Studies examining the relationship between cellular
sortilin and VLDL-B100 secretion demonstrate inconsistent results. Current studies explore the possibility that discrepancies may be related to
insulin sensitivity. McArdle RH7777 cells (McA cells) cultured under serum enriched conditions lose sensitivity to
insulin. Following incubation in serum-free DMEM containing 1% BSA, McA cells become
insulin responsive and demonstrate reduced
apo B secretion. Current studies indicate that
insulin sensitive McA cells express lower cellular
sortilin that corresponds with reduction in VLDL-B100 secretion without changes in
mRNA of either
sortilin or
apo B. When
sortilin expression is further reduced by
siRNA knockdown (KD), there are additional decreases in VLDL-B100 secretion. A crystal structure of human
sortilin (hsortilin) identifies two binding sites on the
luminal domain for the N- and C-termini of
neurotensin (NT). A small organic compound (cpd984) was identified that has strong theoretical binding to the N-terminal site. Both cpd984 and NT bind hsortilin by surface plasmon resonance. In incubations with
insulin sensitive McA cells, cpd984 was shown to enhance VLDL-B100 secretion at each level of
sortilin KD suggesting cpd984 acted through
sortilin in mediating its effect. Current results support a role for
sortilin to facilitate VLDL-B100 secretion which is limited to
insulin sensitive McA cells. Inconsistent reports of the relationship between VLDL-B100 secretion and
sortilin in previous studies may relate to differing functions of
sortilin in VLDL-B100 secretion depending upon
insulin sensitivity.