Sortilin, Encoded by the Cardiovascular Risk Gene SORT1, and Its Suggested Functions in Cardiovascular Disease

Kjølby, Mads; Nielsen, Morten S.; Petersen, Claus Munck

doi:10.1007/s11883-015-0496-7

Cited by 78 publications

(65 citation statements)

References 66 publications

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“…Sortilin 1 (SORT1) encoding the transmembrane type I receptor sortilin is a risk gene for hypercholesterolemia and myocardial infarction [7, 87, 90]. Sortilin is highly expressed in a number of tissues in a distinct and dynamic fashion [17].…”

Section: Posttranslational Regulation Of Pcsk9 Activitymentioning

confidence: 99%

Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease

et al. 2017

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Ischemic heart disease is the main cause of death worldwide and is accelerated by increased levels of low-density lipoprotein cholesterol (LDL-C). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a potent circulating regulator of LDL-C through its ability to induce degradation of the LDL receptor (LDLR) in the lysosome of hepatocytes. Only in the last few years, a number of breakthroughs in the understanding of PCSK9 biology have been reported illustrating how PCSK9 activity is tightly regulated at several levels by factors influencing its transcription, secretion, or by extracellular inactivation and clearance. Two humanized antibodies directed against the LDLR-binding site in PCSK9 received approval by the European and US authorities and additional PCSK9 directed therapeutics are climbing up the phases of clinical trials. The first outcome data of the PCSK9 inhibitor evolocumab reported a significant reduction in the composite endpoint (cardiovascular death, myocardial infarction, or stroke) and further outcome data are awaited. Meanwhile, it became evident that PCSK9 has (patho)physiological roles in several cardiovascular cells. In this review, we summarize and discuss the recent biological and clinical data on PCSK9, the regulation of PCSK9, its extra-hepatic activities focusing on cardiovascular cells, molecular concepts to target PCSK9, and finally briefly summarize the data of recent clinical studies.

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Section: Posttranslational Regulation Of Pcsk9 Activitymentioning

confidence: 99%

Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease

et al. 2017

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“…Plasma CELSR2, PSRC1, and MYBPHL, and a subsequent study has shown that SORT1 affects lipid metabolism 11) . SORT1 encodes sortilin, a type 1 transmembrane protein 12,13) , which acts as a multiligand receptor and is linked to systemic lipoprotein metabolism and PCSK9 secretion [14][15][16][17] . Lowering LDL cholesterol levels is currently considered the most effective strategy for preventing CAD.…”

Section: Laboratory Analysismentioning

confidence: 99%

Effects of Statin Therapy on Plasma Proprotein Convertase Subtilisin/kexin Type 9 and Sortilin Levels in Statin-Naive Patients with Coronary Artery Disease

Nozue

Hashimoto

Ogawa

et al. 2016

JAT

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Aim: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of serum low-density lipoprotein (LDL) cholesterol levels, and sortilin is linked to lipoprotein metabolism. Although statin therapy increases PCSK9 levels, effects of this therapy on plasma sortilin levels have not been evaluated. The purpose of the present study was to examine the effects of statins on plasma PCSK9 and sortilin levels, and association of statin-induced increase in PCSK9 levels with sortilin. Methods: Serum lipid levels and plasma PCSK9 and sortilin levels were measured at baseline and 8 months after statin therapy in 90 statin-naive patients with coronary artery disease (CAD). Pitavastatin 4 mg/day was used to treat 44 patients and pravastatin 20 mg/day to treat the remaining 46 patients. Results: For both statin groups, significant increases in hetero-dimer PCSK9 levels (pitavastatin: 31%, p 0.0001; pravastatin: 34%, p 0.03) and decreases in sortilin levels (pitavastatin: 8%, p 0.02; pravastatin: 16%, p 0.002) were observed. Although a reduction in LDL cholesterol was greater in the pitavastatin group than in the pravastatin group, no significant differences were observed in percentage changes in hetero-dimer PCSK9 and sortilin levels. A significant positive correlation was observed between percentage changes in hetero-dimer PCSK9 levels and those in sortilin levels (pitavastatin: r 0.359, p 0.02; pravastatin: r 0.276, p 0.06). Conclusions: Use of pitavastatin and pravastatin increased plasma PCSK9 and decreased sortilin levels. Statin-induced increases in PCSK9 were associated with changes in sortilin in statin-naive patients with CAD. J Atheroscler Thromb, 2016; 23: 848-856.

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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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Sortilin, Encoded by the Cardiovascular Risk Gene SORT1, and Its Suggested Functions in Cardiovascular Disease

Cited by 78 publications

References 66 publications

Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease

Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease

Effects of Statin Therapy on Plasma Proprotein Convertase Subtilisin/kexin Type 9 and Sortilin Levels in Statin-Naive Patients with Coronary Artery Disease

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

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