Leptin and Acetaldehyde Synergistically Promotes αSMA Expression in Hepatic Stellate Cells by an Interleukin 6-Dependent Mechanism


Reprint requests:Jianhua Wang, PhD, Storr Liver Unit, Westmead Millennium Institute, Westmead, NSW 2145, Australia. E-mail: jianhua.wang@sydney.edu.au


Background:  The mechanisms whereby patients with obesity/overweight are more susceptible to alcohol-associated liver fibrosis are unclear. Leptin, a peptide hormone secreted by white adipose tissue is increased in association with overweight/obesity and is recognized as mediator of liver fibrosis. We sought to assess whether leptin contributes to alcoholic liver fibrosis by in vitro studies in hepatic stellate cells (HSC).

Methods:  Rat HSCs in second or third passage were utilised. Leptin, Acetaldehyde or combination with leptin and acetaldehyde were incubated for specific periods in cultured HSCs. Profibrogenic gene and protein expression were determined and associated-signalling pathways were assessed. Interleukin 6 (IL-6) antibody neutralization was used to evaluate the role of IL-6.

Results:  Leptin did not promote acetaldehyde-induced gene expression of collagen I, transforming growth factor β1 (TGFβ1) and tissue inhibitor of metalloproteinase 1 (TIMP1) in vitro. However, combined treatment of leptin with acetaldehyde synergistically enhanced the protein expression of smooth muscle actin (αSMA), an activation marker of HSCs, and of Interleukin-6 (IL-6). The combination of leptin and acetaldehyde also augmented MAPK/p38 and MAPK/ERK1/2 phosphoprotein expression. IL-6 neutralization down-regulated protein expression of pp38, pERK1/2 and αSMA, while exogenous rat recombinant IL-6 administration up-regulated αSMA. Similarly, MAPK/p38 and MAPK/ERK1/2 inhibition attenuated αSMA expression. H2O2 induction by acetaldehyde was not potentiated by co-treatment with leptin nor did IL-6 neutralization reduce acetaldehyde-induced H2O2 production.

Conclusions:  We conclude that leptin potentiates acetaldehyde-induced HSC activation and αSMA expression by an IL-6-dependent mechanism.