In this report, we provide the first evidence demonstrating that global Ces1/Ces1g inactivation markedly attenuates the development of atherosclerosis by reducing intestinal cholesterol absorption, promoting macrophage cholesterol efflux and M2 macrophage polarization, and inducing bile acid synthesis (Fig. 8F) whereas loss of hepatic Ces1/Ces1g aggravates the development of atherosclerosis. Here, CES1 is linked to atherosclerosis.