Myeloid-specific Acat1 Ablation Attenuates Inflammatory Responses in Macrophages, Improves Insulin Sensitivity, and Suppresses Diet-induced Obesity

Macrophages are phagocytes that play important roles in health and diseases. Acyl-CoA:cholesterol acyltransferase 1 (ACAT1) converts cellular cholesterol to cholesteryl esters and is expressed in many cell types. Unlike global Acat1 knockout (KO), myeloid-specific Acat1 KO ( Acat1) does not cause overt abnormalities in mice. Here, we performed analyses in age- and sex-matched Acat1 and wild-type mice on chow or Western diet and discovered that Acat1 mice exhibit resistance to Western diet-induced obesity. On both chow and Western diets, Acat1 mice display decreased adipocyte size and increased insulin sensitivity. When fed with Western diet, Acat1 mice contain fewer infiltrating macrophages in white adipose tissue (WAT), with significantly diminished inflammatory phenotype. Without Acat1, the Ly6C monocytes express reduced levels of integrin-β, which plays a key role in the interaction between monocytes and the inflamed endothelium. Adoptive transfer experiment showed that the appearance of leukocytes from Acat1 mice to the inflamed WAT of wild-type mice is significantly diminished. Under Western diet, Acat1 causes suppression of multiple proinflammatory genes in WAT. Cell culture experiments show that in RAW 264.7 macrophages, inhibiting ACAT1 with a small-molecule ACAT1-specific inhibitor reduces inflammatory responses to lipopolysaccharide. We conclude that under Western diet, blocking ACAT1 in macrophages attenuates inflammation in WAT. Other results show that Acat1 does not compromise antiviral immune response. Our work reveals that blocking ACAT1 suppresses diet-induced obesity in part by slowing down monocyte infiltration to WAT as well as by reducing the inflammatory responses of adipose tissue macrophages.