative mutant mice ( Krt18 DN), but structure was unaltered. Exogenous Krt18, introduced by electroporation, was localized in a reticulum around the contractile apparatus in wild-type muscle and to a lesser extent in muscle lacking Krt19 or desmin or both proteins. Exogenous Krt19, which was either reticular or aggregated in controls, became reticular more frequently in Krt19-null than in Krt18-null, desmin-null, or double-null muscles. Desmin was assembled into the reticulum normally in all genotypes. Notably, all three IF proteins appeared in overlapping reticular structures. We assessed the effect of Krt18 on susceptibility to injury in vivo by electroporating siRNA into tibialis anterior (TA) muscles of control and Krt19-KO mice and testing 2 wk later. Results showed a 33% strength deficit (reduction in maximal torque after injury) compared with siRNA-treated controls. Conversely, electroporation of siRNA to Krt19 into Krt18-null TA yielded a strength deficit of 18% after injury compared with controls. Our results suggest that Krt18 plays a complementary role to Krt19 in skeletal muscle in both assembling keratin-based filaments and transducing contractile force.

Download Full-text