Plasma membrane phospholipase A2 controls hepatocellular fatty acid uptake and is responsive to pharmacological modulation: implications for nonalcoholic steatohepatitis.
Excess hepatic fat accumulation leads to nonalcoholic steatohepatitis (NASH), a serious threat to health for which no effective treatment is available. However, the mechanism responsible for fatty acid uptake by hepatocytes remains unclear. Using the human hepatocyte-derived tumor cell line HepG2, we found that fatty acid influx is mediated by a heterotetrameric plasma membrane protein complex consisting of plasma membrane fatty acid-binding protein, caveolin-1, CD36, and calcium-independent membrane phospholipase A2 (iPLA2β). Blocking iPLA2β with the bile acid-phospholipid conjugate ursodeoxycholate-lysophosphatidylethanolamide (UDCA-LPE) caused the dissociation of the complex, thereby inhibiting fatty acid influx (IC50 47 μM), and suppressed the synthesis of all subunits through a reduction in lysophosphatidylcholine from 8.0 to 3.5 μmol/mg of protein and corresponding depletion of phosphorylated c-Jun N-terminal kinase. These findings were substantiated by an observed 56.5% decrease in fatty acid influx in isolated hepatocytes derived from iPLA2β-knockout mice. Moreover, steatosis and inflammation were abrogated by UDCA-LPE treatment in a cellular model of NASH. Thus, iPLA2β acts as an upstream checkpoint for mechanisms that regulate fatty acid uptake, and its inhibition by UDCA-LPE qualifies this nontoxic compound as a therapeutic candidate for the treatment of NASH.-Stremmel, W., Staffer, S., Wannhoff, A., Pathil, A., Chamulitrat, W. Plasma membrane phospholipase A2 controls hepatocellular fatty acid uptake and is responsive to pharmacological modulation: implications for nonalcoholic steatohepatitis.
Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany wolfgang.stremmel@med.uni-heidelberg.de.
Wolfgang
W
Stremmel
Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany.
Simone
S
Staffer
Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany.
Andreas
A
Wannhoff
Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany.
Anita
A
Pathil
Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany.
Walee
W
Chamulitrat
D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D050612:Fatty Acid Transport Proteins / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism*; D005260:Female; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D054467:Phospholipases A2 / Q000378:metabolism*
D018955:CD36 Antigens; D051242:Caveolin 1; D050612:Fatty Acid Transport Proteins; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D048031:JNK Mitogen-Activated Protein Kinases; D054467:Phospholipases A2
cJun N-terminal kinase; detergent-resistant membranes; lysophosphatidylcholine; ursodeoxycholate-lysophosphatidyletanolamide