Background and Aims:
Changes in the activity of the IGF1 signaling pathway may participate in the development
of NAFLD. Yet, it is unclear which regulatory components of the IGF1 pathway are affected
in liver steatosis. Here, we performed comparative proteomics for regulatory components
of the IGF1 system on primary hepatocytes from mice with and without hepatic lipid
accumulation. The findings were validated in a human study for associations with NAFLD
and for the impact of a weight-loss intervention that mitigates hepatic steatosis.
Methods:
Proteomics was conducted on cell culture supernatants from hepatocytes from C57Bl6-
and aP2-SREBP-1c mice, the latter displaying massive hepatic lipid accumulation. Serum
from 36 normal-weight and 62 obese men with biopsy-proven NAFLD was used for ELISA-based
validations. Follow-up samples after weight loss by bariatric surgery were available
for 14 participants.
Results:
Comparative proteomic analysis identified IGFBP2 as the major hepatokine that was
changed between healthy and aP2-SREBP-1c-hepatocytes. Reductions in IGFBP2 secretion
associated with hypermethylation of the Igfbp2-promoter region. In humans, circulating
IGFBP2 levels were 279 ng/ml in normal-weight men versus 99.3 ng/ml and 97.2 ng/ml
in men with NAFLD and NASH, respectively. IGFBP2 levels increased from 146 to 395
ng/ml after bariatric surgery, and the increase in IGFBP2 levels associated with a
decrease in fatty liver index (r =-0.701, p = 0.003).
Conclusions:
Reductions in IGFBP2 associate with hepatic lipid accumulation. Accordingly, an intervention
that mitigates hepatic steatosis restores IGFBP2 levels to those found in normal-weight
men.
PF, BK, JK, and DMO contributed equally
