Human PCSK9 promotes hepatic lipogenesis and atherosclerosis development via apoE-and LDLR-mediated mechanisms

Hagai Tavori, Ilaria Giunzioni, Irene M. Predazzi, Deanna Plubell, Anna Shivinsky, Joshua Miles, Rachel M. DeVay, Hong Liang, Shirya Rashid, Mac Rae F Linton, Sergio Fazio

    Research output: Research - peer-reviewArticle

    • 8 Citations

    Abstract

    Aims Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of hepatic low-density lipoprotein (LDL) receptors (LDLR), thereby, decreasing hepatocyte LDL-cholesterol (LDL-C) uptake. However, it is unknown whether PCSK9 has effects on atherogenesis that are independent of lipid changes. The present study investigated the effect of human (h) PCSK9 on plasma lipids, hepatic lipogenesis, and atherosclerotic lesion size and composition in transgenic mice expressing hPCSK9 (hPCSK9tg) on wild-type (WT), LDLR-/-, or apoE-/- background. Methods and results hPCSK9 expression significantly increased plasma cholesterol (+91%), triglycerides (+18%), and apoB (+57%) levels only in WT mice. The increase in plasma lipids was a consequence of both decreased hepatic LDLR and increased hepatic lipid production, mediated transcriptionally and post-transcriptionally by PCSK9 and dependent on both LDLR and apoE. Despite the lack of changes in plasma lipids in mice expressing hPCSK9 and lacking LDLR (the main target for PCSK9) or apoE (a canonical ligand for the LDLR), hPCSK9 expression increased aortic lesion size in the absence of apoE (268 655 ± 97 972 μm2 in hPCSK9tg/apoE-/- vs. 189 423 ± 65 700 μm2 in apoE-/-) but not in the absence of LDLR. Additionally, hPCSK9 accumulated in the atheroma and increased lesion Ly6Chi monocytes (by 21%) in apoE-/- mice, but not in LDLR-/- mice. Conclusions PCSK9 increases hepatic lipid and lipoprotein production via apoE-and LDLR-dependent mechanisms. However, hPCSK9 also accumulate in the artery wall and directly affects atherosclerosis lesion size and composition independently of such plasma lipid and lipoprotein changes. These effects of hPCSK9 are dependent on LDLR but are independent of apoE.

    LanguageEnglish (US)
    Pages268-278
    Number of pages11
    JournalCardiovascular Research
    Volume110
    Issue number2
    DOIs
    StatePublished - May 15 2016

    Fingerprint

    Low Density Lipoprotein Receptor-Related Protein-1
    Lipogenesis
    LDL Receptors
    Atherosclerosis
    Liver
    human PCSK9 protein
    Apolipoproteins E
    Lipids
    Proprotein Convertase 9
    Lipoproteins
    Apolipoproteins B
    Atherosclerotic Plaques
    LDL Cholesterol
    Transgenic Mice
    Monocytes
    Hepatocytes
    Triglycerides
    Arteries
    Cholesterol
    Ligands

    Keywords

    • Atherosclerosis
    • Hepatocytes
    • Lipoproteins
    • Murine models
    • PCSK9

    ASJC Scopus subject areas

    • Cardiology and Cardiovascular Medicine
    • Physiology (medical)
    • Physiology

    Cite this

    Human PCSK9 promotes hepatic lipogenesis and atherosclerosis development via apoE-and LDLR-mediated mechanisms. / Tavori, Hagai; Giunzioni, Ilaria; Predazzi, Irene M.; Plubell, Deanna; Shivinsky, Anna; Miles, Joshua; DeVay, Rachel M.; Liang, Hong; Rashid, Shirya; Linton, Mac Rae F; Fazio, Sergio.

    In: Cardiovascular Research, Vol. 110, No. 2, 15.05.2016, p. 268-278.

    Research output: Research - peer-reviewArticle

    Tavori, H, Giunzioni, I, Predazzi, IM, Plubell, D, Shivinsky, A, Miles, J, DeVay, RM, Liang, H, Rashid, S, Linton, MRF & Fazio, S 2016, 'Human PCSK9 promotes hepatic lipogenesis and atherosclerosis development via apoE-and LDLR-mediated mechanisms' Cardiovascular Research, vol 110, no. 2, pp. 268-278. DOI: 10.1093/cvr/cvw053
    Tavori H, Giunzioni I, Predazzi IM, Plubell D, Shivinsky A, Miles J et al. Human PCSK9 promotes hepatic lipogenesis and atherosclerosis development via apoE-and LDLR-mediated mechanisms. Cardiovascular Research. 2016 May 15;110(2):268-278. Available from, DOI: 10.1093/cvr/cvw053
    Tavori, Hagai ; Giunzioni, Ilaria ; Predazzi, Irene M. ; Plubell, Deanna ; Shivinsky, Anna ; Miles, Joshua ; DeVay, Rachel M. ; Liang, Hong ; Rashid, Shirya ; Linton, Mac Rae F ; Fazio, Sergio. / Human PCSK9 promotes hepatic lipogenesis and atherosclerosis development via apoE-and LDLR-mediated mechanisms. In: Cardiovascular Research. 2016 ; Vol. 110, No. 2. pp. 268-278
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    author = "Hagai Tavori and Ilaria Giunzioni and Predazzi, {Irene M.} and Deanna Plubell and Anna Shivinsky and Joshua Miles and DeVay, {Rachel M.} and Hong Liang and Shirya Rashid and Linton, {Mac Rae F} and Sergio Fazio",
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    T1 - Human PCSK9 promotes hepatic lipogenesis and atherosclerosis development via apoE-and LDLR-mediated mechanisms

    AU - Tavori,Hagai

    AU - Giunzioni,Ilaria

    AU - Predazzi,Irene M.

    AU - Plubell,Deanna

    AU - Shivinsky,Anna

    AU - Miles,Joshua

    AU - DeVay,Rachel M.

    AU - Liang,Hong

    AU - Rashid,Shirya

    AU - Linton,Mac Rae F

    AU - Fazio,Sergio

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    N2 - Aims Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of hepatic low-density lipoprotein (LDL) receptors (LDLR), thereby, decreasing hepatocyte LDL-cholesterol (LDL-C) uptake. However, it is unknown whether PCSK9 has effects on atherogenesis that are independent of lipid changes. The present study investigated the effect of human (h) PCSK9 on plasma lipids, hepatic lipogenesis, and atherosclerotic lesion size and composition in transgenic mice expressing hPCSK9 (hPCSK9tg) on wild-type (WT), LDLR-/-, or apoE-/- background. Methods and results hPCSK9 expression significantly increased plasma cholesterol (+91%), triglycerides (+18%), and apoB (+57%) levels only in WT mice. The increase in plasma lipids was a consequence of both decreased hepatic LDLR and increased hepatic lipid production, mediated transcriptionally and post-transcriptionally by PCSK9 and dependent on both LDLR and apoE. Despite the lack of changes in plasma lipids in mice expressing hPCSK9 and lacking LDLR (the main target for PCSK9) or apoE (a canonical ligand for the LDLR), hPCSK9 expression increased aortic lesion size in the absence of apoE (268 655 ± 97 972 μm2 in hPCSK9tg/apoE-/- vs. 189 423 ± 65 700 μm2 in apoE-/-) but not in the absence of LDLR. Additionally, hPCSK9 accumulated in the atheroma and increased lesion Ly6Chi monocytes (by 21%) in apoE-/- mice, but not in LDLR-/- mice. Conclusions PCSK9 increases hepatic lipid and lipoprotein production via apoE-and LDLR-dependent mechanisms. However, hPCSK9 also accumulate in the artery wall and directly affects atherosclerosis lesion size and composition independently of such plasma lipid and lipoprotein changes. These effects of hPCSK9 are dependent on LDLR but are independent of apoE.

    AB - Aims Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of hepatic low-density lipoprotein (LDL) receptors (LDLR), thereby, decreasing hepatocyte LDL-cholesterol (LDL-C) uptake. However, it is unknown whether PCSK9 has effects on atherogenesis that are independent of lipid changes. The present study investigated the effect of human (h) PCSK9 on plasma lipids, hepatic lipogenesis, and atherosclerotic lesion size and composition in transgenic mice expressing hPCSK9 (hPCSK9tg) on wild-type (WT), LDLR-/-, or apoE-/- background. Methods and results hPCSK9 expression significantly increased plasma cholesterol (+91%), triglycerides (+18%), and apoB (+57%) levels only in WT mice. The increase in plasma lipids was a consequence of both decreased hepatic LDLR and increased hepatic lipid production, mediated transcriptionally and post-transcriptionally by PCSK9 and dependent on both LDLR and apoE. Despite the lack of changes in plasma lipids in mice expressing hPCSK9 and lacking LDLR (the main target for PCSK9) or apoE (a canonical ligand for the LDLR), hPCSK9 expression increased aortic lesion size in the absence of apoE (268 655 ± 97 972 μm2 in hPCSK9tg/apoE-/- vs. 189 423 ± 65 700 μm2 in apoE-/-) but not in the absence of LDLR. Additionally, hPCSK9 accumulated in the atheroma and increased lesion Ly6Chi monocytes (by 21%) in apoE-/- mice, but not in LDLR-/- mice. Conclusions PCSK9 increases hepatic lipid and lipoprotein production via apoE-and LDLR-dependent mechanisms. However, hPCSK9 also accumulate in the artery wall and directly affects atherosclerosis lesion size and composition independently of such plasma lipid and lipoprotein changes. These effects of hPCSK9 are dependent on LDLR but are independent of apoE.

    KW - Atherosclerosis

    KW - Hepatocytes

    KW - Lipoproteins

    KW - Murine models

    KW - PCSK9

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