Janus kinase activation by cytokine oncostatin M decreases PCSK9 expression in liver cells

Aiqin Cao,Minhao Wu,Hai Li,Jingwen Liu

doi:10.1194/jlr.m010603

Aiqin Cao, Minhao Wu + Show 2 more

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https://doi.org/10.1194/jlr.m010603

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Abstract

PCSK9 degrades LDL receptor (LDLR) in liver and thereby influences the circulating level of LDL cholesterol. Hence, mechanisms inhibiting PCSK9 expression have potential for cholesterol-lowering intervention. Previously, we demonstrated that oncostatin M (OM) activates LDLR gene transcription, resulting in an increased LDL uptake in HepG2 cells and a reduction of plasma LDL in hypercholesterolemic hamsters. Here we identify the suppression of PCSK9 expression by OM as one new mechanism that increases LDLR protein in HepG2 cells. Treating HepG2 cells with OM decreases PCSK9 mRNA and protein levels. Inhibition studies and small interfering RNA -targeted depletion revealed a critical role for JAK1 and JAK2 in mediating this OM inhibitory effect. Furthermore, we showed that OM induces transient phosphorylation of STAT1, STAT3, and STAT5 and sustained activation of ERK signaling molecules. While depletion of STAT members in HepG2 cells did not affect OM inhibitory activity on PCSK9 expression, blocking activation of the MEK1/ERK signaling pathway resulted in attenuation of the OM inhibitory effect. Finally, by using an anti-hamster PCSK9 antibody, we demonstrated the in vivo suppression of liver PCSK9 mRNA and protein expression by OM in hypercholesterolemic hamsters. Our study uncovered a cytokine-triggered regulatory network for PCSK9 expression that is linked to JAKs and the ERK signaling pathway.

Highlights

proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades LDL receptor (LDLR) in liver and thereby influences the circulating level of LDL cholesterol
We further showed that the MEK1/ERK signaling pathway downstream of Janus kinase (JAK) is involved in transmitting the oncostatin M (OM) signal that leads to the suppression of PCSK9 expression
To explore the possibility that PCSK9 has a role in OMmediated upregulation of LDLR, we first conducted a kinetics study to examine the time-dependent effect of OM on the expression of PCSK9 and LDLR mRNA by real-time RT-PCR (Fig. 1A)

Summary

Introduction

PCSK9 degrades LDL receptor (LDLR) in liver and thereby influences the circulating level of LDL cholesterol. We demonstrated that oncostatin M (OM) activates LDLR gene transcription, resulting in an increased LDL uptake in HepG2 cells and a reduction of plasma LDL in hypercholesterolemic hamsters. We identify the suppression of PCSK9 expression by OM as one new mechanism that increases LDLR protein in HepG2 cells. While depletion of STAT members in HepG2 cells did not affect OM inhibitory activity on PCSK9 expression, blocking activation of the MEK1/ERK signaling pathway resulted in attenuation of the OM inhibitory effect. Recent studies have identified proprotein convertase subtilisin/kexin type 9 (PCSK9) as a critical new player in the control of plasma LDL cholesterol (LDL-C) levels through its role in mediating the posttranslational degra-. The second transactivator identified for PCSK9 gene transcription is hepatic nuclear factor 1a (HNF1a), which is abundantly expressed in liver.

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