Deletion of SREBF1, a functional bone-muscle pleiotropic gene, alters bone density and lipid signaling in zebrafish

Shochat, C., Wang, Z., Mo, C., Nelson, S., Donaka, R., Huang, J., Karasik, D., Brotto, M.
Endocrinology   162(1): (Journal)
Registered Authors
Karasik, David, Shochat Carvalho, Chen
bone mineral density, gene expression, lipid mediators, muscle and bone, zebrafish
MeSH Terms
  • Animals
  • Bone Density/genetics*
  • Bone Density/physiology
  • Gene Deletion*
  • Gene Expression Regulation/physiology*
  • Lipid Metabolism/genetics
  • Lipid Metabolism/physiology*
  • Muscle, Skeletal/metabolism
  • Sterol Regulatory Element Binding Protein 1/genetics
  • Sterol Regulatory Element Binding Protein 1/metabolism*
  • Zebrafish
33068391 Full text @ Endocrinology
Through a genome-wide analysis of bone mineral density (BMD) and muscle mass, identification of a signalling pattern on 17p11.2 recognized the presence of sterol regulatory element-binding factor 1 (SREBF1), a gene responsible for the regulation of lipid homeostasis. In conjunction with lipid-based metabolic functions, SREBF1 also codes for the protein, SREBP-1, a transcription factor known for its role in adipocyte differentiation. We conducted a quantitative correlational study. We established a zebrafish SREBF1 knockout (KO) model and used a targeted customized lipidomics approach to analyze the extent of the SREBF1 capabilities. For lipidomics profiling, we isolated the dorsal muscles of wild type (WT) and KO fishes and performed liquid chromatography-tandem mass spectrometry screening assays of these samples. In our analysis, we profiled 48 Lipid Mediators (LMs) derived from various essential polyunsaturated fatty acids to determine potential targets regulated by SREBF1, and found that the levels of 11,12 epoxyeicosatrienoic acid (11,12-EET) were negatively associated with the number of SREBF1 alleles (p=0.006 for a linear model). We also compared gene expression between KO and WT zebrafishes by genome-wide RNA-sequencing. Significantly enriched pathways included fatty acid elongation, linoleic acid metabolism, arachidonic acid metabolism, adipocytokine signaling, and DNA replication. We discovered trends indicating that BMD in adult fish was significantly lower in KO than in the WT population (p < 0.03). These studies reinforce the importance of lipidomics investigation by detailing how KO of SREBF1 affects both BMD and lipid-signaling mediators, thus confirming the importance of SREBF1 for musculoskeletal homeostasis.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes