Hepatic
inflammation is a key feature of progressive
liver disease. Alterations of
fatty acid (FA) metabolism and signaling may play an important role in the pathogenesis of
nonalcoholic fatty liver disease (
NAFLD) and its progression to
nonalcoholic steatohepatitis (NASH). Moreover, FAs activate
peroxisome proliferator-activated receptor α (PPARα) as a key transcriptional regulator of hepatic FA metabolism and
inflammation. Since adipose
triglyceride lipase (ATGL/PNPLA2) is the key
enzyme for intracellular hydrolysis of stored
triglycerides and determines FA signaling through PPARα, we explored the role of ATGL in hepatic
inflammation in mouse models of NASH and
endotoxemia. Mice lacking ATGL or
hormone-sensitive lipase (HSL) were challenged with a
methionine-
choline-deficient (MCD) diet as a nutritional model of NASH or
lipopolysaccharide (LPS) as a model of acute hepatic
inflammation. We further tested whether a PPARα agonist (
fenofibrate) treatment improves the hepatic phenotype in MCD- or LPS-challenged ATGL-knockout (KO) mice. MCD-fed ATGL-KO mice, although partially protected from peripheral lipolysis, showed exacerbated hepatic steatosis and
inflammation. Moreover, ATGL-KO mice challenged by LPS showed enhanced hepatic
inflammation, increased mortality, and torpor, findings which were attributed to impaired PPARα
DNA binding activity due to reduced FABP1
protein levels, resulting in impaired nuclear FA import. Notably, liganding PPARα through
fenofibrate attenuated hepatic
inflammation in both MCD-fed and LPS-treated ATGL-KO mice. In contrast, mice lacking HSL had a phenotype similar to the WT mice on MCD and LPS challenge.
CONCLUSION: