Genome-wide coactivation analysis of PGC-1alpha identifies BAF60a as a regulator of hepatic lipid metabolism

Cell Metab. 2008 Aug;8(2):105-17. doi: 10.1016/j.cmet.2008.06.013.


Impaired mitochondrial function has been implicated in the pathogenesis of type 2 diabetes, heart failure, and neurodegeneration as well as during aging. Studies with the PGC-1 transcriptional coactivators have demonstrated that these factors are central components of the regulatory network that controls mitochondrial function in mammalian cells. Here we describe a genome-wide coactivation assay to globally identify transcription factors and cofactors in this pathway. These analyses revealed a molecular signature of the PGC-1alpha transcriptional network and identified BAF60a (SMARCD1) as a molecular link between the SWI/SNF chromatin-remodeling complexes and hepatic lipid metabolism. Adenoviral-mediated expression of BAF60a stimulates fatty acid beta-oxidation in cultured hepatocytes and ameliorates hepatic steatosis in vivo. PGC-1alpha mediates the recruitment of BAF60a to PPARalpha-binding sites, leading to transcriptional activation of peroxisomal and mitochondrial fat-oxidation genes. These results define a role for the SWI/SNF complexes in the regulation of lipid homeostasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites / genetics
  • Cells, Cultured
  • Chromatin Assembly and Disassembly / genetics
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism
  • Chromosomal Proteins, Non-Histone / physiology*
  • Gene Expression Profiling
  • Genome / genetics*
  • Hepatocytes / metabolism
  • Lipid Metabolism / genetics*
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • PPAR alpha / genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Peroxisomes / genetics
  • Peroxisomes / metabolism
  • Trans-Activators / genetics*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcriptional Activation / genetics*


  • Chromosomal Proteins, Non-Histone
  • PPAR alpha
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • SWI-SNF-B chromatin-remodeling complex
  • Smarcd1 protein, mouse
  • Trans-Activators
  • Transcription Factors