Whenever you breathe, walk, run from a lion, type on the keyboard, move your eyes to read this blog, etc. ATP is broken down into ADP (Adenosine Di-Phosphate)and AMP (AdenosineMono-Phosphate). The energy released by these reactions is what allows other cellular reactions to occur. Pretty much everything you need to live is regulated by the making and breaking of these bonds.

A Chain Reaction of Chain Reactions

The star of Chopra’s paper is a protein called NCoA-2 (Nuclear receptor CoActivator 2). Like a boy scout helping an old lady across a busy street, NCoA-2 is a helper protein that assists other proteins called Nuclear Receptors (NR) express their target genes.

Chopra et al. first observed that mice missing NCoA-2(called a knock out or KO mouse) in their livers were not absorbing fat from their food, it was simply passing right through them. They also noticed the KO mice were acquiring high concentrations of bile acids (BAs) in their liver. The breakdown and absorption of fat into the body is always accompanied by bile acids (BA). 

To see if the cause of fat malabsorption was due specifically to the BAs not reaching the intestines, the researchers simply included BAs in the food of the KO mice. Like magic the mice began absorbing fat again. Next, using a genetic screen Chopra began comparing the expression of genes of normal liver cells to that of cells missing NCoA-2. They observed that the expression of the bile salt export pump (BSEP) gene was significantly diminished in the cells lacking NCoA-2. BSEP is the primary protein responsible for transporting bile acids from the liver into the gall bladder and it is well known that either absence or mutation of the BSEP causes cholestasis. Previous researchers have shown that the gene responsible for the synthesis of BSEP is under the direction of a NR called FXR (Farnesoid X Receptor).

 

Um, who cares?

Along with fat ingestion, NCoA-2 has also been found to be a critical player in glucose maintenance, and this places it as a major co-activator for total metabolic control. At first, finding a direct link from a cellular to a whole body request for energy may seem merely academic, but there is certainly a bigger picture: With obesity in the US being near almost 70%, we simply do not know enough about how our bodies obtain and use energy. While the “Eat less, Exercise more” mantra works for some, it simply doesn’t work on the morbidly obese, injured, elderly or those with metabolic disorders and therefore alternative treatments must be found.