Myeloid-specificAcat1ablation attenuates inflammatory responses in macrophages, improves insulin sensitivity, and suppresses diet-induced obesity

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) 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.

Myeloid Acat1/Soat1 KO attenuates pro-inflammatory responses in macrophages and protects against atherosclerosis in a model of advanced lesions

“…For Western blotting analysis, we chose to monitor two proteins: iNOS and COX2. These are two of the nonsecretory proteins in macrophages that are known to respond positively to pro-inflammatory signals, including lipopolysaccharides (41). The results showed that in peritoneal ApoE Ϫ/Ϫ macrophages, loading AcLDL significantly induced iNOS expression; under this condition, inhibiting ACAT1 with K604 significantly attenuated the induced expression of iNOS (Fig.…”

α-Mangostin remodels visceral adipose tissue inflammation to ameliorate age-related metabolic disorders in mice

“…The SVF from eWAT was isolated as previously described [60, 61]. eWAT from each mouse was minced with scissors in KRB buffer.…”

Ulcerative colitis immune cell landscapes and differentially expressed gene signatures determine novel regulators and predict clinical response to biologic therapy

“…In intestinal stem cells, HMGCS2 has a vital role in regulation of cellular differentiation and homeostasis, and its loss could impact barrier renewal and function 50 , 51 . ACAT1 plays an important role in ketone body metabolism and recently was implicated in inflammatory responses in macrophages as well as diet-induced obesity 52 . Another important aspect of altered energy dynamics in intestinal inflammation involves mitochondrial function.…”