6 research outputs found
Pituitary regulation of plasma lipoprotein metabolism and intestinal cholesterol absorption
Increased levels of plasma cholesterol are associated with a higher risk
to develop atherosclerosis, the leading cause of death in Western
societies. The major part of cholesterol in human blood is transported
within low-density lipoproteins (LDL-C) that bind to specific cell
surface receptors (LDLRs). The liver plays a central role in cholesterol
metabolism, regulation of LDLRs, and in the de novo synthesis and
degradation of cholesterol. The excretion of cholesterol and bile acids
from the liver is the major route for elimination of cholesterol from the
body. The pituitary exerts important regulatory effects on cholesterol
metabolism and the hypophysectomized (Hx) rat constitutes a valuable
model to study this regulation. Hx rats show severely altered basal
cholesterol metabolism (increased LDL-C, reduced HDL-C, suppressed LDLR
and cholesterol 7alphahydroxylase, CYP7A1), concomitant with a striking
loss of resistance to dietary cholesterol. Growth hormone (GH)
substitution partly normalizes lipid metabolism of Hx rats but the cause
for the lost resistance to dietary cholesterol in Hx rats is still
unclear. In this thesis, the role of the pituitary in the regulation of
hepatic cholesterol metabolism has been further explored. The main
findings are:
1) Human GH (hGH) can bind to GH receptors (GHRs) and to prolactin
receptors (PRLRs), which are both abundant in the liver. It is
demonstrated that the PRLR is not involved in the GH-elicited effects on
lipid metabolism of rats; PRL directly administered to Hx rats does not
alter the lipid metabolism of Hx rats, and GHs from different species are
suitable for research in this field.
2) The Hx mouse is shown to be a novel tool for studies on the role of
the pituitary in lipid metabolism. The lipid profiles of Hx mice from 3
strains and the LDLR deficient-Hx mouse model have been characterized.
The suppression of LDLRs and CYP7A l in Hx mice cannot fully explain the
increased sensitivity to cholesterol feeding following Hx.
3) Cholesterol absorption is strongly increased in Hx rats and can be
normalized by treatment with ezetimibe.
4) Plasma cholesterol increases in old rats and humans. However,
intestinal cholesterol absorption is unaltered in old rats, and treatment
with GH does not affect it.
In summary, the lactogenic binding of hGH does not affect lipid
metabolism of rats. Compared to the Hx rat, the Hx mouse model shows
qualitatively similar but less pronounced metabolic aberrations.
Cholesterol absorption is under pituitary control in rats, and the
increased intestinal absorption of cholesterol in Hx rats may be the
cause for the higher sensitivity to dietary cholesterol following Hx of
rats.
This study further highlights and extends the role of the pituitary in
lipid metabolism in vivo, and shows that a most important pituitary
control is exerted on intestinal cholesterol absorption