Reduced levels of the hepatokine igfbp2 associate with nafld

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