Justyna Jozefczuk, Karl Kashofer, Ramesh Ummanni, Frauke Henjes, Samrina Rehman, Suzanne Geenen, Wasco Wruck, Christian Regenbrecht, Andriani Daskalaki, Christoph Wierling, Paola Turano, Ivano Bertini, Ulrike Korf, Kurt Zatloukal, Hans V. Westerhoff, Hans Lehrach, James Adjaye
Abstract
Non-alcoholic fatty liver disease comprises a broad spectrum of disease states ranging from simple steatosis to non-alcoholic steatohepatitis. As a result of increases in the prevalences of obesity, insulin resistance, and hyperlipidemia, the number of people with hepatic steatosis continues to increase. Differences in susceptibility to steatohepatitis and its progression to cirrhosis have been attributed to a complex interplay of genetic and external factors all addressing the intracellular network. Increase in sugar or refined carbohydrate consumption results in an increase of insulin and insulin resistance that can lead to the accumulation of fat in the liver. Here we demonstrate how a multidisciplinary approach encompassing cellular reprogramming, transcriptomics, proteomics, metabolomics, modeling, network reconstruction, and data management can be employed to unveil the mechanisms underlying the progression of steatosis. Proteomics revealed reduced AKT/mTOR signaling in fibroblasts derived from steatosis patients and further establishes that the insulin-resistant phenotype is present not only in insulin-metabolizing central organs, e.g., the liver, but is also manifested in skin fibroblasts. Transcriptome data enabled the generation of a regulatory network based on the transcription factor SREBF1, linked to a metabolic network of glycerolipid, and fatty acid biosynthesis including the downstream transcriptional targets of SREBF1 which include LIPIN1 (LPIN) and low density lipoprotein receptor. Glutathione metabolism was among the pathways enriched in steatosis patients in comparison to healthy controls. By using a model of the glutathione pathway we predict a significant increase in the flux through glutathione synthesis as both gamma-glutamylcysteine synthetase and glutathione synthetase have an increased flux. We anticipate that a larger cohort of patients and matched controls will confirm our preliminary findings presented here.
Pharmacology, Toxicology and Pharmaceutical Science
3
6%
Nursing and Health Professions
2
4%
Other
10
19%
Unknown
13
24%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 24 July 2013.
All research outputs
#17,664,478
of 22,675,759 outputs
Outputs from Frontiers in Physiology
#7,070
of 13,467 outputs
Outputs of similar age
#191,325
of 244,088 outputs
Outputs of similar age from Frontiers in Physiology
#170
of 309 outputs
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