PCSK9 blockade helps clear pathogenic lipids

Bray, Natasha

doi:10.1038/nrd4492

Cited by 5 publications

(6 citation statements)

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“…Incubation with PCSK9 indeed reduced LPS uptake by hepatocytes. Toxic pathogen lipids such as LPS are carried in lipoprotein particles including HDL, LDL, and VLDL [ 7 , 27 ] which results in the inactivation of inflammatory effect of LPS by sequestration [ 7 , 27 , 30 – 32 ]. For our in vitro studies, the incubation medium contained 20% serum.…”

Section: Discussionmentioning

confidence: 99%

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Lipopolysaccharide Is Cleared from the Circulation by Hepatocytes via the Low Density Lipoprotein Receptor

et al. 2016

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Sepsis is the leading cause of death in critically ill patients. While decreased Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) function improves clinical outcomes in murine and human sepsis, the mechanisms involved have not been fully elucidated. We tested the hypothesis that lipopolysaccharide (LPS), the major Gram-negative bacteria endotoxin, is cleared from the circulation by hepatocyte Low Density Lipoprotein Receptors (LDLR)—receptors downregulated by PCSK9. We directly visualized LPS uptake and found that LPS is rapidly taken up by hepatocytes into the cell periphery. Over the course of 4 hours LPS is transported towards the cell center. We next found that clearance of injected LPS from the blood was reduced substantially in Ldlr knockout (Ldlr-/-) mice compared to wild type controls and, simultaneously, hepatic uptake of LPS was also reduced in Ldlr-/- mice. Specifically examining the role of hepatocytes, we further found that primary hepatocytes isolated from Ldlr-/- mice had greatly decreased LPS uptake. In the HepG2 immortalized human hepatocyte cell line, LDLR silencing similarly resulted in decreased LPS uptake. PCSK9 treatment reduces LDLR density on hepatocytes and, therefore, was another independent strategy to test our hypothesis. Incubation with PCSK9 reduced LPS uptake by hepatocytes. Taken together, these findings demonstrate that hepatocytes clear LPS from the circulation via the LDLR and PCSK9 regulates LPS clearance from the circulation during sepsis by downregulation of hepatic LDLR.

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Section: Discussionmentioning

confidence: 99%

“…Decreased lipoprotein levels are observed in sepsis, for example HDL levels drop by 40–70% in septic patients [ 31 ]. These decreased levels upregulate PCSK9 transcription so that PCSK9 levels are increased during human sepsis [ 32 ]. Elevated PCSK9, in turn, decreases LDLR density on hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide Is Cleared from the Circulation by Hepatocytes via the Low Density Lipoprotein Receptor

et al. 2016

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“…3 Studies suggest that drugs that inhibit the PCSK9 gene could have potential as a new treatment for sepsis. 4,5,6,7…”

Section: Introductionmentioning

confidence: 99%

“…3 Studies suggest that drugs that inhibit the PCSK9 gene could have potential as a new treatment for sepsis. [4][5][6][7] The PCSK9 gene increases low-density lipoprotein cholesterol (LDL-C) concentrations by targeting LDL receptors (LDLRs) for destruction, thereby decreasing transport of LDL into the liver and thus increasing circulating LDL-C concentrations. 8,9 Therefore, as expected, gain-of-function (GOF) and loss-of-function (LOF) variants in the PCSK9 gene (OMIM 607786) are associated with increased and decreased LDL-C concentrations, respectively.…”

Section: Introductionmentioning

confidence: 99%

A Genetic Approach to the Association Between PCSK9 and Sepsis

et al. 2019

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Key PointsQuestionIn patients admitted to the hospital with serious infection, is there a significant association between PCSK9 genetic variation and risk of sepsis?FindingsIn this cohort study of 10 922 patients, the risk of sepsis was not significantly associated with PCSK9 functional variants, PCSK9 genetic risk score, or genetic estimation of PCSK9 expression levels.MeaningThese findings suggest that PCSK9 genetic variations are not significantly associated with the risk of sepsis in patients hospitalized with infection.

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“…Thus, it is vital to enhance the LDLR expression in hepatocytes, prompt LPS endocytosis, and lysosomal degradation, and avoid triggering the inflammatory response through TLRs (Harris and others ; dos Santos and others ). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a central regulatory molecule which could reduce LDLR expression in the surface of hepatocytes by promoting LDLR‐PCSK9 compound internalization and degradation (Abifadel and others ; Bray ). PCSK9 inhibitor was recently reported not only to act as a hyperlipidemia therapy, but also to play an important role in pathogen lipid (LPS) clearance (Walley and others ).The aim of the current study was to investigate the anti‐ETM effect of curcumin on tetrachloride (CCl 4 )‐induced liver cirrhosis in rats by targeting PCSK9.…”

Section: Introductionmentioning

confidence: 99%

Curcumin Protects Against Intestinal Origin Endotoxemia in Rat Liver Cirrhosis by Targeting PCSK9

Cai

Zou

et al. 2017

Journal of Food Science

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Intestinal origin endotoxemia always occurs in severe liver injury. The aim of the current study was to test antiendotoxemia effect of curcumin on tetrachloride (CCl )-induced liver cirrhosis rats, and to elucidate the underlying molecular mechanism. Rat cirrhosis models were constructed with CCl subcutaneous injections with curcumin (200 mg/kg/d) administered via gavages for 12 wk until the rats were sacrificed. We found that the administration of curcumin improved the physiological condition pertaining to activity index and temperature, and ameliorated the liver injury in CCl -induced cirrhosis rats. Enzyme-linked immunosorbent assay (ELISA) and real-time quantitative polymerase chain reaction (qRT-PCR) showed that curcumin could reduce c-reaction protein levels and inflammatory cytokine (TNF-α, IL-1β, IL-6, and CINC-1/IL-8) concentrations in peripheral serum and liver tissue. Furthermore, curcumin treatment decreased lipopolysaccharide (LPS) levels in peripheral vein, but not in portal vein. As low-density lipoprotein receptor (LDLR) is the important receptor on the surface of hepatocyte during LPS detoxification process, we used qRT-PCR, western blot, and immunohistochemistry (IHC), finding that curcumin significantly increased LDLR protein levels, but not gene levels in the liver tissues. We also tested proprotein convertase subtilisin/kexin type 9 (PCSK9), one negative regulator of LDLR, by qRT-PCR, western blot, and IHC. The results showed that PCSK9 significantly decreased both gene and protein levels in the rat liver tissues of curcumin treatment. Thus, we concluded that curcumin could function to protect against intestinal origin endotoxemia by inhibiting PCSK9 to promote LDLR expression, thereby enhancing LPS detoxification as one pathogen lipid through LDLR in the liver.

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PCSK9 blockade helps clear pathogenic lipids

Cited by 5 publications

References 1 publication

Lipopolysaccharide Is Cleared from the Circulation by Hepatocytes via the Low Density Lipoprotein Receptor

Lipopolysaccharide Is Cleared from the Circulation by Hepatocytes via the Low Density Lipoprotein Receptor

A Genetic Approach to the Association Between PCSK9 and Sepsis

Curcumin Protects Against Intestinal Origin Endotoxemia in Rat Liver Cirrhosis by Targeting PCSK9

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