Naturally Occurring PCSK9 Inhibitors

Adorni, Maria Pia; Zimetti, Francesca; Lupo, Maria Giovanna; Ruscica, Massimiliano; Ferri, Nicola

doi:10.3390/nu12051440

Cited by 55 publications

(52 citation statements)

References 191 publications

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Section: Discussionmentioning

confidence: 99%

TNFɑ-induced LDL cholesterol accumulation involve elevated LDLR cell surface levels and SR-B1 downregulation in human arterial endothelial cells

Okoro

2021

Preprint

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Background Excess lipid droplets are frequently observed in arterial endothelial cells at sites of advanced atherosclerotic plaques. The mechanism or implication of this observation is unknown. Methods The role of tumor necrosis factor alpha (TNFɑ) in modulating low density lipoprotein (LDL) content in confluent primary human aortic endothelial cells (pHAECs) was investigated. Results TNFɑ promoted up to 2 folds increase in cellular cholesterol, which was resistant to ACAT inhibition. The cholesterol increase was associated with increased 125I-LDL surface binding. Using the non-hydrolysable label, Dil, TNFɑ could induce a massive increase in Dil-LDL by over 200 folds. The elevated intracellular Dil-LDL was blocked with excess unlabeled LDL and PCSK9, but not oxidized LDL (oxLDL), RAP, or apoE depletion. Moreover, TNFɑ-induced increase of LDL-derived lipids was elevated through lysosome inhibition. Using specific LDLR antibody, the Dil-LDL accumulation was reduced by over 99%. Effects of TNFɑ included LDLR cell surface increase by 138%, and very large increases in ICAM-1 total and surface proteins, respectively. In contrast, that of scavenger receptor B1 (SR-B1) was reduced. Additionally, LDLR antibody bound rapidly in TNFɑ-treated cells by about 30 folds, inducing a migrating shift in the LDLR protein. The effect of TNFɑ on Dil-LDL accumulation was inhibited by the antioxidant tetramethythiourea (TMTU) dose-dependently, but not by downstream cascade inhibitors against NF-κB, stress kinases, ASK1, JNK, p38, or apoptosis caspases. Grown on transwell inserts, TNFɑ did not enhance apical (AP) to basolateral (BL) LDL cholesterol or Dil release. Conclusions It is concluded that TNFɑ promotes LDLR functions through combined increase at the cell surface and SR-B1 downregulation. This may have important implications on progression of atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

TNFɑ-induced LDL cholesterol accumulation involve elevated LDLR cell surface levels and SR-B1 downregulation in human arterial endothelial cells

Okoro

2021

Preprint

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“…Excess cholesterol in arterial endothelial cells is likely to lead to endothelial dysfunction due, in part, to space and membrane disruption [96]. General upregulation of the LDLR receptor function through inhibition of PCSK9 have been reported to bene t against coronary artery disease [97,98]. Notwithstanding, PCSK9 also downregulates other receptors in the LDLR family [79,80], and binds the scavenger receptor, CD36, concurrent with thrombosis [97,99].…”

Section: Discussionmentioning

confidence: 99%

TNFɑ-induced LDL cholesterol accumulation involve elevated LDLR cell surface levels and SR-B1 downregulation in human arterial endothelial cells

Okoro

2021

Preprint

View full text Add to dashboard Cite

Excess lipid droplets are frequently observed in arterial endothelial cells at sites of advanced atherosclerotic plaques. Here, the role of tumor necrosis factor alpha (TNFɑ) in modulating low density lipoprotein (LDL) content in confluent primary human aortic endothelial cells (pHAECs) was investigated. TNFɑ promoted up to 2 folds increase in cellular cholesterol, which was resistant to ACAT inhibition. The cholesterol increase was associated with increased 125I-LDL surface binding. Using the non-hydrolysable label, Dil, TNFɑ could induce a massive increase in Dil-LDL by over 200 folds. The elevated intracellular Dil-LDL was blocked with excess unlabeled LDL and PCSK9, but not oxidized LDL (oxLDL), receptor associated protein (RAP), or apolipoprotein (apoE) depletion. Moreover, TNFɑ-induced increase of LDL-derived lipids was elevated through lysosome inhibition. Using specific LDLR antibody, the Dil-LDL accumulation was reduced by over 99%. Effects of TNFɑ included LDLR cell surface increase by 138%, and very large increases in ICAM-1 total and surface proteins, respectively. In contrast, that of scavenger receptor B1 (SR-B1) was reduced. Additionally, LDLR antibody bound rapidly in TNFɑ-treated cells by about 30 folds, inducing a migrating shift in the LDLR protein. The effect of TNFɑ on Dil-LDL accumulation was inhibited by the antioxidant tetramethythiourea (TMTU) dose-dependently, but not by inhibitors against NF-κB, stress kinases, ASK1, JNK, p38, or apoptosis caspases. Grown on transwell inserts, TNFɑ did not enhance apical to basolateral LDL cholesterol or Dil release. It is concluded that TNFɑ promotes LDLR functions through combined increase at the cell surface and SR-B1 downregulation.

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“…The hypolipaemic effects of Bberberine are associated with increasing the expression of the LDL receptors, which suggests a mechanism similar to that of statins [31], and with lowering the expression of PCSK9 (Protein Convertase Subtilisin KexinType 9) in the HepG2 cells [32]. Berberine can also lower serum cholesterol concentration by inhibiting lipid synthesis in hepatocytes by activating the AMP-activated protein kinase (AMPK) [29,33].…”

Section: Annals Of Agricultural and Environmental Medicinementioning

confidence: 99%

“…In clinical studies on dyslipidaemic patients,B berberine was also used in combination with other hypolipaemic nutraceutics, such as red rice, policosanol, artichoke, silymarin, chitosan, Morus Alba extract [1,32]. Pirro et al conducted a meta-analysis of 14 studies with 1,670 subjects taking nutraceutics (3 mg of monacolin K, 10 mg of policosanol, 500 mg of berberine), and 1,484 subjects in the control group [17].…”

Section: Annals Of Agricultural and Environmental Medicinementioning

confidence: 99%

Hypolipaemic nutraceutics: red yeast rice and Armolipid, berberine and bergamot

Kłosiewicz−Latoszek

Cybulska

Stós

et al. 2020

Ann Agric Environ Med.

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Introduction. Increased serum cholesterol levels constitute one of the main risk factors for cardiovascular diseases. Statins are a major method for reducing the levels which also lower the risk of cardiovascular events. However, these valuable drugs cannot be used in all patients who need them due to contraindications and intolerance. In such cases, help can be sought from nutraceutics that reduce the serum cholesterol concentration. Since there are numerous products of this type available at drugstores, registered as supplements, there seems to be a need to demonstrate their effectiveness in preventing cardiovascular diseases induced by atherosclerosis. In literature, increasingly more attention is drawn to red yeast rice, Armolipid, berberine and bergamot. Brief description. This article presents knowledge about these nutraceutics based on clinical studies and expert statements relating to their use. The results of clinical studies and metaanalyses have shown that nutraceutics with cholesterol lowering properties, red yeast rice and Armolipid are the most favourable for reducing cardiovascular events. However, the evidence of benefits of berberine and bergamot is not so conclusive. Conclusions. Red yeast rice products and Armolipid may be used as an alternative treatment in statin intolerant patients, especially in combination with ezetimibe. These nutraceutics can be also considered, as an adjunct to diet therapy in primary prevention of cardiovascular diseases in patients with mild and moderate hypercholesterolaemia. The opinion of experts on berberine and bergamot is ambiguous.

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Naturally Occurring PCSK9 Inhibitors

Cited by 55 publications

References 191 publications

TNFɑ-induced LDL cholesterol accumulation involve elevated LDLR cell surface levels and SR-B1 downregulation in human arterial endothelial cells

TNFɑ-induced LDL cholesterol accumulation involve elevated LDLR cell surface levels and SR-B1 downregulation in human arterial endothelial cells

TNFɑ-induced LDL cholesterol accumulation involve elevated LDLR cell surface levels and SR-B1 downregulation in human arterial endothelial cells

Hypolipaemic nutraceutics: red yeast rice and Armolipid, berberine and bergamot

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