Adiponectin inhibits steatotic CD95/Fas up-regulation by hepatocytes: therapeutic implications for hepatitis C.
OBJECTIVE
Steatosis may trigger hepatocytes to up-regulate CD95/Fas thereby increasing susceptibility to apoptosis, inflammation and fibrosis. We investigated this concept and potential roles of adiponectin and its receptors (AdipoR1; AdipoR2) in chronically HCV-infected patients.


METHODS
In 98 HCV+ patients and 20 controls, sera were tested for HCV genotypes, FFAs, adiponectin and the M30 apoptosis indicator, and biopsies were evaluated for steatosis/inflammation/fibrosis, CD95/Fas (mRNA/protein), adiponectin (mRNA/protein), AdipoR1/-R2 (mRNA) and M30 (protein). We also questioned whether adiponectin protects HepG2 hepatoblastoma cells from FFA-triggered CD95/Fas up-regulation and apoptosis.


RESULTS
Patients [HCV clades 1 (78%), 2 (3%) and 3 (19%)] revealed increased FFA and adiponectin serum levels (p = .005). Hepatocyte CD95/Fas up-regulation correlated with steatosis, inflammation and fibrosis (p = .004). Advanced fibrosis correlated significantly (p = .05) with serum M30. Liver adiponectin correlated with steatosis (p = .016), CD95/Fas (p < .001) and inflammation/fibrosis. Hepatocyte AdipoR2 mRNA specifically correlated with serum adiponectin and steatosis (p = .003), while hepatocyte AdipoR1 mRNA dropped in pronounced fibrosis (p = .060). Finally, adiponectin protected HepG2 cells from FFA-triggered CD95/Fas expression and induction of apoptosis (p = .0396).


CONCLUSIONS
In chronic HCV infection, steatosis up-regulates hepatocyte CD95/Fas and thus increases apoptosis, which facilitates inflammation and fibrosis. The physiologic countermeasure of adiponectin up-regulation may offer clues for future therapeutic intervention.
Wedemeyer
Inga
I
Institute for Pathology, University Hospital, University of Cologne, Cologne, Germany.
Bechmann
Lars P
LP
Odenthal
Margarethe
M
Jochum
Christoph
C
Marquitan
Guido
G
Drebber
Uta
U
Gerken
Guido
G
Gieseler
Robert K
RK
Dienes
Hans P
HP
Canbay
Ali
A
D052242:Adiponectin / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018197:Hepatoblastoma / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D054419:Receptors, Adiponectin / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology*; D019014:fas Receptor / Q000037:antagonists & inhibitors* / Q000378:metabolism
C475420:ADIPOR2 protein, human; D052242:Adiponectin; D005230:Fatty Acids, Nonesterified; D054419:Receptors, Adiponectin; D019014:fas Receptor