bioRxiv : the preprint server for biology · 2026
The COPI coatomer influences LDL receptor activity, hepatic lipid storage, and apoB secretion.
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Panteloglou Grigorios, Robert Jérôme, Smit Marieke, Huijkman Nicolette, Kloosterhuis Niels, Law Christopher S, Woods Brian, Othman Alaa, Kleber Marcus E, Delgado Graciela E, Tarugi Patrizia, Lone Museer A, Wolters Justina Clarinda, Rimbert Antoine, Kerksiek Anja, Lütjohann Dieter, Rohrer Lucia, Zanoni Paolo, Kakava Sofia, Häusler Stephanie, Schlumpf Eveline, Futema Marta, Humphries Steve E, Chou Janet, März Winfried, Geha Raif S, Shum Anthony K, Kuivenhoven Jan Albert, van de Sluis Bart, von Eckardstein Arnold
Аннотация
BACKGROUND: Decreased hepatic removal of low density lipoproteins (LDL) and increased apolipoprotein B (apoB) production cause hypercholesterolemia, a major causal risk factor of atherosclerotic cardiovascular disease (ASCVD). By a genome-wide siRNA screen, we previously identified subunits of the Coat protein I (COPI) complex to limit LDL uptake into Huh-7 hepatocarcinoma cells.
METHODS: These findings were validated by targeted in vitro experiments as well as genetic association studies in humans and three mouse models with mutated or disrupted COPI genes.
RESULTS: Silencing of COPA, COPB1, COPB2, ARCN1, COPG1, and COPZ1 in Huh-7 cells resulted in decreased uptake of LDL and aberrant glycosylation and altered cell surface abundance of the LDL receptor (LDLR) as well as increased apoB secretion and cellular lipid storage. Single nucleotide polymorphisms of ARCN1 were associated with lower ARCN1 expression and higher levels of LDL-cholesterol (LDL-C). Rare variants of COPA and COPG1 were enriched among patients with LDL-C > 5 mmol/L. Patients and mice carrying other rare immunopathogenic missense variants of COPA and COPG1 did not present with elevated plasma levels of LDL-C, while hepatic knockdown of murine Copg1 increased the concentrations of non-HDL-cholesterol in plasma and triglycerides in the liver.
CONCLUSIONS: The COPI coatomer regulates LDLR activity and apoB secretion as well as lipid content of liver cells. Loss of function of some variants of COPI genes are associated with higher LDL-C levels.
METHODS: These findings were validated by targeted in vitro experiments as well as genetic association studies in humans and three mouse models with mutated or disrupted COPI genes.
RESULTS: Silencing of COPA, COPB1, COPB2, ARCN1, COPG1, and COPZ1 in Huh-7 cells resulted in decreased uptake of LDL and aberrant glycosylation and altered cell surface abundance of the LDL receptor (LDLR) as well as increased apoB secretion and cellular lipid storage. Single nucleotide polymorphisms of ARCN1 were associated with lower ARCN1 expression and higher levels of LDL-cholesterol (LDL-C). Rare variants of COPA and COPG1 were enriched among patients with LDL-C > 5 mmol/L. Patients and mice carrying other rare immunopathogenic missense variants of COPA and COPG1 did not present with elevated plasma levels of LDL-C, while hepatic knockdown of murine Copg1 increased the concentrations of non-HDL-cholesterol in plasma and triglycerides in the liver.
CONCLUSIONS: The COPI coatomer regulates LDLR activity and apoB secretion as well as lipid content of liver cells. Loss of function of some variants of COPI genes are associated with higher LDL-C levels.