Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Jha, P.
Role of Adipose Triglyceride Lipase (ATGL) in Non-alcoholic Fatty Liver Disease (NAFLD).
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medical University of Graz; 2014. pp. 84
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- Autor*innen der Med Uni Graz:
- Jha Pooja
- Betreuer*innen:
- Höfler Gerald
- Trauner Michael
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- Abstract:
- Non-alcoholic fatty liver disease (NAFLD) affects nearly 45% of the Western population with prevalence in diabetic and obese individuals approaching 75%. Our understanding of its pathogenesis and the mechanisms underlying the progression to steatohepatitis (NASH) resulting in life-threatening complications such as cirrhosis and cancer are still very limited. Inflammation is one of the key features of NASH progression. Polymorphisms of PNPLA3 (adiponutrin) have been identified as key genetic determinant for NAFLD and progression to NASH in humans. Additionally, in humans, increased peripheral FA flux has been shown to contribute to ~59% to the hepatic TG content in NAFLD patients. Since adipose triglyceride lipase (ATGL) is the closest homologue of PNPLA3 and a rate limiting intracellular lipase our objective was to study the role of ATGL in lipid partitioning, hepatic lipotoxicity and inflammation in mouse models of NAFLD and NASH. In the present study, we demonstrate a hitherto unknown anti-inflammatory role of adipose triglyceride lipase (ATGL/PNPLA2) and provide compelling evidence that ATGL exerts a key role in modulating hepatic inflammation and progression to NASH by critically determining the ligand availability (in particular 18:2n6) for PPAR¿ activation. Using methionine choline deficient diet (MCD) to induce NASH in ob/ob mice we demonstrate that increased ATGL and hormone sensitive lipase (HSL) activity is responsible for massive loss of adipose tissue (AT) followed by hepatic steatosis and inflammation. A comprehensive lipidomic profiling revealed that 18:2n6 fatty acid (FA), an important PPAR¿ ligand was predominantly elevated in serum and livers of MCD-fed ob/ob mice. MCD-fed ATGL-KO mice were partially protected from WAT loss but showed attenuated hepatic PPAR¿ signalling, severe hepatic steatosis, inflammation and mild fibrosis. Furthermore, when subjected to endotoxin (LPS, as a potential second hit in progression to NASH), ATGL-KO mice displayed more pronounced hepatic inflammation, defective thermogenesis and torpor due to impaired PPAR¿ signalling pathway as a result of deficiency in lipolytic products of ATGL to activate PPAR¿, in particular the deficiency of 18:2n6 and decreased fatty acid transport to the nucleus. On the contrary, mice lacking hormone-sensitive lipase (HSL) had a relatively benign phenotype which resembled that of the WT mice on both MCD feeding and on LPS injection. Notably, PPAR¿ agonist treatment with fenofibrate partially restored PPAR¿ signaling and attenuated hepatic inflammation in both MCD-fed and LPS-injected ATGL-KO mice thus strengthening our conclusion that ATGL exerts important anti-inflammatory roles counteracting the progression to NASH via the modulation of PPAR¿ activity. Our findings suggest that ATGL plays a critical role in (i) susceptibility to fatty liver development by modulating lipolysis in adipose tissue and (ii) in progression to NASH by exerting an anti-inflammatory role in liver by modulating PPAR¿ signaling. Our data also demonstrates that the role of ATGL in liver per se is imperative to counteract steatosis and inflammation. Future studies will have to address whether therapeutic targeting of ATGL is able to counteract hepatic inflammation in progression to NASH and to potentially lethal consequences such as liver cirrhosis and cancer. The demonstration that ATGL deficiency leads to exaggerated inflammatory response fuels optimism that ATGL could represent an exciting therapeutic target for preventing the transition from fatty liver to NASH. Apart from potential implications for NASH, these findings may have general relevance for understanding the role of ATGL in acute and chronic hepatic inflammation.