Potential of PCSK9 as a new target for the management of LDL cholesterol

Mombelli, Giuliana; Castelnuovo, S.; Pavanello, Chiara

doi:10.2147/rrcc.s52961

Cited by 8 publications

(5 citation statements)

References 117 publications

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“…On the other hand, decreases in LDL-C levels were observed in the D-allulose groups after week 8 in our study (Table 2), which appears to be associated with PCSK9. PCSK9 is known to degrade the LDL recep-tor and regulate blood LDL-C levels; its inhibitors have drawn attention as new LDL-C-lowering drugs (Giugliano and Sabatine, 2015;Mombelli et al, 2015). A previous report mentioned that the suppression of LDL receptors induced by CDCA treatment is counterbalanced by a reduction of PCSK9 (Laskar et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Safety and efficacy of a 48-week long-term ingestion of D-allulose in subjects with high LDL cholesterol levels

Tanaka

Kanasaki

Hayashi

et al. 2020

Fundam. Toxicol. Sci.

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-D-allulose is one of the rare sugars with almost zero calories and several health benefits. Previous studies have reported the safety of D-allulose in normal, overweight/obese, and diabetic humans. However, one study reported significant increases in T-Cho and LDL-C after 12 weeks of D-allulose intake; this report was not a randomized controlled trial and these changes were considered to be due to seasonal variations. We, therefore, conducted a randomized, double-blind, placebo-controlled trial in 90 subjects with high LDL-C levels for 48 weeks to clarify the influence of long-term D-allulose consumption on cholesterol metabolism and efficacy. Subjects were randomly divided into 3 groups: highdose D-allulose (15 g D-allulose/day), low-dose D-allulose (5 g D-allulose/day), and placebo group (0 g D-allulose/day); each subject consumed a daily test beverage for 48 weeks. Clinical examinations were performed every eight weeks, beginning from initial consumption until week 52. No significant increases in T-Cho and LDL-C between test groups were observed, and 48 weeks of D-allulose consumption did not change risk factors for atherosclerotic cardiovascular disease. Furthermore, no clinical problems were recognized for other parameters. Additionally, significant improvements in hepatic enzyme activities, fatty liver score, and glucose metabolism after long-term D-allulose consumption were observed. The results from our study revealed that 1) D-allulose consumption is considered safe for long-term intake up to a year, and 2) D-allulose may be effective for improving hepatic functions and glucose metabolism.

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Section: Discussionmentioning

confidence: 99%

Safety and efficacy of a 48-week long-term ingestion of D-allulose in subjects with high LDL cholesterol levels

Tanaka

Kanasaki

Hayashi

et al. 2020

Fundam. Toxicol. Sci.

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“…There are several potential approaches for targeting cholesterol homeostasis in cancer cells such as inhibition of cholesterol biosynthesis, blockade of cholesterol uptake, and modulation of intracellular cholesterol trafficking. Increased serum levels of cholesterol in humans can be effectively lowered by PCSK9 inhibitors and statins [58][59][60][61]. PCSK9 is a proprotein convertase that is involved in the degradation of LDLR in the liver [62].…”

Section: Discussionmentioning

confidence: 99%

Targeting NPC1 in Renal Cell Carcinoma

Fazliyeva,

Makhov,

Uzzo

et al. 2024

Cancers

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Rapidly proliferating cancer cells have a greater requirement for cholesterol than normal cells. Tumor cells are largely dependent on exogenous lipids given that their growth requirements are not fully met by endogenous pathways. Our current study shows that ccRCC cells have redundant mechanisms of cholesterol acquisition. We demonstrate that all major lipoproteins (i.e., LDL, HDL, and VLDL) have a comparable ability to support the growth of ccRCC cells and are equally effective in counteracting the antitumor activities of TKIs. The intracellular trafficking of exogenous lipoprotein-derived cholesterol appears to be distinct from the movement of endogenously synthesized cholesterol. De novo synthetized cholesterol is transported from the endoplasmic reticulum directly to the plasma membrane and to the acyl-CoA: cholesterol acyltransferase, whereas lipoprotein-derived cholesterol is distributed through the NPC1-dependent endosomal trafficking system. Expression of NPC1 is increased in ccRCC at mRNA and protein levels, and high expression of NPC1 is associated with poor prognosis. Our current findings show that ccRCC cells are particularly sensitive to the inhibition of endolysosomal cholesterol export and underline the therapeutic potential of targeting NPC1 in ccRCC.

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“…In addition, PCSK9 is observed in carotid atherosclerotic lesions, especially in vascular smooth muscle cells [55]. Additional roles [56] are shown in Figure 5.…”

Section: Proprotein Convertase Subtilisin/kexin Type 9 (Pcsk9)mentioning

confidence: 94%

Apolipoproteins A and B and PCSK9: Nontraditional Cardiovascular Risk Factors in Chronic Kidney Disease and in End-Stage Renal Disease

Vlad

Foia

Popescu

et al. 2019

Journal of Diabetes Research

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Purpose. Nontraditional cardiovascular risk factors as apolipoprotein A (ApoA), apolipoprotein B (ApoB), and the proprotein convertase subtilisin/kexin type 9 (PCSK9) increase the prevalence of cardiovascular mortality in chronic kidney disease (CKD) or in end-stage renal disease (ESRD) through quantitative alterations. This review is aimed at establishing the biomarker (ApoA, ApoB, and PCSK9) level variations in uremic patients, to identify the studies showing the association between these biomarkers and the development of cardiovascular events and to depict the therapeutic options to reduce cardiovascular risk in CKD and ESRD patients. Methods. We searched the electronic database of PubMed, Scopus, EBSCO, and Cochrane CENTRAL for studies evaluating apolipoproteins and PCSK9 in CKD and ESRD. Randomized controlled trials, observational studies (including case-control, prospective or retrospective cohort), and reviews/meta-analysis were included if reference was made to those keys and cardiovascular outcomes in CKD/ESRD. Results. 18 studies met inclusion criteria. Serum ApoA-I has been significantly associated with the development of new cardiovascular event and with cardiovascular mortality in ESRD patients. ApoA-IV level was independently associated with maximum carotid intima-media thickness (cIMT) and was a predictor for sudden cardiac death. The ApoB/ApoA-I ratio represents a strong predictor for coronary artery calcifications, cardiovascular mortality, and myocardial infarction in CKD/ESRD. Plasma levels of PCSK9 were not associated with cardiovascular events in CKD patients. Conclusions. Although the “dyslipidemic status” in CKD/ESRD is not clearly depicted, due to different research findings, ApoA-I, ApoA-IV, and ApoB/ApoA-I ratio could be predictors of cardiovascular risk. Serum PCSK9 levels were not associated with the cardiovascular events in patients with CKD/ESRD. Probably in the future, the treatment of dyslipidemia in CKD/ESRD will be aimed at discovering new effective therapies on the action of these biomarkers.

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Potential of PCSK9 as a new target for the management of LDL cholesterol

Cited by 8 publications

References 117 publications

Safety and efficacy of a 48-week long-term ingestion of D-allulose in subjects with high LDL cholesterol levels

Safety and efficacy of a 48-week long-term ingestion of D-allulose in subjects with high LDL cholesterol levels

Targeting NPC1 in Renal Cell Carcinoma

Apolipoproteins A and B and PCSK9: Nontraditional Cardiovascular Risk Factors in Chronic Kidney Disease and in End-Stage Renal Disease

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