The enigmatic role of sortilin in lipoprotein metabolism

Sparks, Charles E.; Sparks, Robert P.; Sparks, Janet D.

doi:10.1097/mol.0000000000000244

Cited by 13 publications

(12 citation statements)

References 21 publications

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“…Considering the downstream role PIP3 plays in insulin signaling and the enigmatic role sortilin has in VLDL metabolism [19], the finding that sortilin is a PIP3 binding protein could have important implications for VLDL. We suggest that the presence of PIP3 on VLDL could influence the relative binding of B100 and apoE to various receptors including sortilin.…”

Section: Resultsmentioning

confidence: 99%

Phosphatidylinositol (3,4,5)-trisphosphate binds to sortilin and competes with neurotensin: Implications for very low density lipoprotein binding

Sparks

Jenkins

Miner

et al. 2016

Biochemical and Biophysical Research Communications

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Sortilin is a multi-ligand sorting receptor that interacts with B100-containing VLDL and LDL as well as other ligands including neurotensin (NT). The current study investigates the hypothesis that phosphatidylinositol (3,4,5)-trisphosphate (PIP3) generated downstream of insulin action can directly bind to sortilin. NT binds to sortilin at a well characterized site via its carboxy terminus (C-term). Using a crystal structure of human sortilin (hsortilin), PIP3 is predicted to bind at this C-term site. Binding of PIP3 to hsortilin is demonstrated using surface plasmon resonance (SPR) flowing PIP3 nanodiscs over immobilized hsortilin. Studies were performed using SPR where dibutanoyl PIP3 is shown to compete with NT for sortilin binding. Rat VLDL and LDL were evaluated for PIP3 content immunologically using monoclonal antibodies directed against PIP3. Rat plasma VLDL contained three times more immunoreactive PIP3 than LDL per µg of protein. Because VLDL contains additional ligands that bind sortilin, to distinguish specific PIP3 binding, we used PIP3 liposomes. Liposome floatation assays were used to demonstrate PIP3 liposome binding to sortilin. Using SPR and immobilized hsortilin, the C-term NT tetrapeptide (P-Y-I-L) is shown to bind to hsortilin. A compound (cpd984) was identified with strong theoretical binding to the site on sortilin involved in NT N-terminal binding. When cpd984 is co-incubated with the tetrapeptide, the affinity of binding to sortilin is increased. Similarly, the affinity of PIP3 liposome binding increased in the presence of cpd984. Overall, results demonstrate that sortilin is a PIP3 binding protein with binding likely to occur at the C-term NT binding site. The presence of multiple ligands on B100-containing lipoproteins, VLDL and LDL, raises the interesting possibility for increased interaction with sortilin based on the presence of PIP3.

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Section: Resultsmentioning

confidence: 99%

Phosphatidylinositol (3,4,5)-trisphosphate binds to sortilin and competes with neurotensin: Implications for very low density lipoprotein binding

Sparks

Jenkins

Miner

et al. 2016

Biochemical and Biophysical Research Communications

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“…The demand for clean water is rising constantly. 1 This has led to the increased need for purification processes incorporating membranes and filters since sources of water are and will be increasingly limited.…”

Section: Introductionmentioning

confidence: 99%

Grafting of polyaniline by a dynamic inverse emulsion polymerization technique onto reverse osmosis membranes as an antibiofouling agent

Suckeveriene¹

2019

Polymers for Advanced Techs

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This study reports on the benefits of an in situ interfacial dynamic inverse emulsion polymerization process under sonication of aniline in the presence of a commercial reverse osmosis (RO) membrane. This polymerization method is simple and much faster (5‐15 min) than systems reported in the literature. During polymerization, the membranes are coated with polyaniline (PANI) as verified by high‐resolution scanning electron microscopy (HRSEM) images and Fourier‐transform‐infrared (FTIR) measurements. A colony‐counting antimicrobial activity test showed that whereas the reference RO membrane developed a large bacterial colony, the polyaniline‐coated RO membrane had no colonies at all. Surface resistivity was the lowest when the pH levels were below 6, which corresponded to the polyaniline‐grafted conductive layer. The membrane flow properties were only modified slightly as a result of the polyaniline grafting, compared with a pristine reference membrane.

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“…The role of sortilin in VLDL-B100 secretion is controversial [1], and inconsistencies have been summarized [2, 3]. Some studies suggest sortilin serves as a chaperone where sortilin is hypothesized to facilitate secretion of VLDL-B100 [4].…”

Section: Introductionmentioning

confidence: 99%

Sortilin facilitates VLDL-B100 secretion by insulin sensitive McArdle RH7777 cells

Sparks

Guida

Sowden

et al. 2016

Biochemical and Biophysical Research Communications

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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.

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The enigmatic role of sortilin in lipoprotein metabolism

Cited by 13 publications

References 21 publications

Phosphatidylinositol (3,4,5)-trisphosphate binds to sortilin and competes with neurotensin: Implications for very low density lipoprotein binding

Phosphatidylinositol (3,4,5)-trisphosphate binds to sortilin and competes with neurotensin: Implications for very low density lipoprotein binding

Grafting of polyaniline by a dynamic inverse emulsion polymerization technique onto reverse osmosis membranes as an antibiofouling agent

Sortilin facilitates VLDL-B100 secretion by insulin sensitive McArdle RH7777 cells

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