Abstract
Increased fatty acid (FA) flux from adipose tissue to the liver contributes to the development of NAFLD. Because free FAs are key lipotoxic triggers accelerating disease progression, inhibiting adipose triglyceride lipase (ATGL)/patatin-like phospholipase domain containing 2 (PNPLA2), the main enzyme driving lipolysis, may attenuate steatohepatitis. Hepatocyte-specific ATGL knockout (ATGL LKO) mice were challenged with methionine-choline-deficient (MCD) or high-fat high-carbohydrate (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 endoplasmic reticulum (ER) stress markers were investigated. DNA binding activity for peroxisome proliferator-activated receptor (PPAR) α and PPARδ was measured. After short hairpin RNA-mediated ATGL knockdown, HepG2 cells were treated with lipopolysaccharide (LPS) or oleic acid:palmitic acid 2:1 (OP21) to explore the direct role of ATGL in inflammation in vitro. On MCD and HFHC challenge, ATGL LKO mice showed reduced PPARα and increased PPARδ DNA binding activity when compared with challenged wild-type (WT) mice. Despite histologically and biochemically pronounced hepatic steatosis, dietary-challenged ATGL LKO mice showed lower hepatic inflammation, reflected by the reduced number of Galectin3/MAC-2 and myeloperoxidase-positive cells and low mRNA expression levels of inflammatory markers (such as IL-1β and F4/80) when compared with WT mice. In line with this, protein levels of the ER stress markers protein kinase R-like endoplasmic reticulum kinase and inositol-requiring enzyme 1α were reduced in ATGL LKO mice fed with MCD diet. 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 proinflammatory cytokines and chemokines such as chemokine (C-X-C motif) ligand 5, chemokine (C-C motif) ligand (Ccl) 2, and Ccl5. 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 through ATGL inhibition represents a promising therapeutic strategy for the treatment of steatohepatitis.
Highlights
Introduction nsequence of the pandemic of obesity and diabetes, non-alcoholic fatty liver (NAFLD) has become a leading cause of liver disease in the Western world [1, uch, more than 20% of the general population [3] and 75% of obese individuals lop NAFLD
NAFLD is characterized by benign hepatic fat accumulation (i.e., s) which can progress to non-alcoholic steatohepatitis (NASH), advanced fibrosis, and cancer [5, 6], with inflammation as central feature in the disease ion from benign steatosis to the more severe stages of the disease spectrum [7]. d free fatty acids (FAs) are key lipotoxic triggers driving hepatocyte injury and ation and the progression from NAFLD to NASH [8]
Results e of hepatic ATGL reduces peroxisome proliferator-activated receptor (PPAR) activity in mice fed a ine choline deficient (MCD)-induced steatohepatitis
Summary
Introduction nsequence of the pandemic of obesity and diabetes, non-alcoholic fatty liver (NAFLD) has become a leading cause of liver disease in the Western world [1, uch, more than 20% of the general population [3] and 75% of obese individuals lop NAFLD. Upon MCD and HFHC challenge, ATGL LKO mice reduced PPAR and increased PPAR DNA binding activity when compared to ed WT mice. MRNA expression levels of established target genes were significantly lower in MCD fed ATGL LKO compared to MCD animals (Supporting Figure 1B).
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