Hedgehog signaling is a potent regulator of liver lipid metabolism and reveals a GLI-code associated with steatosis

Elife. 2016 May 17;5:e13308. doi: 10.7554/eLife.13308.

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized countries and is increasing in prevalence. The pathomechanisms, however, are poorly understood. This study assessed the unexpected role of the Hedgehog pathway in adult liver lipid metabolism. Using transgenic mice with conditional hepatocyte-specific deletion of Smoothened in adult mice, we showed that hepatocellular inhibition of Hedgehog signaling leads to steatosis by altering the abundance of the transcription factors GLI1 and GLI3. This steatotic 'Gli-code' caused the modulation of a complex network of lipogenic transcription factors and enzymes, including SREBP1 and PNPLA3, as demonstrated by microarray analysis and siRNA experiments and could be confirmed in other steatotic mouse models as well as in steatotic human livers. Conversely, activation of the Hedgehog pathway reversed the "Gli-code" and mitigated hepatic steatosis. Collectively, our results reveal that dysfunctions in the Hedgehog pathway play an important role in hepatic steatosis and beyond.

Keywords: Hedgehog signalling; NAFLD; biochemistry; cell biology; hepatocytes; human; liver; mouse; smoothened; steatotic Gli-code.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Expression Profiling
  • Humans
  • Kruppel-Like Transcription Factors / metabolism*
  • Lipid Metabolism*
  • Liver / metabolism*
  • Mice
  • Mice, Transgenic
  • Microarray Analysis
  • Nerve Tissue Proteins / metabolism*
  • Non-alcoholic Fatty Liver Disease / physiopathology*
  • Signal Transduction*
  • Smoothened Receptor / deficiency
  • Smoothened Receptor / metabolism*
  • Zinc Finger Protein GLI1 / metabolism*
  • Zinc Finger Protein Gli3

Substances

  • GLI1 protein, human
  • GLI3 protein, human
  • Kruppel-Like Transcription Factors
  • Nerve Tissue Proteins
  • Smo protein, mouse
  • Smoothened Receptor
  • Zinc Finger Protein GLI1
  • Zinc Finger Protein Gli3

Grant support

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.