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The COPI coatomer influences LDL receptor activity, hepatic lipid storage, and apoB secretion

Grigorios Panteloglou1, Jérôme Robert1, Marieke Smit2

  • 1Institute for Clinical Chemistry, University of Zurich and University Hospital Zurich, Zurich, Switzerland.

Biorxiv : the Preprint Server for Biology
|June 12, 2026
PubMed

Insights

The Coat protein I (COPI) complex regulates low-density lipoprotein (LDL) uptake and apolipoprotein B (apoB) secretion in liver cells. Genetic variants in COPI genes are linked to hypercholesterolemia and atherosclerotic cardiovascular disease (ASCVD) risk.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Hypercholesterolemia, a risk factor for atherosclerotic cardiovascular disease (ASCVD), stems from reduced hepatic low-density lipoprotein (LDL) removal and increased apolipoprotein B (apoB) production.
  • A genome-wide siRNA screen identified Coat protein I (COPI) complex subunits as regulators of LDL uptake in liver cells.

Purpose of the Study:

  • To investigate the role of COPI complex subunits in regulating LDL metabolism and their association with hypercholesterolemia.
  • To validate the findings from the siRNA screen through in vitro experiments and genetic studies.

Main Methods:

  • Genome-wide siRNA screen in Huh-7 hepatocarcinoma cells.
  • Targeted in vitro experiments.
  • Genetic association studies in human populations and mouse models.
  • Analysis of single nucleotide polymorphisms (SNPs) and rare variants in COPI genes.
  • Hepatic knockdown of murine Copg1.

Main Results:

  • Silencing of COPI genes (COPA, COPB1, COPB2, ARCN1, COPG1, COPZ1) in Huh-7 cells decreased LDL uptake, altered LDL receptor (LDLR) glycosylation and cell surface abundance, increased apoB secretion, and enhanced cellular lipid storage.
  • ARCN1 SNPs correlated with reduced ARCN1 expression and elevated LDL-cholesterol (LDL-C).
  • Rare variants in COPA and COPG1 were enriched in patients with high LDL-C (> 5 mmol/L).
  • Hepatic knockdown of Copg1 in mice increased non-HDL-cholesterol and liver triglycerides.

Conclusions:

  • The COPI coatomer complex plays a crucial role in regulating LDLR activity, apoB secretion, and hepatic lipid metabolism.
  • Loss-of-function variants in COPI genes are associated with increased LDL-C levels and may contribute to hypercholesterolemia and ASCVD risk.
Abstract

Keywords:
ARCN1COPACOPG1LDLLDL-receptorapolipoprotein B

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