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

Cardiovasc Res. 2016 May 15;110(2):268-78. doi: 10.1093/cvr/cvw053. Epub 2016 Mar 15.


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 µm(2) in apoE⁻/⁻) but not in the absence of LDLR. Additionally, hPCSK9 accumulated in the atheroma and increased lesion Ly6C(hi) 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.

Keywords: Atherosclerosis; Hepatocytes; Lipoproteins; Murine models; PCSK9.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apolipoproteins E / genetics
  • Atherosclerosis / metabolism*
  • Cholesterol, LDL / metabolism
  • Hepatocytes / metabolism*
  • Humans
  • Lipogenesis / physiology*
  • Liver / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Proprotein Convertase 9 / genetics
  • Proprotein Convertase 9 / metabolism*
  • Receptors, LDL / metabolism
  • Triglycerides / metabolism


  • Apolipoproteins E
  • Cholesterol, LDL
  • Receptors, LDL
  • Triglycerides
  • PCSK9 protein, human
  • Pcsk9 protein, mouse
  • Proprotein Convertase 9