November 2002 • Volume 36 • Number 5
Hepatology highlights
The RON receptor is a heterodimeric tyrosine kinase found in macrophages
and Kupffer cells. Deletion of the tyrosine kinase domaine (Ron TK–/–)
of this gene is known to increase mortality in response to high dose
endotoxin, suggesting a protective role for this receptor against the
biological effects of endotoxin. Leonis et al. have extended their
studies on Ron TK–/– mice using the galactosamine/low
dose endotoxin model of liver injury. Surprisingly, these mice were
protected and exhibited marked decreased hemorrhage and apoptosis by
Tunel stain (see Fig.), DNA laddering, and caspase 3.
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The Ron TK–/– mice exhibited an altered serum cytokine
profile in response to endotoxin with enhanced TNF and decreased IL-10
and IFN- levels. The Ron TK–/–
mice were not protected against exogenous TNF plus galactosamine. Thus,
protection by elimination of Ron signaling despite exaggerated TNF
strongly supports the concept that the cytokine network and interplay of
various cytokines rather than TNF alone determines the fate of the liver
in response to endotoxin/galactosamine. (See HEPATOLOGY
2002;36:1053-1060.)
Two gene loci that account for susceptibility to cholesterol gallstones
have previously been identified in inbred mice: Lith 1 and 2, which
encode for canalicular transporters. To address the importance of these
genes, Lammert et al. have cross-bred these mice (AKR/J) with another
inbred species (A/J) that does not develop gallstones. After being fed a
lithogenic diet, the mice were phenotyped and genotyped for
microsatellite markers, and quantitative trait loci were identified by
linkage analysis. Phenotyping included mucin, cholesterol crystals, and
gallstones. A new locus, Lith 3, was identified, which was associated
with susceptibility to cholesterol gallstones. Although Lith 3 maps to
the vicinity of the choline transporter, the sequence and the expression
of the latter were not affected. Therefore, Lith 3 gene awaits
identification. Gallbladder mucin gel accumulation is an important
prerequisite for stone formation. Phenotyping/genotyping revealed that
mucin hypersecretion was localized on distal chromosome 15, which is the
site of the mucin gene, Glycam 1. The investigators showed that Glycam 1
is expressed on biliary epithelia. This is a very important observation
because it suggests that genetic control of mucin secretion rather than
increased secretion secondary to the effects of crystals and stones may
be important in the pathophysiology of stone formation. These ongoing
studies are revealing important genetic associations that determine
mucin gel accumulation, cholesterol crystals, and gallstone formation.
(See HEPATOLOGY 2002;36:1145-1154.)
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Preservation injury affects graft performance after orthotopic liver
transplantation. Yagnik et al. have addressed the importance of nitric
oxide (NO) in this phenomenon using a rat model of OLT. Strikingly,
within 1 hour after liver transplantation a 10-fold decrease in serum
arginine, the precursor of NO, was observed. This was associated with
increased serum arginase I, presumably released by the injured liver,
and increased serum ornithine, the product of arginase action on
arginine. Supplementation of the graft and recipient with L-arginine
protected against liver injury, whereas D-arginine
was not protective. In addition, NOS expression was up-regulated in
periportal hepatocytes after OLT. Treatment with L-NAME,
a nonselective NOS inhibitor, worsened liver injury and apoptosis,
whereas iNOS selective inhibitor L-NIL had less
effect on serum ALT but enhanced apoptosis. This work suggests that NO
exerts a protective effect against liver injury after OLT. The
consumption of arginine may limit NO production in this setting,
although other beneficial effects of arginine supplementation are
possible. The data suggest that eNOS-derived NO protects perfusion and
iNOS-derived NO protects against hepatocyte apoptosis in this model.
Work with eNOS and iNOS null mice is anticipated, which will help
clarify the locus and mechanisms of NO protection. (See HEPATOLOGY
2002;36:573-581.)
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Ursodeoxycholic acid is used in the treatment of a number of liver
diseases. Among its beneficial effects is the inhibition of apoptosis,
which has been thought to be exerted at the level of mitochondrial
participation in cell death. Recently, a mode of cell death has been
described in response to endoplasmic reticulum (ER) stress, which may
not involve mitochondria. Agents that disturb Ca+2
sequestration or that cause accumulation of misfolded proteins induce
this pathway, which involves a repertoire of effects including
activation of a unique ER resident caspase (caspase 12) that can
directly activate the apoptosis cascade downstream of mitochondria. Xie
et al. have examined the protective effect of taurourso on this pathway
in Huh 7 cells that undergo ER stress–induced apoptosis in response to
thapsigargin (Ca+2 pump inhibitor). Taurourso protected
against thapsigargin (TG)-induced apoptosis, procaspase 12 processing
(see Fig.), GRP78 (ER chaperone) induction, increased cytosol calcium,
calpain activation, and downstream activation of caspase 3 and 7.
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Thapsigargin did not depolarize mitochondria but did lead to delayed
release of cytochrome c, which was also inhibited by taurourso. Thus,
protection against Ca+2-induced ER stress can be added to the
list of beneficial effects of urso. It remains to be seen if urso will
protect against ER stress that is primarily induced by protein
misfolding. (See HEPATOLOGY 2002;36:592-601.)
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Porphyria cutanea tarda (PCT) is the most common porphyria. It is caused
by mutations in uroporphyrinogen decarboxylase (URO-D) leading to excess
uroporphyrin production in the liver. Hepatic siderosis is a constant
feature and HFE homozygosity is found in 20% of cases. Franklin et al.
have explored these relationships in mice null for Uro-D or Hfe. Uro-D+/–
animals were susceptible to the expression of uroporphyria when crossed
with Hfe–/–, treated with iron dextran or with the
polychlorinated biphenyl (PCB), Aroclor 1254. The untreated Uro-D+/–
mouse showed no porphyria despite a 50% decrease of the enzyme, and Hfe–/–
alone showed no porphyria. The combination caused the uroporphyria
phenotype. Aroclor 1254 elicited porphyria in Uro-D+/– but
not Hfe–/– mice. In all cases in which uroporphyria was
induced, the effect was greater in female animals and was associated
with depression of Uro-D activity and the appearance of a novel
heat-stable cytosol inhibitor of Uro-D (see Fig.).
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This model will prove invaluable in elucidating the pathogenesis of
PCT. (See HEPATOLOGY 2002;36:805-811.)
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Bile acids such as taurolithocholate sulfate (TLCS) and
glycochenodeoxycholic acid (GCDC) are known to induce hepatocyte
apoptosis. Betaine, a natural product of choline oxidase, has been
suggested to act as a protective agent possibly as a chemical chaperone,
organic osmolyte, or a precursor of SAMe as a methyl donor for
remethylation of methionine. Graf et al. have studied the effect of
betaine on bile acid–induced apoptosis in culture rat hepatocytes.
Marked protection was observed against apoptosis, oxidative stress, and
activation of caspases 3, 8, and 9, and cytochrome c release with
betaine pretreatment. Another osmolyte, taurine, was not protective.
However, bile acid–induced MAP kinase (JNK, Erks, p38) activation and
PKB inhibition were not affected by betaine nor was bile acid–induced
membrane targeting of death receptors (in contrast to protection by urso).
Betaine supplementation of the drinking water reduced bile duct ligation–induced
apoptosis in vivo by 80%. Overall, betaine in some way protected
against apoptosis at the level of the mitochondrial gateway in vitro
but may also have affected the production of inflammatory mediators in
vivo. Betaine may be joining the ranks of SAMe and urso as natural
hepatoprotectants, each probably with somewhat distinct mechanisms of
action. (See HEPATOLOGY 2002;36:829-839.)
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