Biomedical Engineering Reference
In-Depth Information
additional members of the PACAP/glucagon families including glucagon, VIP,
gastrin-releasing peptide (GRP), GRF, PACAP, and GLP-2 (Table 1.1); many
of these substrates are involved in processes of nutrient metabolism and glucose
homeostasis. GLP-2, derived from the same pro-glucagon molecule as GLP-1
and GIP, is of particular interest to our group. Expressed mainly in the gut,
GLP-2 functions as a highly potent promoter of gastrointestinal growth and
reduces the severity of intestinal injury that arises during inflammatory con-
ditions of the bowel.
193
In a similar fashion to GLP-1 regulation, DP4 is
responsible for the rapid inactivating degradation of GLP-2.
156
Research by
our own group and others demonstrates the ecacy of DP4 inhibition in
ameliorating the effects of inflammatory disease of the gastrointestinal tract
such as inflammatory bowel disease, presumably partly due to the prolonged
half-life of GLP-2 in circulation.
193
Interestingly, targeted deletion of NPY, an
additional DP4 substrate, is also shown to be involved with inflammatory
disorders with its ablation leading to attenuated inflammation in an experi-
mentally induced dextran sulfate sodium (DSS) colitis model;
194
thus, it may
prove to be an important avenue for future investigations into this work.
NPY is an additional in vivo substrate of DP4. Both NPY and PYY are 36-
amino-acid members of the pancreatic polypeptide family. NPY is a widely
distributed neurotransmitter, abundant in brain, while PYY is produced by L-
type endocrine cells of the gastrointestinal tract, where it colocalizes with GLP-
1.
195
NPY
(1-36)
acts through multiple Y receptor types, functioning as a potent
vasoconstrictor through receptor Y1,
196
and playing an important role in the
stimulation of feeding through receptors Y1 and/or Y5.
197,198
Like NPY
(1-36)
,
PYY
(1-36)
acts through the same Y receptors and is involved in inhibiting
gastrointestinal function, insulin secretion, blood pressure homeostasis and
appetite and weight control (reviewed in
195
). In vitro, NPY and PYY are
rapidly cleaved to their truncated forms NPY
(3-36)
and PYY
(3-36)
by DP4.
169
DP4 proteolysis of NPY results in a shift in NPY receptor selectivity, changing
its biological action from being a vasoconstrictor to a promoter of the angio-
genic process.
171
Ghersi et al. demonstrated that DP4 expression is upregulated
in migrating cells at sites of wounding and that the increase in DP4 activity is
required for the generation of NPY
(3-36)
and observed effects of NPY
(3-36)
in
promoting cell migration and wound healing.
200
Both PYY
(1-36)
and PYY
(3-36)
are abundant in circulation. Truncated PYY
(3-36)
, generated by DP4 proteo-
lysis, specifically acts through the Y2-receptor subtype,
199
again highlighting
the resultant shift in receptor selectivity of a molecule upon DP4 cleavage.
PYY
(3-36)
inhibits food intake and reduces weight gain,
201
the opposite effects
to those observed for PYY
(1-36)
. Thus, DP4 regulates effects in feeding,
metabolism, and weight control via proteolytic cleavage of PYY, NPY, GLP-1,
and also enterostatin, and this highlights the potential application of targeting
DP4 for the treatment of obesity.
Recently, in vitro studies have demonstrated that both DP8 and DP9 are
capable of cleaving GLP-1, GLP-2, NPY, and PYY (Table 1.2), but cleavage
rates by DP8/9 are much slower than DP4.
122,133
Interestingly, DP8/9 are the
predominant enzymes responsible for DP activity in brain compared to DP4
133
