Novel mechanism links BCAA metabolism to lipid metabolism

A new paper from DMPI has just been published online in Cell Metabolism featuring six of our faculty (P. White, McGarrah, Astapova, Herman, Zhang, and Newgard) as co-authors as well as important contributions from multiple students, fellows, and staff. 

The paper, entitled “The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP-Citrate Lyase” describes a novel mechanism that links branched chain amino acid (BCAA) metabolism to lipid metabolism.  Specifically, the team discovered that the same kinase and phosphatase that regulate the rate-limiting enzyme of BCAA metabolism also regulate phosphorylation and activity of ATP-citrate lyase, a key lipogenic enzyme.  The paper also demonstrates regulation of the kinase/phosphatase pair by diets high in fructose, working via activation of the ChREBP transcription factor.  This represents a strong example of the “retrotranslation” approach that is a guiding principal at DMPI, involving use of molecular signatures to guide development and testing of mechanistic hypotheses.