Hepatic steatosis

Novel regulators for the etiology and reversal of hepatic steatosis

Hepatic lipid accumulation in mice fed standard chow or high fat diet. Lipids in liver slices are visualized by Oil Red O staining (S. Schriever).

Obesity-induced ectopic fat disposition in the liver is a major risk factor in the pathogenesis of hepatic insulin resistance and type 2 diabetes. Treatment of hepatic steatosis is largely based upon calorie restriction (CR) or exercise to facilitate substantial weight loss, which initiates a complex and incompletely understood metabolic reprogramming of the liver. For the development and implementation of efficient prevention and treatment strategies against fatty liver disease it is crucial to better understand the pathogenesis of hepatic steatosis, including the identification of novel genes that are involved in the regulation of liver metabolism under excess energy supply and during weight loss. 

Correlation-based network integration to identify local regulator genes for hepatic steatosis
We recently developed a new bioinformatic correlation-based network integration (CoNI) approach for Omics datasets that allowed us to identify genes regulating metabolic networks in livers of mice that if solely analyzing the transcriptome dataset would have remained hidden. These novel local regulator genes (LRG) can subsequently be assessed for differential expression patterns e.g. in diet-induced obese mice compared to lean controls or for their assignment to SNPs associated with obesity in humans. The CoNI approach can be applied to any existing murine or human Omics datasets to identify previously overseen genes with metabolic relevance.

From bench to bedside: hepatic steatosis in mice and men
In collaboration with the Institute for Diabetes Research and Metabolic Diseases (IDM) at the Helmholtz Center Munich and the Institute for Clinical Chemistry and Pathobiochemistry at the University Hospital of Tübingen, we aim to advance our understanding of the molecular events that drive liver reprogramming, obesity-related hepatic steatosis and CR-induced hepatic lipid clearance in patients diagnosed with biopsy-proven fatty liver and subjects undergoing lifestyle interventions. Our translational, clinical studies are complemented by studies in mice subjected to hepatic overexpression or silencing of promising gene candidates. 

Role of miRNAs in hepatic steatosis
Recently, miRNAs were discovered to modulate liver function in hepatic steatosis, highlighting the potential of miRNAs to become future liver therapeutics. In collaboration with the Center of Brain, Behavior and Metabolism (CBBM), we investigate the role and dynamic regulation of miRNAs in murine models of hepatic steatosis reversal where mice are undergoing weight loss by either bariatric surgery, by calorie restriction or Glp1-agonism. State-of-the art genetic, microscopic, transcriptomic and proteomic approaches are applied to screen for conserved hepatic miRNAs that act as master regulators which dynamically induce and reverse hepatic steatosis.