Cholesterol-Lowering Action of a Novel Nutraceutical Combination in Uremic Rats: Insights into the Molecular Mechanism in a Hepatoma Cell Line

Lupo, Maria Giovanna; Biancorosso, Noemi; Brilli, Elisa; Tarantino, Germano; Adorni, Maria Pia; Vivian, Greta; Salvalaio, Marika; Dall’Acqua, Stefano; Sut, Stefania; Neutel, Cédric; Chen, Hạixia; Bressan, A.; Faggin, Elisabetta; Rattazzi, Marcello; Ferri, Nicola

doi:10.3390/nu12020436

Cited by 12 publications

(13 citation statements)

References 45 publications

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“…MK4 had no beneficial effect on the coronary artery calcification score in patients with at least one coronary risk factor 12 and MK7 tended to increase active calcification in type 2 diabetic patients with cardiovascular disease 13 . Similarly, MK7 had no effect on aortic calcification in haemodialytic chronic kidney disease patients or in uremic Sprague-Dawley rats 14,15 . Furthermore, MK-4 was reported to accelerate aortic valve calcification in cultured human aortic valve interstitial cells 16 .…”

Section: Discussionmentioning

confidence: 94%

Menaquinone 4 increases plasma lipid levels in hypercholesterolemic mice

Weisell

Ruotsalainen

Näpänkangas

et al. 2021

Sci Rep

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In calcific aortic valve disease (CAVD) progressive valvular calcification causes aortic valve dysfunction. CAVD has several risk factors such as age and dyslipidemia. Vitamin K was shown to inhibit vascular calcification in mice and valvular calcification in patients with CAVD. We studied the effect of menaquinone 4 (MK4/vitamin K2) on valvular calcification in the hypercholesterolemic mouse model of CAVD. LDLr−/−ApoB100/100 male mice were fed with a Western diet for 5 months, with (n = 10) or without (n = 10) added 0.2 mg/g MK4. Body weight gain was followed weekly. Morphology of aortic valves and liver was assessed with immunohistochemistry. Plasma cholesterol levels and cytokines from hepatic tissue were assessed in the end of the study. Hepatic gene expression of lipid metabolism regulating genes were assessed after 18 h diet. MK4 exacerbated the lipoprotein lipid profile without affecting aortic valve morphology in hypercholesterolemic LDLr−/− ApoB100/100 mice. The MK4-containing WD diet increased plasma levels of LDL and triglycerides, hepatic steatosis, and mRNA expression of genes required for triglyceride and cholesterol synthesis. MK4 diminished levels of several cytokines and chemokines in liver, including IL-6, TNFα and MCP1, as measured by hepatic cytokine array. Consequently, MK4 may exert non-beneficial effects on circulating lipid levels, especially in hypercholesterolemic individuals.

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Section: Discussionmentioning

confidence: 94%

Menaquinone 4 increases plasma lipid levels in hypercholesterolemic mice

Weisell

Ruotsalainen

Näpänkangas

et al. 2021

Sci Rep

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“…In response to the inhibition of cholesterol synthesis, MK7 induces LDLR, similarly to statins, and this effect was prevented by the co-incubation with squalene [148]. However, differently from statin, which induces PCSK9 expression, MK7 was shown to suppress PCSK9 synthesis and secretion by hepatoma cells [148]. This is thus very similar to what is observed with berberine, although the mechanism of action of MK7 is still unknown ( Table 1).…”

Section: Vitamin Mk7mentioning

confidence: 52%

“…By in vitro experiments conducted in hepatoma cells, it was found that MK7 alone reduces the cholesterol biosynthesis, by potentially affecting an enzymatic step of the mevalonate pathway upstream of the squalene synthase [148]. In response to the inhibition of cholesterol synthesis, MK7 induces LDLR, similarly to statins, and this effect was prevented by the co-incubation with squalene [148]. However, differently from statin, which induces PCSK9 expression, MK7 was shown to suppress PCSK9 synthesis and secretion by hepatoma cells [148].…”

Section: Vitamin Mk7mentioning

confidence: 99%

“…More recently, we have observed a reduction of TC levels in uremic rats after the administration of a nutraceutical combination named RenaTris ® , containing MK-7, magnesium carbonate, and Sucrosomial ® Iron [ 148 ]. By in vitro experiments conducted in hepatoma cells, it was found that MK7 alone reduces the cholesterol biosynthesis, by potentially affecting an enzymatic step of the mevalonate pathway upstream of the squalene synthase [ 148 ]. In response to the inhibition of cholesterol synthesis, MK7 induces LDLR, similarly to statins, and this effect was prevented by the co-incubation with squalene [ 148 ].…”

Section: Nutrientsmentioning

confidence: 99%

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Naturally Occurring PCSK9 Inhibitors

et al. 2020

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Genetic, epidemiological and pharmacological data have led to the conclusion that antagonizing or inhibiting Proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces cardiovascular events. This clinical outcome is mainly related to the pivotal role of PCSK9 in controlling low-density lipoprotein (LDL) cholesterol levels. The absence of oral and affordable anti-PCSK9 medications has limited the beneficial effects of this new therapeutic option. A possible breakthrough in this field may come from the discovery of new naturally occurring PCSK9 inhibitors as a starting point for the development of oral, small molecules, to be used in combination with statins in order to increase the percentage of patients reaching their LDL-cholesterol target levels. In the present review, we have summarized the current knowledge on natural compounds or extracts that have shown an inhibitory effect on PCSK9, either in experimental or clinical settings. When available, the pharmacodynamic and pharmacokinetic profiles of the listed compounds are described.

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“…An in vitro study hints at the possibility that calcium and lanthanum carbonate potentially bind to vitamin K, preventing their absorption [ 62 ]. Furthermore, the vitamin K-lowering effects of phosphate binders may also lead to impaired cholesterol metabolism [ 63 ], modifying the subsequent risk of atherosclerosis and VC as well.…”

Section: Gastrointestinal Decontamination For Toxin Removal and Vcmentioning

confidence: 99%

Uremic Vascular Calcification: The Pathogenic Roles and Gastrointestinal Decontamination of Uremic Toxins

Chao

Lin

2020

Toxins

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Uremic vascular calcification (VC) commonly occurs during advanced chronic kidney disease (CKD) and significantly increases cardiovascular morbidity and mortality. Uremic toxins are integral within VC pathogenesis, as they exhibit adverse vascular influences ranging from atherosclerosis, vascular inflammation, to VC. Experimental removal of these toxins, including small molecular (phosphate, trimethylamine-N-oxide), large molecular (fibroblast growth factor-23, cytokines), and protein-bound ones (indoxyl sulfate, p-cresyl sulfate), ameliorates VC. As most uremic toxins share a gut origin, interventions through gastrointestinal tract are expected to demonstrate particular efficacy. The “gastrointestinal decontamination” through the removal of toxin in situ or impediment of toxin absorption within the gastrointestinal tract is a practical and potential strategy to reduce uremic toxins. First and foremost, the modulation of gut microbiota through optimizing dietary composition, the use of prebiotics or probiotics, can be implemented. Other promising strategies such as reducing calcium load, minimizing intestinal phosphate absorption through the optimization of phosphate binders and the inhibition of gut luminal phosphate transporters, the administration of magnesium, and the use of oral toxin adsorbent for protein-bound uremic toxins may potentially counteract uremic VC. Novel agents such as tenapanor have been actively tested in clinical trials for their potential vascular benefits. Further advanced studies are still warranted to validate the beneficial effects of gastrointestinal decontamination in the retardation and treatment of uremic VC.

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Cholesterol-Lowering Action of a Novel Nutraceutical Combination in Uremic Rats: Insights into the Molecular Mechanism in a Hepatoma Cell Line

Cited by 12 publications

References 45 publications

Menaquinone 4 increases plasma lipid levels in hypercholesterolemic mice

Menaquinone 4 increases plasma lipid levels in hypercholesterolemic mice

Naturally Occurring PCSK9 Inhibitors

Uremic Vascular Calcification: The Pathogenic Roles and Gastrointestinal Decontamination of Uremic Toxins

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