Pharmacologic transglutaminase inhibition attenuates drug-primed liver hypertrophy but not Mallory body formation.
Mallory bodies (MBs) are characteristic of several liver disorders, and consist primarily of keratins with transglutaminase-generated keratin crosslinks. We tested the effect of the transglutaminase-2 (TG2) inhibitor KCC009 on MB formation in a mouse model fed 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). KCC009 decreased DDC-induced liver enlargement without affecting MB formation or extent of liver injury. TG2 protein and activity increased after DDC feeding and localized within and outside hepatocytes. KCC009 inhibited DDC-induced hepatomegaly by affecting hepatocyte cell size rather than proliferation. Hence, TG2 is a potential mediator of injury-induced hepatomegaly via modulation of hepatocyte hypertrophy, and KCC009-mediated TG2 inhibition does not affect mouse MB formation.
Strnad
Pavel
P
Department of Medicine, Palo Alto VA Medical Center, Palo Alto, CA 94304, USA.
Siegel
Matthew
M
Toivola
Diana M
DM
Choi
Kihang
K
Kosek
Jon C
JC
Khosla
Chaitan
C
Omary
M Bishr
MB
D000818:Animals; D048429:Cell Size / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury; D003997:Dicarbethoxydihydrocollidine / Q000008:administration & dosage / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006529:Hepatomegaly / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D006801:Humans; D002479:Inclusion Bodies / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007555:Isoxazoles / Q000008:administration & dosage*; D007633:Keratins / Q000378:metabolism; D008107:Liver Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011506:Proteins / Q000378:metabolism*; D011503:Transglutaminases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D007555:Isoxazoles; C510621:KCC 009; C488922:Mallory body protein, mouse; D011506:Proteins; D003997:Dicarbethoxydihydrocollidine; D007633:Keratins; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins