Keratin-8 null mice have different gallbladder and liver susceptibility to lithogenic diet-induced injury.
Keratin transgenic mouse models and the association of human keratin mutations with liver disease highlight the importance of keratins in protecting the liver from environmental insults, but little is known regarding keratins and their function in the gallbladder. We characterized keratin expression pattern and filament organization in normal and keratin polypeptide-8 (K8)-null, K18-null and K19-null gallbladders, and examined susceptibility to liver and gallbladder injury induced by a high-fat lithogenic diet (LD) in K8-null mice. The major keratins of normal mouse gallbladder are K8>K19>K18 which become markedly depleted in K8-null mice with minor K18/K19 remnants and limited K7 over-expression. Compensatory K18/K20 protein and RNA overexpression occur in K19-null but not in K18-null gallbladders, probably because of the higher levels of K19 than K18 in normal gallbladder. LD challenge causes more severe liver injury in K8-null than wild-type mice without altering keratin protein levels. In contrast, wild-type and K8-null gallbladders are equally susceptible to LD-induced injury and stone formation, but wild-type gallbladders do overexpress keratins upon LD challenge. LD-induced injury triggers keratin hyperphosphorylation in wild-type livers and gallbladders. Hence, mouse gallbladder K8/K18/K19 expression is induced in response to cholelithiasis injury. A high-fat LD increases the susceptibility of K8-null mice to liver but not gallbladder injury, which suggests that keratin mutations may increase the risk of liver damage in patients with steatohepatitis. Differences between K8-null mouse gallbladder and hepatocyte susceptibility to injury may be related to their minimal versus absent keratin expression, respectively.
Tao
Guo-Zhong
GZ
Palo Alto VA Medical Center, Palo Alto, Mail code 154J, 3801 Miranda Avenue, Palo Alto, CA 94304 and Stanford University School of Medicine Digestive Disease Center, Stanford, CA 94305, USA.
Toivola
Diana M
DM
Zhong
Bihui
B
Michie
Sara A
SA
Resurreccion
Evelyn Z
EZ
Tamai
Yoshitaka
Y
Taketo
Makoto M
MM
Omary
M Bishr
MB
D000818:Animals; D004032:Diet; D004198:Disease Susceptibility / Q000473:pathology; D019084:Fluorescent Antibody Technique, Indirect; D005704:Gallbladder / Q000378:metabolism* / Q000473:pathology; D053533:Keratin-8; D007633:Keratins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction
D053533:Keratin-8; C486595:Krt8 protein, mouse; D007633:Keratins