A
novel dual-effect, small-molecule therapy that plays 2 crucial roles in the
central control pathways for lipids and carbohydrates.
The
first involves inhibition of adenosine
triphosphate citrate lyase, the enzyme crucial for the production of
adenosine triphosphate citrate essential to the synthesis of both fatty acids and cholesterol.
The
second effect attributable to this single, small molecule is the activation of
adenosine monophosphate activated protein kinase (AMPK)—resident in the liver, striated muscle, and the
brain—the protein that is at the heart of the directional control of energy
substrates. It is effectively a sensor of the energy-depleted form of adenosine
triphosphate (ATP) (i.e., AMP) and thus is able to redirect energy substrates
at the time of need, such as during skeletal muscle activity. Its effect is
concerted in several coordinated pathways, all of which increase the uptake and consumption of glucose and fatty
acids
and inhibit anabolic processes. These include
increased beta-oxidation of fatty
acids,
gluconeogenesis, and increased
numbers of mitochondria in the cell.[3] There is evidence
that AMPK also plays a role in the increased metabolic activity of
mitochondria, at least in response to acute exercise, an activity that would
contribute further to the consumption of fatty acids. In this setting, AMPK
increases the activity of the peroxisome proliferator-activated receptor (PPAR)-gamma coactivator-1
(PGC)-alpha,
a transcription factor with a recognized role in the regulation of genes
involved in ketogenesis and gluconeogenesis. This activity suggests that possible
synergy could exist with PPAR-gamma agonists. At the same time, the activation
of AMPK decreases the synthesis of
cholesterol and of fatty acids and, thus, of triglycerides. Also, the
complement of the Glut-4 glucose transporter in striated red muscle fibers is
increased by translocation, an effect associated with exercise.[4,5] In addition, AMPK
appears to increase the phosphorylation of glucose by hexokinase in muscle
cells, favoring the flux into muscle.[4]
This array of metabolic-regulatory activities would suggest
multiple effects of this agent,
clearly on cholesterol
metabolism,
but also on diabetes and
hypertriglyceridemia.
