Endothelial group IVA phospholipase A2 promotes hepatic fibrosis with sinusoidal capillarization in the early stage of non-alcoholic steatohepatitis in mice
2022
Kawashita, Eri | Ozaki, Takeyoshi | Ishihara, Keiichi | Kashiwada, Chihiro | Akiba, Satoshi
Non-alcoholic steatohepatitis (NASH) is characterized by steatosis, inflammatory responses and fibrosis. Our previous studies provided evidence that group IVA phospholipase A₂ (IVA-PLA₂), a key PLA₂ isozyme in the arachidonic acid cascade, is involved in the development of NASH. However, which types of cells are critical for the IVA-PLA₂-dependent onset and progression of NASH is unclear. We elucidated the effects of the cell-type-specific deficiency of IVA-PLA₂ in mice on the development of NASH. Cell-type-specific IVA-PLA₂-conditional knockout (cKO) mice and littermate controls were fed a choline-deficient, L-amino-acid-defined, high-fat diet with 0.1% methionine as a NASH model. The degree of hepatic fibrosis was evaluated by staining with picric acid-Sirius red, and the number of activated hepatic stellate cells was determined by immunoblotting and immunostaining for α-smooth muscle actin. Sinusoidal capillarization was analyzed by scanning electron microscopy. The deposition of collagen and number of activated hepatic stellate cells were markedly reduced in endothelial cell/liver sinusoidal endothelial cell (EC/LSEC)-specific IVA-PLA₂ cKO mice but not in hepatocyte-, monocyte/macrophage-, or hepatic stellate cell-specific IVA-PLA₂ cKO mice. In addition, EC/LSEC-specific IVA-PLA₂-deficient mice showed more fenestrae than control mice fed a CDAHFD, indicating suppression of sinusoidal capillarization. These results suggest that ECs/LSECs contribute to the IVA-PLA₂-dependent onset and/or progression of NASH. Endothelial IVA-PLA₂ is a promising factor for promoting sinusoidal capillarization and the ensuing HSC activation and fibrosis; thus IVA-PLA₂ in ECs/LSECs is a potential therapeutic target for NASH.
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