Chronic liver disease is triggered by taurine transporter knockout in the mouse.
Taurine is an abundant organic osmolyte with antioxidant and immunomodulatory properties. Its role in the pathogenesis of chronic liver disease is unknown. The liver phenotype was studied in taurine transporter knockout (taut-/-) mice. Hepatic taurine levels were ~21, 15 and 6 mumol/g liver wet weight in adult wild-type, heterozygous (taut+/-) and homozygous (taut-/-) mice, respectively. Immunoelectronmicroscopy revealed an almost complete depletion of taurine in Kupffer and sinusoidal endothelial cells, but not in parenchymal cells of (taut-/-) mice. Compared with wild-type mice, (taut-/-) and (taut+/-) mice developed moderate unspecific hepatitis and liver fibrosis with increased frequency of neoplastic lesions beyond 1 year of age. Liver disease in (taut-/-) mice was characterized by hepatocyte apoptosis, activation of the CD95 system, elevated plasma TNF-alpha levels, hepatic stellate cell and oval cell proliferation, and severe mitochondrial abnormalities in liver parenchymal cells. Mitochondrial dysfunction was suggested by a significantly lower respiratory control ratio in isolated mitochondria from (taut-/-) mice. Taut knockout had no effect on taurine-conjugated bile acids in bile; however, the relative amount of cholate-conjugates acid was decreased at the expense of 7-keto-cholate-conjugates. In conclusion, taurine deficiency due to defective taurine transport triggers chronic liver disease, which may involve mitochondrial dysfunction.
Warskulat
Ulrich
U
Clinic for Gastroenterology, Hepatology, and Infectiology, Heinrich Heine University, Düsseldorf, Germany.
Borsch
Elena
E
Reinehr
Roland
R
Heller-Stilb
Birgit
B
Mönnighoff
Irmhild
I
Buchczyk
Darius
D
Donner
Markus
M
Flögel
Ulrich
U
Kappert
Günther
G
Soboll
Sibylle
S
Beer
Sandra
S
Pfeffer
Klaus
K
Marschall
Hanns-Ulrich
HU
Gabrielsen
Marcus
M
Amiry-Moghaddam
Mahmood
M
Ottersen
Ole Petter
OP
Dienes
Hans Peter
HP
Häussinger
Dieter
D
D000818:Animals; D017209:Apoptosis; D001647:Bile Acids and Salts / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D042783:Endothelial Cells / Q000737:chemistry / Q000473:pathology; D005260:Female; D005838:Genotype; D006505:Hepatitis / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D022781:Hepatocytes / Q000737:chemistry / Q000473:pathology; D007728:Kupffer Cells / Q000737:chemistry / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D026901:Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000648:ultrastructure; D018384:Oxidative Stress; D010587:Phagocytosis; D013654:Taurine / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D019014:fas Receptor / Q000378:metabolism; D000099247:Taurine Transporters
D001647:Bile Acids and Salts; D016207:Cytokines; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D013654:Taurine; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D000099247:Taurine Transporters