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- Macchi, Chiara, et al.
(author)
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Leptin, Resistin, and Proprotein Convertase Subtilisin/Kexin Type 9 - The Role of STAT3
- 2020
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In: The American journal of pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 190:11, s. 2226-2236
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Journal article (peer-reviewed)abstract
- In a condition of dysfunctional visceral fat depots, as in the case of obesity, alterations in adipokines levels may be detrimental for the cardiovascular system. The proinflammatory leptin and resistin adipokines have been described as possible links between obesity and atherosclerosis. The present study was aimed at evaluating whether proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein metabolism, is induced by leptin and resistin through the involvement of the inflammatory pathway of signal transducer and activator of transcript 3 (STAT3). In HepG2 cells, leptin and resistin upregulated PCSK9 gene and protein expression as well as the phosphorylation of STAT3. Upon STAT3 silencing, leptin and resistin lost their ability to activate PCSK9. The knock-down of STAT3 did not affect the expression of leptin and resistin receptors as well as that of PCSK9. The analysis of human PCSK9 promoter region showed that the two adipokines raise PCSK9 promoter activity via the involvement of sterol regulatory element motif. In healthy male, a positive association between circulating leptin and PCSK9 levels was found only when BMI was < 25 kg/m2. In conclusion, our study identified STAT3 as one of the molecular regulators of leptin- and resistin-mediated transcriptional induction of PCSK9.
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2. |
- Mach, François, et al.
(author)
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Adverse effects of statin therapy: perception vs. the evidence - focus on glucose homeostasis, cognitive, renal and hepatic function, haemorrhagic stroke and cataract
- 2018
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In: European heart journal. - : Oxford University Press (OUP). - 1522-9645 .- 0195-668X. ; 39:27
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Research review (peer-reviewed)abstract
- To objectively appraise evidence for possible adverse effects of long-term statin therapy on glucose homeostasis, cognitive, renal and hepatic function, and risk for haemorrhagic stroke or cataract.A literature search covering 2000-2017 was performed. The Panel critically appraised the data and agreed by consensus on the categorization of reported adverse effects. Randomized controlled trials (RCTs) and genetic studies show that statin therapy is associated with a modest increase in the risk of new-onset diabetes mellitus (about one per thousand patient-years), generally defined by laboratory findings (glycated haemoglobin ≥6.5); this risk is significantly higher in the metabolic syndrome or prediabetes. Statin treatment does not adversely affect cognitive function, even at very low levels of low-density lipoprotein cholesterol and is not associated with clinically significant deterioration of renal function, or development of cataract. Transient increases in liver enzymes occur in 0.5-2% of patients taking statins but are not clinically relevant; idiosyncratic liver injury due to statins is very rare and causality difficult to prove. The evidence base does not support an increased risk of haemorrhagic stroke in individuals without cerebrovascular disease; a small increase in risk was suggested by the Stroke Prevention by Aggressive Reduction of Cholesterol Levels study in subjects with prior stroke but has not been confirmed in the substantive evidence base of RCTs, cohort studies and case-control studies.Long-term statin treatment is remarkably safe with a low risk of clinically relevant adverse effects as defined above; statin-associated muscle symptoms were discussed in a previous Consensus Statement. Importantly, the established cardiovascular benefits of statin therapy far outweigh the risk of adverse effects.
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