COPI Coatomer Regulates Several Steps of HDL Metabolism
Grigorios Panteloglou, Paolo Zanoni, Christopher S. Law, Brian Woods, Alaa Othman, Mustafa Yalcinkaya, Simon F. Norrelykke, Andrzej J. Rzepiela, Szymon Stoma, Michael Stebler, Anja Kerksiek, Michele Visentin, Marieke Smit, Justina Clarinda Wolters, Sofia Kakava, Anton Potapenko, Eveline Schlumpf, Silvija Radosavljevic, Stephanie Häusler, Marta Futema, Nawar Dalila, Anne Tybjaerg-Hansen, Steve E. Humphries, Jan Albert Kuivenhoven, Bart van de Sluis, Dieter Lütjohann, Roger Meier, Jérôme Robert, Janet Chou, Raif S. Geha, Anthony K. Shum, Lucia Rohrer, Arnold von EckardsteinBACKGROUND:
Reverse cholesterol transport by HDLs (high-density lipoproteins) is considered an antiatherogenic metabolic pathway. Hepatocytes are the main contributors to the efficacy of this pathway by the production of apoA-I (apolipoprotein A1) and its lipidation by ABCA1 (ATP-binding cassette transporter A1), selective uptake of cholesterol via SR-BI (scavenger receptor class B type 1), and uptake of entire HDL particles. The molecular determinants of the latter step are not well understood.
METHODS:
We performed a genome-wide RNA interference screen for genes limiting the uptake of HDL fluorescently labeled at its protein moiety into Huh-7 hepatocarcinoma cells. Top hit genes were validated by targeted in vitro experiments and the analysis of associations between their variants and HDL-C (HDL-cholesterol) levels in the databases of the Global Lipids Genetics Consortium and the UK Biobank, as well as inborn errors of metabolism and their respective mouse models.
RESULTS:
The knockdown of 128 genes significantly inhibited HDL uptake. Six of them encode components of the COPI (coat protein I) coatomer, namely,
CONCLUSIONS:
In hepatocytes, the COPI coatomer regulates HDL holoparticle uptake, selective lipid uptake, apoA-I secretion, and cholesterol efflux, and thereby, it influences plasma levels of HDL-C.