Hepatocyte-specific deletion of adipose triglyceride lipase (ATGL/PNPLA2) ameliorates dietary induced steatohepatitis in mice.

Background and aims Increased FA flux from adipose tissue to the liver contributes to the development of NAFLD. Since free FAs are key lipotoxic triggers accelerating disease progression, inhibiting ATGL/PNPLA2, the main enzyme driving lipolysis, may attenuate steatohepatitis. Approach and results Hepatocyte-specific ATGL knockout (ATGL LKO) mice were challenged with MCD or HFHC diet. Serum biochemistry, hepatic lipid content and liver histology were assessed. Mechanistically, hepatic gene and protein expression of lipid metabolism, inflammation, fibrosis, apoptosis and ER stress markers were investigated. DNA binding activity for PPARα and PPARδ was measured. After sh-RNA mediated ATGL-knockdown, HepG2 cells were treated with LPS or OP21 to explore the direct role of ATGL in inflammation in vitro. Upon MCD and HFHC challenge, ATGL LKO mice showed reduced PPARα and increased PPARδ DNA binding activity when compared to challenged WT mice. Despite histologically and biochemically pronounced hepatic steatosis, dietary challenged ATGL LKO mice showed lower hepatic inflammation, reflected by reduced number of MAC-2 and MPO positive cells and low mRNA expression levels of inflammatory markers (such as IL1β and F4/80) when compared to WT mice. In line, protein levels of ER stress markers PERK and IRE1α were reduced in ATGL LKO MCD fed mice. Accordingly, pretreatment of LPS treated HepG2 cells with the PPARδ agonist GW0742, suppressed mRNA expression of inflammatory markers. Additionally, ATGL-knockdown in HepG2 cells attenuated LPS/OP21-induced expression of pro-inflammatory cytokines and chemokines such as Cxcl5, Ccl2 and Ccl5. Conclusions Low hepatic lipolysis and increased PPARδ activity in ATGL/PNPLA2 deficiency may counteract hepatic inflammation and ER stress despite increased steatosis. Therefore, lowering hepatocyte lipolysis via ATGL inhibition represents a promising therapeutic strategy for the treatment of steatohepatitis.