Deficiency of Group IVA Phospholipase A2 in Collagen-Producing Cells Alleviates the Aggravated Hepatic Fibrosis in High-Fat Diet-Fed Mice after Returning to a Normal Diet.

Hepatic fibrosis, a primary feature of non-alcoholic steatohepatitis (NASH), develops with inflammation and subsequent activation of hepatic stellate cells (HSCs), the main extracellular matrix-producing cells. Currently, no approved pharmacotherapy is available to treat hepatic fibrosis, even under dietary intervention. The activation of cultured HSCs has been shown to be attenuated by pharmacological inhibition of group IVA phospholipase A2 (IVA-PLA2), an enzyme initiating the generation of lipid proinflammatory mediators. We examined the potential utility of IVA-PLA2 of HSCs as a therapeutic target for hepatic fibrosis in NASH under dietary modification using collagen-producing cell-specific IVA-PLA2-conditional knockout mice fed a high-fat diet and then returned to a normal one. Apparent hepatic fibrosis and the accumulation of hepatic lipid droplets developed in the IVA-PLA2-conditional knockout mice on a high-fat diet for nine weeks to a similar degree as in control mice. Most of the lipid droplets disappeared five weeks after switching the diet back to a normal one in both genetic mice. In contrast, the hepatic fibrosis in control mice still progressed even after changing back to a normal diet. However, deficiency of IVA-PLA2 in collagen-producing cells alleviated the aggravated hepatic fibrosis under dietary modification. Our results revealed that the protective effects of an HSC-specific IVA-PLA2 deficiency on fibrogenesis appear after switching the diet from a high-fat one back to a normal one, supporting the promising beneficial effects of the inhibition of IVA-PLA2 on progressive hepatic fibrosis under dietary intervention in NASH treatment.

Endothelial group IVA phospholipase A2 promotes hepatic fibrosis with sinusoidal capillarization in the early stage of non-alcoholic steatohepatitis in mice.

AIM: 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. MAIN METHODS: 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. 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-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. SIGNIFICANCE: 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.