A Druggable G Protein Checkpoint in Cholesterol Efflux

Immunometabolic diseases such as obesity, fatty liver, and atherosclerosis arise when lipid-associated macrophages (LAMs) fail to clear excess lipids. Reverse cholesterol transport (RCT), the bodys sole macrophage-to-feces lipid-clearance pathway, remains therapeutically inaccessible. By integrating systems modeling with human plaque transcriptomes, we identify LAM subpopulations that drive plaque progression and nominate GIV (CCDC88A) as a molecular brake on RCT. Myeloid-specific GIV deletion reduces aortic plaque burden, mobilizes hepatic and adipose lipids, and restores systemic RCT. Mechanistically, GIV traps the efflux transporter ABCA1 in endomembranes and activates Gi[bullet]{beta}{gamma} to suppress cAMP/PKA-CREB signaling, silencing ABCA1 activity. Genetic or pharmacologic disruption of this checkpoint releases ABCA1 to the membrane, reactivating efflux and reprogramming LAMs toward an anti-atherogenic state. In murine and human plaque-in-a-dish models, targeting the GIV[bullet]Gi-cAMP checkpoint restored efflux where statins and {beta}-blockers failed, reducing modeled plaque-progression risk by [~]98%. Findings establish RCT-restoration as a druggable, macrophage-intrinsic therapeutic paradigm for immunometabolic disease. GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/705962v1_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@1b1c85org.highwire.dtl.DTLVardef@1ed9f6aorg.highwire.dtl.DTLVardef@17d153forg.highwire.dtl.DTLVardef@fdf47b_HPS_FORMAT_FIGEXP M_FIG C_FIG eTOC blurbLipid-associated macrophages drive immunometabolic disease. Katkar et al. show that disabling a GIV-dependent G-protein brake restores cholesterol efflux, reverses plaque lipid accumulation, and establishes reverse cholesterol transport as a druggable therapeutic axis. HighlightsO_LIStatins slow but rarely reverse plaque burden, leaving residual risk driven by LAM dysfunction C_LIO_LIGIV (CCDC88A) non-canonically modulates Gi to suppress macrophage cholesterol efflux C_LIO_LIGIV loss or inhibition restores ABCA1 activity via transcriptional and post-translational control C_LIO_LIBlocking the GIV[bullet]Gi checkpoint defats LAMs, regresses plaques, and relieves systemic lipid overload C_LIO_LIIdentifies a druggable node that redefines RCT restoration as a therapeutic paradigm in immunometabolic disease C_LI