Diagnosing Resistance to a Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor

Shapiro, Michael D.; Miles, Joshua; Tavori, Hagai; Fazio, Sergio

doi:10.7326/m17-2485

Cited by 41 publications

(34 citation statements)

References 4 publications

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“…Interestingly, recent studies have demonstrated that FDA-approved monoclonal antibodies targeted against the LDLR-binding domain of circulating PCSK9 increase its concentrations 7-fold as a result of antagonizing LDLRmediated clearance. 41 Given that it is likely that the domain utilized by PCSK9 to interact with CD36 differs from its LDLRbinding domain, 18 it remains possible and even likely that such antibodies may also reduce CD36 expression as a byproduct of increasing the circulating pool of PCSK9. Additional studies, however, are required to answer this important question and to determine whether anti-PCSK9 antibodies could be utilized to protect against CD36-driven diseases like NAFLD and NASH.…”

Section: Discussionmentioning

confidence: 99%

Pcsk9 knockout exacerbates diet-induced non-alcoholic steatohepatitis, fibrosis and liver injury in mice

et al. 2019

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Background & Aims: The fatty acid translocase, also known as CD36, is a well-established scavenger receptor for fatty acid (FA) uptake and is abundantly expressed in many metabolically active tissues. In the liver, CD36 is known to contribute to the progression of non-alcoholic fatty liver disease and to the more severe non-alcoholic steatohepatitis, by promoting triglyceride accumulation and subsequent lipid-induced endoplasmic reticulum (ER) stress. Given the recent discovery that the hepatocyte-secreted proprotein convertase subtilisin/kexin type 9 (PCSK9) blocks CD36 expression, we sought to investigate the role of PCSK9 in liver fat accumulation and injury in response to saturated FAs and in a mouse model of diet-induced hepatic steatosis. Methods: In this study, we investigated the role of PCSK9 on the uptake and accumulation of FAs, as well as FA-induced toxicity, in a variety of cultured hepatocytes. Diet-induced hepatic steatosis and liver injury were also assessed in Pcsk9-/mice. Results: Our results indicate that PCSK9 deficiency in cultured hepatocytes increased the uptake and accumulation of saturated and unsaturated FAs. In the presence of saturated FAs, PCSK9 also protected cultured hepatocytes from ER stress and cytotoxicity. In line with these findings, a metabolic challenge using a high-fat diet caused severe hepatic steatosis, ER stress inflammation and fibrosis in the livers of Pcsk9-/mice compared to controls. Given that inhibition of CD36 ablated the observed accumulation of lipid in vitro and in vivo, our findings also highlight CD36 as a strong contributor to steatosis and liver injury in the context of PCSK9 deficiency. Conclusions: Collectively, our findings demonstrate that PCSK9 regulates hepatic triglyceride content in a manner dependent on CD36. In the presence of excess dietary fats, PCSK9 can also protect against hepatic steatosis and liver injury.

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Section: Discussionmentioning

confidence: 99%

Pcsk9 knockout exacerbates diet-induced non-alcoholic steatohepatitis, fibrosis and liver injury in mice

et al. 2019

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“…As discussed earlier, the measurement of total plasma PCSK9 concentration is not likely to be useful in risk prediction models. However, we recently proposed that measurement of total plasma PCSK9 levels in patients on PCSK9 inhibitor therapy may become useful as a diagnostic tool 115 . We demonstrated that patients treated with PCSK9 mAb exhibit an ~7-fold increase in total plasma PCSK9 levels relative to pretreatment levels.…”

Section: Therapeutic Approaches To Inhibit Pcsk9 and Lower Plasma Lipidsmentioning

confidence: 99%

Pcsk9

Shapiro

Tavori

Fazio

2018

Circulation Research

Self Cite

221

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Unknown 15 years ago, PCSK9 (proprotein convertase subtilisin/kexin type 9) is now common parlance among scientists and clinicians interested in prevention and treatment of atherosclerotic cardiovascular disease. What makes this story so special is not its recent discovery nor the fact that it uncovered previously unknown biology but rather that these important scientific insights have been translated into an effective medical therapy in record time. Indeed, the translation of this discovery to novel therapeutic serves as one of the best examples of how genetic insights can be leveraged into intelligent target drug discovery. The PCSK9 saga is unfolding quickly but is far from complete. Here, we review major scientific understandings as they relate to the role of PCSK9 in lipoprotein metabolism and atherosclerotic cardiovascular disease and the impact that therapies designed to inhibit its action are having in the clinical setting.

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“…The induction of increase PCSK9 levels after immunogen treatment was observed in humans treated with monoclonal antibodies (Alirocumab or Evolocumab). The changes in plasma PCSK9 levels varied from no change to a more than 20-fold increase, compared with before treatment [ 19 ]. This observation is most likely caused by the delay clearance of the PCSK9-immune complex by immune cells.…”

Section: Resultsmentioning

confidence: 99%

Non-Native Conformational Isomers of the Catalytic Domain of PCSK9 Induce an Immune Response, Reduce Lipids and Increase LDL Receptor Levels

Jiang

Nischal

Sun

et al. 2018

IJMS

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PCSK9 (Proprotein convertase subtilisin/kexin type 9) increases plasma cholesterol levels by promoting LDL receptor degradation. Current antibody inhibitors block the interaction between PCSK9 and LDL receptors, significantly decrease plasma cholesterol levels, and provide beneficial clinical outcomes. To reduce the action of PCSK9 in plasma, a novel strategy that will produce a panel of non-native, conformationally-altered isomers of PCSK9 (X-PCSK9) to develop active immunotherapy targeting of native PCSK9 and inhibiting/blocking the interaction of PCSK9 with LDL receptor, thus decreasing plasma cholesterol levels is proposed. The authors used the scrambled disulfide bond technique to generate conformationally-altered isomers of the catalytic domain of mouse PCSK9. The focus was on the immune response of four X-isomers and their effects on plasma cholesterol and triglyceride levels in both C57BL/6J and Apoe−/− mice. The authors showed that the four immunogens produced significant immunogenicity against native PCSK9 to day 120 after immunization of C57BL/6J and Apoe−/− mice. This resulted in significantly decreased plasma cholesterol levels in C57BL/6J mice, and to a lesser degree in Apoe−/− mice. The X-PCSK9-B1 treated mice had increased LDL receptor mRNA and protein levels at day 120 after treatment. Thus, this study provides a new, potentially promising approach that uses long-term immunotherapy for a treatment of hypercholesterolemia.

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Diagnosing Resistance to a Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor

Cited by 41 publications

References 4 publications

Pcsk9 knockout exacerbates diet-induced non-alcoholic steatohepatitis, fibrosis and liver injury in mice

Pcsk9 knockout exacerbates diet-induced non-alcoholic steatohepatitis, fibrosis and liver injury in mice

Pcsk9

Non-Native Conformational Isomers of the Catalytic Domain of PCSK9 Induce an Immune Response, Reduce Lipids and Increase LDL Receptor Levels

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