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  4. Differential Lipidomics, Metabolomics and Immunological Analysis of Alcoholic and Non-Alcoholic Steatohepatitis in Mice
 
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2023
Journal Article
Title

Differential Lipidomics, Metabolomics and Immunological Analysis of Alcoholic and Non-Alcoholic Steatohepatitis in Mice

Abstract
Non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) are the leading causes of liver disease worldwide. To identify disease-specific pathomechanisms, we analyzed the lipidome, metabolome and immune cell recruitment in livers in both diseases. Mice harboring ASH or NASH had comparable disease severities regarding mortality rate, neurological behavior, expression of fibrosis marker and albumin levels. Lipid droplet size was higher in NASH than ASH and qualitative differences in the lipidome were mainly based on incorporation of diet-specific fatty acids into triglycerides, phosphatidylcholines and lysophosphatidylcholines. Metabolomic analysis showed downregulated nucleoside levels in both models. Here, the corresponding uremic metabolites were only upregulated in NASH suggesting stronger cellular senescence, which was supported by lower antioxidant levels in NASH as compared to ASH. While altered urea cycle metabolites suggest increased nitric oxide synthesis in both models, in ASH, this depended on increased L-homoarginine levels indicating a cardiovascular response mechanism. Interestingly, only in NASH were the levels of tryptophan and its anti-inflammatory metabolite kynurenine upregulated. Fittingly, high-content immunohistochemistry showed a decreased macrophage recruitment and an increased polarization towards M2-like macrophages in NASH. In conclusion, with comparable disease severity in both models, higher lipid storage, oxidative stress and tryptophan/kynurenine levels were seen in NASH, leading to distinct immune responses.
Author(s)
Dorochow, Erika
Kraus, Nico
Chenaux-Repond, Nicolas
Pierre, Sandra C.
Kolbinger, Anja
Geisslinger, Gerd  
Fraunhofer-Institut für Translationale Medizin und Pharmakologie ITMP  
Ortiz, Cristina
Welsch, Christoph
Trebicka, Jonel K.
Gurke, Robert
Fraunhofer-Institut für Translationale Medizin und Pharmakologie ITMP  
Hahnefeld, Lisa
Fraunhofer-Institut für Translationale Medizin und Pharmakologie ITMP  
Klein, Sabine
Scholich, Klaus  
Fraunhofer-Institut für Translationale Medizin und Pharmakologie ITMP  
Journal
International journal of molecular sciences  
Open Access
DOI
10.3390/ijms241210351
Additional full text version
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Language
English
Fraunhofer-Institut für Translationale Medizin und Pharmakologie ITMP  
Keyword(s)
  • alcoholic fatty liver disease

  • lipid droplets

  • lipidomics

  • metabolomics

  • non-alcoholic fatty liver disease

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