257 Lack of Gp130/Stat in Hepatocytes Leads to the Emergence of Oval Cells and Extensive Liver Fibrosis in a Model of Chronic Cholestatic Liver Injury

Plum, Werner; Corsten, E.; Dierssen, U.; Erschfeld, S.; Tschaharganeh, Darjus F.; Streetz, Konrad L.

doi:10.1016/s0168-8278(08)60259-7

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“…Non-alcoholic fatty liver disease (NAFLD) is on the rise in the western population affecting one-third of adults and an increasing proportion of children (de Alwis and Day, 2008; Vuppalanchi and Chalasani, 2009). Early stages of this disease exhibit accumulation of lipids in the liver leading to hepatic steatosis which is followed by advancing levels of fibrosis and inflammation.…”

Section: Introductionmentioning

confidence: 99%

A Systems Biology Approach to Deciphering the Etiology of Steatosis Employing Patient-Derived Dermal Fibroblasts and iPS Cells

et al. 2012

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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.

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Section: Introductionmentioning

confidence: 99%