A Druggable G Protein Checkpoint in Cholesterol Efflux

SUMMARY Immunometabolic diseases such as obesity, fatty liver, and atherosclerosis arise when lipid-associated macrophages (LAMs) fail to resolve lipid overload via reverse cholesterol transport (RCT), the body’s sole pathway for lipid disposal. How RCT is restrained in disease remains unknown. Integrating systems modeling with human plaque transcriptomes, we identify LAM subpopulations associated with plaque progression and uncover CCDC88A (GIV) as a macrophage-intrinsic checkpoint on RCT. Myeloid-specific GIV deletion in mice reduces aortic plaque burden, mobilizes hepatic and adipose lipid stores and promotes fecal sterol disposal. Mechanistically, GIV sequesters the cholesterol transporter ABCA1 within endomembranes and activates Gαi●βγ signaling to suppress cAMP/PKA–CREB-dependent efflux programs. Pharmacogenomic disruption of this checkpoint reactivates efflux programs. In human plaque-in-a-dish models targeting this pathway restored efflux where statins and β-blockers failed, translating to an estimated ∼98% reduction in plaque-progression risk in outcome modeling. Thus, RCT-restoration represents a macrophage-intrinsic therapeutic paradigm for immunometabolic disease. GRAPHIC ABSTRACT eTOC blurb Lipid-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. Highlights Statins slow but rarely reverse plaque burden, leaving residual risk driven by LAM dysfunction GIV (CCDC88A) non-canonically modulates Gαi to suppress macrophage cholesterol efflux GIV loss or inhibition restores ABCA1 activity via transcriptional and post-translational control Blocking GIV●Gαi checkpoint defats LAMs, regresses plaques, and relieves systemic lipid overload SIdentifies a druggable node that redefines RCT restoration as a therapeutic paradigm in immunometabolic disease