Fuchs_2021_Hepatology__

Reference

Title : Hepatocyte-specific deletion of adipose triglyceride lipase (ATGL\/PNPLA2) ameliorates dietary induced steatohepatitis in mice - Fuchs_2021_Hepatology__
Author(s) : Fuchs CD , Radun R , Dixon ED , Mlitz V , Timelthaler G , Halilbasic E , Herac M , Jonker JW , Ronda O , Tardelli M , Haemmerle G , Zimmermann R , Scharnagl H , Stojakovic T , Verkade HJ , Trauner M
Ref : Hepatology , : , 2021
Abstract :

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 PPARalpha and PPARdelta 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 PPARalpha and increased PPARdelta 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 IL1beta and F4/80) when compared to WT mice. In line, protein levels of ER stress markers PERK and IRE1alpha were reduced in ATGL LKO MCD fed mice. Accordingly, pretreatment of LPS treated HepG2 cells with the PPARdelta 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 PPARdelta 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.

PubMedSearch : Fuchs_2021_Hepatology__
PubMedID: 34387896

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Citations formats

Fuchs CD, Radun R, Dixon ED, Mlitz V, Timelthaler G, Halilbasic E, Herac M, Jonker JW, Ronda O, Tardelli M, Haemmerle G, Zimmermann R, Scharnagl H, Stojakovic T, Verkade HJ, Trauner M (2021)
Hepatocyte-specific deletion of adipose triglyceride lipase (ATGL\/PNPLA2) ameliorates dietary induced steatohepatitis in mice
Hepatology :

Fuchs CD, Radun R, Dixon ED, Mlitz V, Timelthaler G, Halilbasic E, Herac M, Jonker JW, Ronda O, Tardelli M, Haemmerle G, Zimmermann R, Scharnagl H, Stojakovic T, Verkade HJ, Trauner M (2021)
Hepatology :