A complex role of activin A in non-alcoholic fatty liver disease.
OBJECTIVE
Recent studies suggest that activin A, a member of the transforming growth factor (TGF) superfamily, is involved in the pathogenesis of liver disorders. We sought to explore its possible role in non-alcoholic fatty liver disease (NAFLD).


METHODS
Serum levels of activin A and its natural inhibitor, follistatin, were measured in patients with NAFLD (n=70) and in control subjects (n=30). Gene expression was quantified in liver biopsies obtained from patients with NAFLD (n=13) and controls (n=6). Effects of activin A were examined in Huh7 (human hepatoma cell line) hepatocytes.


RESULTS
Patients with NAFLD had significantly elevated serum levels of activin A and follistatin compared with healthy controls. In patients with non-alcoholic steatohepatitis (NASH, n=38), there were particularly high levels of activin A that were significantly related to the degree of hepatic fibrosis. Liver biopsies from NAFLD patients showed a markedly increased activin A-follistatin mRNA ratio, indicating increased hepatic activin A activity. In hepatocytes, activin A enhanced the expression of collagen and TGF-beta(1), promoted matrix metalloproteinase activity, induced mitochondrial beta-oxidation, downregulated fatty acid (FA) synthase activity, promoted decreased weight percentage of saturated FAs, and altered the composition of polyunsaturated FAs.


CONCLUSIONS
Our findings support the complex role of activin A in the pathogenesis of NAFLD, involving effects on fibrosis and lipid accumulation.
Yndestad
Arne
A
Research Institute for Internal Medicine, Rikshospitalet, Oslo University Hospital, Oslo, N-0027, Norway. arne.yndestad@rr-research.no
Haukeland
John Willy
JW
Dahl
Tuva Børresdatter
TB
Bjøro
Kristian
K
Gladhaug
Ivar Prydz
IP
Berge
Christ
C
Damås
Jan Kristian
JK
Haaland
Terese
T
Løberg
Else Marit
EM
Linnestad
Paul
P
Birkeland
Kåre
K
Konopski
Zbigniew
Z
Halvorsen
Bente
B
Berge
Rolf Kristian
RK
Aukrust
Pål
P
D028341:Activins / Q000097:blood* / Q000378:metabolism; D000328:Adult; D045744:Cell Line, Tumor; D005234:Fatty Liver / Q000097:blood* / Q000503:physiopathology; D005260:Female; D038681:Follistatin / Q000097:blood* / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008103:Liver Cirrhosis / Q000097:blood* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged
D038681:Follistatin; C422405:activin A; D028341:Activins