| First Author | Kawashita E | Year | 2022 |
| Journal | Life Sci | Volume | 294 |
| Pages | 120355 | PubMed ID | 35093339 |
| Mgi Jnum | J:347395 | Mgi Id | MGI:7622085 |
| Doi | 10.1016/j.lfs.2022.120355 | Citation | Kawashita E, et al. (2022) Endothelial group IVA phospholipase A(2) promotes hepatic fibrosis with sinusoidal capillarization in the early stage of non-alcoholic steatohepatitis in mice. Life Sci 294:120355 |
| abstractText | AIM: Non-alcoholic steatohepatitis (NASH) is characterized by steatosis, inflammatory responses and fibrosis. Our previous studies provided evidence that group IVA phospholipase A(2) (IVA-PLA(2)), a key PLA(2) isozyme in the arachidonic acid cascade, is involved in the development of NASH. However, which types of cells are critical for the IVA-PLA(2)-dependent onset and progression of NASH is unclear. We elucidated the effects of the cell-type-specific deficiency of IVA-PLA(2) in mice on the development of NASH. MAIN METHODS: Cell-type-specific IVA-PLA(2)-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 alpha-smooth muscle actin. Sinusoidal capillarization was analyzed by scanning electron microscopy. KEY FINDINGS: 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-PLA(2) cKO mice but not in hepatocyte-, monocyte/macrophage-, or hepatic stellate cell-specific IVA-PLA(2) cKO mice. In addition, EC/LSEC-specific IVA-PLA(2)-deficient mice showed more fenestrae than control mice fed a CDAHFD, indicating suppression of sinusoidal capillarization. SIGNIFICANCE: These results suggest that ECs/LSECs contribute to the IVA-PLA(2)-dependent onset and/or progression of NASH. Endothelial IVA-PLA(2) is a promising factor for promoting sinusoidal capillarization and the ensuing HSC activation and fibrosis; thus IVA-PLA(2) in ECs/LSECs is a potential therapeutic target for NASH. |
