Ghrelin attenuates hepatocellular injury and liver fibrogenesis in rodents and influences fibrosis progression in humans.
There are no effective antifibrotic therapies for patients with liver diseases. We performed an experimental and translational study to investigate whether ghrelin, an orexigenic hormone with pleiotropic properties, modulates liver fibrogenesis. Recombinant ghrelin was administered to rats with chronic (bile duct ligation) and acute (carbon tetrachloride) liver injury. Hepatic gene expression was analyzed by way of microarray analysis and quantitative polymerase chain reaction. The hepatic response to chronic injury was also evaluated in wild-type and ghrelin-deficient mice. Primary human hepatic stellate cells were used to study the effects of ghrelin in vitro. Ghrelin hepatic gene expression and serum levels were assessed in patients with chronic liver diseases. Ghrelin gene polymorphisms were analyzed in patients with chronic hepatitis C. Recombinant ghrelin treatment reduced the fibrogenic response, decreased liver injury and myofibroblast accumulation, and attenuated the altered gene expression profile in bile duct-ligated rats. Moreover, ghrelin reduced the fibrogenic properties of hepatic stellate cells. Ghrelin also protected rats from acute liver injury and reduced the extent of oxidative stress and inflammation. Ghrelin-deficient mice developed exacerbated hepatic fibrosis and liver damage after chronic injury. In patients with chronic liver diseases, ghrelin serum levels decreased in those with advanced fibrosis, and ghrelin gene hepatic expression correlated with expression of fibrogenic genes. In patients with chronic hepatitis C, polymorphisms of the ghrelin gene (-994CT and -604GA) influenced the progression of liver fibrosis.


CONCLUSIONS
Ghrelin exerts antifibrotic effects in the liver and may represent a novel antifibrotic therapy.
Moreno
Montserrat
M
Liver Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
Chaves
Javier F
JF
Sancho-Bru
Pau
P
Ramalho
Fernando
F
Ramalho
Leandra N
LN
Mansego
Maria L
ML
Ivorra
Carmen
C
Dominguez
Marlene
M
Conde
Laura
L
Millán
Cristina
C
Marí
Montserrat
M
Colmenero
Jordi
J
Lozano
Juan J
JJ
Jares
Pedro
P
Vidal
Josep
J
Forns
Xavier
X
Arroyo
Vicente
V
Caballería
Juan
J
Ginès
Pere
P
Bataller
Ramón
R
D000818:Animals; D002478:Cells, Cultured; D018450:Disease Progression; D054439:Ghrelin / Q000502:physiology* / Q000627:therapeutic use*; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000473:pathology*; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000627:therapeutic use
D054439:Ghrelin; D011994:Recombinant Proteins