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Myeloid-specific Acat1 ablation attenuates inflammatory responses in
macrophages, improves insulin sensitivity, and suppresses diet-induced obesity.

Authors	Huang LH, Melton EM, Li H, Sohn P, Jung D, Tsai CY, Ma T, Sano H, Ha H, Friedline RH, Kim JK, Usherwood E, Chang CC, Chang TY
Submitted By	Submitted Externally on 5/25/2018
Status	Published
Journal	American journal of physiology. Endocrinology and metabolism
Year	2018
Date Published	3/1/2018
Volume : Pages	Not Specified : Not Specified
PubMed Reference	29533741
Abstract	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-M/-M] does not cause overt abnormalities in mice. Here we performed analyses in age and sex matched Acat1-M/-M and wild-type mice on chow or Western diet, and discovered that Acat1-M/-M mice exhibit resistance to Western diet-induced obesity. On both chow and Western diets, Acat1-M/-M mice display decreased adipocyte size and increased insulin sensitivity. When.fed with Western diet, Acat1-M/-M mice contain fewer infiltrating macrophages in white adipose tissue (WAT), with significantly diminished inflammatory phenotype. Without Acat1, the [Ly6Chi] monocytes express reduced levels of integrin beta 1, 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-M/-M mice to the inflamed WAT of WT mice is significantly diminished. Under Western diet, Acat1-M/-M causes suppression of multiple pro-inflammatory 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-M/-M does not compromise anti-viral immune response. Our work reveals that blocking ACAT1-M/-M 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.

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