Molecular medicine-Mobilization and Release of Stored Lipid into the Circulation

Triglycerides are typically stored within the
adipocyte as a single lipid droplet. Recent
work indicates that the lipid droplet is an
extension of the endoplasmic reticulum
surrounded by a single phospholipid layer.
Closely associated with the lipid droplet
are ‘‘coat proteins’’, especially perilipin
isoforms and caveolin 2. Perilipin is the
most abundant target for phosphorylation
by cyclic AMP-dependent protein kinase
(PK) in fat cells, and plays a key role
in the retention and mobilization of
energy from lipid droplets. The energy
contained in the droplet is liberated when
the triglyceride is hydrolyzed into free
fatty acids and glycerol. The rate-limiting
step in this process is the activity of
hormone-sensitive lipase (HSL) at the
surface of the lipid droplet. Although
several protein kinases can influence
lipolytic rate, the most significant of these
is cyclic AMP-dependent protein kinase
(PKA). Overall, the rate of lipolysis is
6 Adipocytes
closely governed by the phosphorylation
state of perilipin and HSL. Recent work
indicates that phosphorylation of perilipin
on multiple residues allows recruitment of
phosphorylated HSL to the surface of the
lipid droplet where triglyceride hydrolysis
can take place. Phosphorylation of HSL
has only a modest effect on the activity of
the enzyme; rather, the dramatic increase
in lipolysis produced by PKA-activation
reflects the translocation and accessibility
of the enzyme to its substrate within
the cell. HSL appears to be physically
associated with the cytosolic FABP4 (aP2).
The significance of this association is not
known, but could involve regulation of
HSL activity or efflux of mobilized fatty
acids. In this regard, mice lacking FABP4
show reduced rates of lipolysis.
Efflux of fatty acids from the fat cell
and their transport across the capillary
endothelium are thought to occur through
passive diffusion across a concentration
gradient, although this process has not
been studied in detail. Long-chain fatty
acids are essentially insoluble in aqueous
solution and thus rely on carrier proteins
for transport. In plasma, fatty acids are
immediately bound with high affinity to
serum albumin, which serves as a carrier
of these substrates to the sites of oxidation.
During fasting, mobilized fatty acids are
quickly removed from the circulation, with
a half-life of about two minutes, and
provide an important source of energy for
heart and skeletal muscle.