Liver fat accumulation is associated with circulating PCSK9

Ruscica, Massimiliano; Ferri, Nicola; Macchi, Chiara; Meroni, Marica; Lanti, Claudia; Ricci, Chiara; Maggioni, Marco; Fracanzani, Anna Ludovica; Badiali, Sara; Fargion, Silvia; Magni, Paolo; Valenti, Luca; Dongiovanni, Paola

doi:10.1080/07853890.2016.1188328

Cited by 120 publications

(110 citation statements)

References 32 publications

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“…LDL-cholesterol lowering (up to 50-60%) in very high-risk patients (123,124), especially FH (125) The relationship between PCSK9 and the inflammatory process is the object of intensive investigation. While, in fact, inflammation raises PCSK9 liver expression (135) and PCSK9 is positively linked to TNF-α levels (136), no significant relationship has been observed between PCSK9 levels and hsCRP (137). This last finding is in line with the observation that PCSK9…”

Section: Proprotein Convertase Subtilisin/kexin 9 (Pcsk9) Antagonistssupporting

confidence: 57%

Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes?

et al. 2018

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Inflammatory changes are responsible for maintenance of the atherosclerotic process and may underlie some of the most feared vascular complications. Among the multiple mechanisms of inflammation, the arterial deposition of lipids and particularly of cholesterol crystals is the one responsible for the activation of inflammasome NLRP3, followed by the rise of circulating markers, mainly C-reactive protein (CRP). Elevation of lipoproteins, LDL but also VLDL and remnants, associates with increased inflammatory changes and coronary risk. Lipid lowering medications can reduce cholesterolemia and CRP: patients with elevations of both are at greatest cardiovascular (CV) risk and receive maximum benefit from therapy. Evaluation of the major drug series indicates that statins exert the largest LDL and CRP reduction, accompanied by reduced CV events. Other drugs, mainly active on the triglyceride/HDL axis, for example, PPAR agonists, may improve CRP and the lipid pattern, especially in patients with metabolic syndrome. PCSK9 antagonists, the newest most potent medications, do not induce significant changes in inflammatory markers, but patients with the highest baseline CRP levels show the best CV risk reduction. Parallel evaluation of lipids and inflammatory changes clearly indicates a significant link, both guiding to patients at highest risk, and to the best pharmacological approach. Key messages Lipid lowering agents with "pleiotropic" effects provide a more effective approach to CV prevention In CANTOS study, patients achieving on-treatment hsCRP concentrations ≤2 mg/L had a higher benefit in terms of reduction in major CV events The anti-inflammatory activity of PCSK9 antagonists appears to be of a minimal extent.

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Section: Proprotein Convertase Subtilisin/kexin 9 (Pcsk9) Antagonistssupporting

confidence: 57%

Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes?

et al. 2018

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“…Plasma PCSK9 concentrations were measured by a commercial ELISA kit (R&D Systems, MN) able to recognize free and LDLR-bound PCSK9 [24]. Plasma samples were diluted 1:20 and incubated onto a microplate pre-coated with a monoclonal antibody specific for human PCSK9.…”

Section: Biochemical Analysesmentioning

confidence: 99%

Plasma PCSK9 levels and lipoprotein distribution are preserved in carriers of genetic HDL disorders

Ruscica

Simonelli

Botta

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Proprotein convertase subtilisin/kexin 9 (PCSK9), a protein regulating the number of cell-surface LDL receptors (LDLR), circulates partially associated to plasma lipoproteins. How this interaction alters PCSK9 plasma levels is still unclear. In the present study, we took advantage of the availability of a large cohort of carriers of genetic HDL disorders to evaluate how HDL defects affect plasma PCSK9 levels and its distribution among lipoproteins. Plasma PCSK9 concentrations were determined by ELISA in carriers of mutations in LCAT, ABCA1, or APOAI genes, and lipoprotein distribution was analyzed by FPLC. Carriers of one or two mutations in the LCAT gene show plasma PCSK9 levels comparable to that of unaffected family controls (homozygotes, 159.4 ng/mL (124.9;243.3); heterozygotes, 180.3 ng/mL (127.6;251.5) and controls, 190.4 ng/mL (146.7;264.4); P for trend = 0.33). Measurement of PCSK9 in plasma of subjects carrying mutations in ABCA1 or APOAI genes confirmed normal values. When fractionated by FPLC, PCSK9 peaked in a region between LDL and HDL in control subjects. In carriers of all HDL defects, lipoprotein profile shows a strong reduction of HDL, but the distribution of PCSK9 was superimposable to that of controls. In conclusion, the present study demonstrates that in genetically determined low HDL states plasma PCSK9 concentrations and lipoprotein distribution are preserved, thus suggesting that HDL may not be involved in PCSK9 transport in plasma.

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“…This observation might not be surprising since recent epidemiological studies did not find an effect of the R46L loss-of-function mutation of human PCSK9 on glucose and insulin homeostasis, including type 2 diabetes risk [26]. Although it is possible that the observed relationship between PCSK9 and insulin sensitivity in CF patients with NGT is fortuitous, it is also possible that, in these CF patients, the link between insulin resistance, hepatic steatosis and the circulating levels of PCSK9 is preserved [27,28] whereas this relationship might be lost in patients categorized as dysglycemic (INDET/IGT/CFRD). Further studies are necessary to identify the mechanism by which PCSK9 might influence insulin sensitivity in CF.…”

Section: Discussionmentioning

confidence: 68%

Proprotein Convertase Subtilisin/Kexin type 9 affects insulin but not lipid metabolism in cystic fibrosis

Coriati

Arslanian

Bouvet

et al. 2017

CIM

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Proprotein Convertase Subtilisin/ Kexin type 9 affects insulin but not lipid metabolism in cystic fibrosis Abstract Purpose: Cystic Fibrosis (CF) is the most common genetic disorder and, with improved survival, glucose abnormalities have emerged as a major comorbidity. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a regulator of plasma LDL-cholesterol homeostasis, is associated with lipid and glucose metabolism in healthy individuals. Here we report on the link between PCSK9 and markers of metabolism in CF.Methods: Cross-sectional analysis was performed on CF patients (≥ 18 years, N=94) from the Montreal Cohort, without known diabetes, and on healthy individuals (N=19). The levels of PCSK9 and lipid markers were quantified and all subjects underwent a 2 h oral glucose tolerance test.Results: No significant differences in PCSK9 levels were found between healthy individuals and patients with CF, or between the groups with different degrees of glucose tolerance. No association was found between PCSK9 and markers of lipid metabolism; however, a positive correlation was found between PCSK9 and total insulin secretion and a negative one with insulin sensitivity in CF patients who had normal glucose tolerance. Conclusion:Circulating levels of PCSK9 in the CF population are comparable to those in the healthy population. There are no associations between PCSK9 levels and either glucose or lipid homeostasis parameters. Nevertheless, a statistically significant link was observed between PCSK9 and markers of insulin homeostasis, solely in CF patients who presented normal glucose tolerance. Further exploration of the relationship between PCSK9 and insulin homeostasis in CF patients with normal glucose tolerance is warranted.

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Liver fat accumulation is associated with circulating PCSK9

Cited by 120 publications

References 32 publications

Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes?

Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes?

Plasma PCSK9 levels and lipoprotein distribution are preserved in carriers of genetic HDL disorders

Proprotein Convertase Subtilisin/Kexin type 9 affects insulin but not lipid metabolism in cystic fibrosis

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