of the Max - MDC

Figure 2. Uptake of lipoprotein (A) and
carrier bound (B) steroids.
Protein components of respective transport
particles (apoprotein or carrier) bind to
endocytic receptors of the LDL receptor gene
family on target cells. Following endocytosis,
the proteins components are degraded in
lysosomes while the lipids translocate into
the cytosol for further metabolism.
domain (Sortilin, SorCS-1, -2, and -3) suggested the existence
of a unique class of mammalian receptors that act in
endocytosis as well as in protein trafficking. Similar to our
studies on LRPs, we apply functional genomics approaches
in transgenic mouse and zebrafish models to uncover the
(patho)physiological roles of Sortilins.
Megalin, an endocytic receptor for steroid
hormones
According to current concepts, steroid hormones enter target
cell by free diffusion through the plasma membrane.
However, we have shown previously that Megalin, a member
of the LDL receptor gene family acts as endocytic receptor
for the steroid 25-OH vitamin D 3 bound to carrier proteins.
This pathway ensures delivery of the inactive precursor 25-
OH vitamin D 3 to cells of the renal proximal tubules for conversion
into 1,25-(OH) 2 vitamin D 3 , a potent regulator of
calcium homeostasis. Initially considered a unique feature
of vitamin D metabolites, we now gained proof that endocytosis
is a general concept that also applies to other classes
of steroid hormones such as sex steroids. We demonstrated
that in cultured cells megalin mediates the uptake of androgens
and estrogens bound to their carrier sex hormonebinding
globulin. Impaired activity of the receptor in mice
results in insensitivity to sex steroids and in impaired maturation
of male and female reproductive organs (e.g., maldescend
of the testes, occlusion of the vagina cavity) – phenocopies
of defects seen in rodents treated with androgen or
estrogen receptors antagonists. In conclusion, our findings
uncovered the existence of endocytic pathways for proteinbound
sex steroids, and their crucial role in development of
the urogenital tract. Intriguingly, the molecular concept of
uptake of steroid hormones complexed with carrier proteins
parallels pathways whereby cells acquire cholesterol transported
in lipoproteins, suggesting functional conservation
of lipid uptake mechanisms (Figure 2).
Mouse models lacking expression of steroid
carrier proteins
As well as studying mice with receptor gene defects, we also
generated mouse models genetically deficient for carrier
proteins to independently confirm the biological relevance
of steroid-carrier-complexes for hormone action. For example,
we have generated a mouse line lacking expression of
the corticosteroid-binding globulin (CBG), the plasma carrier
for glucocorticoids. Absence of CBG results in a ∼10-fold
increase in free corticosterone levels in CBG null mice, consistent
with its role in regulation of circulating free hormone
levels. Surprisingly, cbg -/- animals do not present features
seen in organisms with enhanced glucocorticoid signaling.
Conversely, these mice exhibit increased activity of
the pituitary axis of hormonal control, reduced levels of gluconeogenetic
enzymes, as well as an aggravated response
to septic shock, indicating an inability to appropriately
respond to the excess free corticosterone in the absence of
CBG. Thus, our data suggest an active role for the steroid
carrier CBG in bioavailability, local delivery, and/or cellular
signal transduction of glucocorticoids that extends beyond
a mere function as lipid transporter.
Cardiovascular and Metabolic Disease Research 7