From Genetic Findings to new Intestinal Molecular Targets in Lipid Metabolism

While lipid-lowering therapies demonstrate efficacy, many patients still contend with significant residual risk of atherosclerotic cardiovascular diseases (ASCVD). The intestine plays a pivotal role in regulating circulating lipoproteins levels, thereby exerting influence on ASCVD pathogenesis. This review underscores recent genetic findings from the last six years that delineate new biological pathways and actors in the intestine which regulate lipid-related ASCVD risk.

Specifically, we detail the role of LIMA1 in cholesterol absorption within enterocytes, the function of PLA2G12B in the expansion and lipidation of chylomicrons, the involvement of SURF4 in lipoprotein secretion, and the discovery of a gut-derived hormone named CHOLESIN that modulates cholesterol homeostasis through GPR146 via a gut-liver crosstalk. We further discuss the potential of these newly identified genes and pathways as novel targets for pharmaceutical intervention. Newly identified genetic and intestinal molecular mechanisms offer promising opportunities for preventing and treating ASCVD, but careful evaluation and further research are needed to optimize their clinical application.