Phospholipase A2 controls fatty acid uptake into liver cells in a pharmacologically-responsive way

Excess fat accumulation within the liver leads to non-alcoholic steatohepatitis (NASH)-a serious health threat worldwide. However, the responsible mechanisms and regulation of fatty acid uptake by hepatocytes remain to be uncovered. Using the hepatocyte-derived tumor cell line HepG2, we report that fatty acid influx is mediated by a specific (heterotetrameric) plasma membrane-protein complex constituted of FABPPM, caveolin1, CD36, and phospholipase A2 (iPLA2ß). Within this complex, iPLA2ß serves as a key regulator: iPLA2ß inhibition by the non-toxic bile acid-phospholipid conjugate ursodeoxycholic acid-lysophosphatidylethanolamide (UDCA-LPE) inhibits fatty acid influx due to disintegration of the iPLA2ß-sensitive complex from detergent-resistant plasma membranes, and reduces transcript levels for all 4 evaluated subunits. The latter is explained by reduced generation of intracellular levels of lysophosphatidylcholine, leading to decreased JNK1-phosphorylation. Ultimately, this chain of events diminishes the synthesis of the involved fatty acid transport proteins and induces lipoapoptosis. We confirmed the suppression of fatty acid influx using primary hepatocytes of iPLA2ß knock-out mice. Finally, we demonstrate that steatosis and inflammation as features of NASH that can be reversed in HepG2 cells exposed to a NASH-like milieu by UDCA-LPE. Thus, iPLA2ß acts as a critical upstream checkpoint for downstream effector mechanisms of membrane fatty acid uptake. Its inhibition by UDCA-LPE blocks fatty acid transport and inflammation, qualifying this non-toxic compound as a therapeutic candidate for the treatment of NASH for which no clinically effective therapy is currently available.