Hepatocyte‐specific deletion of adipose triglyceride lipase (adipose triglyceride lipase/patatin‐like phospholipase domain containing 2) ameliorates dietary induced steatohepatitis in mice

Abstract

Background and Aims 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. Approach and Results 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. 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 through ATGL inhibition represents a promising therapeutic strategy for the treatment of steatohepatitis.

A new perspective on NAFLD: Focusing on lipid droplets

“…77,78 Previous studies showed that liver-specific ATGL deficiency improved glucose tolerance by increasing hepatic glucose utilisation and reducing hepatic glucose output without reducing hepatic steatosis. 79,80 However, the use of atglistatin, a chemical inhibitor of ATGL, in mice fed a high-fat diet reduced adipose tissue lipolysis, leading to a reduction in FA flux from the adipose tissue to the liver. 81 This was accompanied by a decrease in liver steatosis due to reduced expression of the genes involved in lipid uptake, storage, and de novo lipogenesis.…”

Hepatic Lipid Homeostasis in NAFLD

“…Studies found that ATGL encoded by the patatin-like phospholipase domain-containing protein 2 (PNPLA2) gene may participate in NAFLD, of which ATGL knockout leads to LDs accumulation, while overexpression of ATGL could alleviate hepatic steatosis and increase FAs oxidation [53,54]. Recent study identified that despite enhancing hepatic steatosis, ATGL/PNPLA2 deficiency may decrease hepatic lipolysis and increase PPARδ, which protects hepatocyte from inflammation and ER stress [55]. HSL was considered a rate-limiting enzyme for TG hydrolysis.…”

Endoplasmic reticulum stress in nonalcoholic (metabolic associated) fatty liver disease (NAFLD/MAFLD)

“…138 Furthermore, in in vitro models of inflammation induced in HepG2 hepatic cells by fatty acids and lipopolysaccharides (LPS), the effects of ATGL knockdown and PPARδ activation were protective against inflammation. 138 In addition, ATGL deficiency in the liver alleviated ER stress in MCD-and HFHC-diet-fed mice, as was shown by the lower protein levels of PERK and IRE1α and the reduced mRNA levels of Grp78. 138…”