Prolyl-hydroxylase inhibition ameliorates NAFLD-like hepatocyte alterations via OATP1B1

Background Nonalcoholic fatty liver disease (NAFLD), comprising a sequence of steatosis, non-alcoholic steatohepatitis (NASH), and liver fibrosis, significantly increases surgical morbidity in patients undergoing liver resection. Improving liver function in NAFLD patients is therefore of particular importance. We previously demonstrated that the prolyl hydroxylase (PHD) small-molecule inhibitor ethyl-3,4-dihydroxybenzoate (EDHB) promotes liver regeneration, putatively via organic anion transporting polypeptide 1B1 (OATP1B1). Here, we investigate whether this effect can be exploited in the setting of NAFLD.

Methods Huh7 cells were stimulated with palmitic acid (PA) for 48 hours to induce NAFLD-like alterations. EDHB-treatment of cells was performed upon the siRNA-mediated knockdown of OATP1B1 or control transfection. The effects of EDHB treatment were assessed by quantification of changes in lipid metabolism, apoptosis, and fat accumulation.

Results PA treatment expectedly caused lipid accumulation, apoptosis, and lipid metabolism in Huh7 cells. Pretreatment with EDHB significantly mitigated lipid aggregation, improved fatty acid oxidation, and reduced LDH release and cell apoptosis. These protective effects of EDHB could be abrogated by the simultaneous knockdown of OATP1B1.

Conclusions EDHB ameliorates NAFLD-like hepatocyte alterations in an in vitro model. This effect is likely dependent on hepatocyte expression of OATP1B1.

Publication History

Article published online:
04 January 2021