Butyrate acts on the gut-brain neural circuit to improve energy metabolism via reducing energy intake and enhancing fat oxidation by activating BAT.

Objective-The purpose of this study was to evaluate the effect of the combined deletion of ABCA1 and ABCG1 expression in macrophages on foam cell formation and atherosclerosis. Methods and Results-LDL receptor knockout (KO) mice were transplanted with bone marrow from ABCA1/ABCG1 double KO (dKO) mice. Plasma cholesterol levels after 6 weeks of Western-type diet (WTD) feeding were significantly lower in dKO transplanted mice than ABCA1 KO, ABCG1 KO, and control transplanted animals. Extreme foam cell formation was present in macrophages of various tissues and the peritoneal cavity of dKO transplanted animals. Furthermore, severe hypoplasia of the thymus and a significant decrease in CD4-positive T cells in blood was observed. Despite relatively low plasma cholesterol levels dKO transplanted animals developed lesion sizes of 156Ϯ19ϫ10 3 m 2 after only 6 weeks of WTD feeding. Lesions, however, were smaller than single ABCA1 KO transplanted animals (226Ϯ30ϫ10 3 m 2 ; PϽ0.05) and not significantly different from single ABCG1 KO (117Ϯ22ϫ10 3 m 2 ) and WT transplanted mice (112Ϯ15ϫ10 3 m 2 ). Conclusions-Macrophage ABCA1 and ABCG1 play a crucial role in the prevention of macrophage foam cell formation, whereas combined deletion only modestly influences atherosclerosis which is associated with an attenuated increase in WTD-induced plasma cholesterol and decreased proinflammatory CD4-positive T cell counts. Key Words: ABCA1 Ⅲ ABCG1 Ⅲ atherosclerosis Ⅲ macrophage Ⅲ transplantation Ⅲ cholesterol T he transport of excess cholesterol by HDL from macrophages in the periphery back to the liver for catabolism and excretion in bile and feces, called reverse cholesterol transport (RCT), plays an important protective role in the development of atherosclerosis. 1 Several ATP-binding cassette (ABC) transporters have been implicated in macrophage lipid metabolism, RCT, and atherosclerosis. 2,3 The fulltransporter ABCA1 is highly induced in lipid-laden macrophages where it facilitates cellular cholesterol and phospholipid efflux to lipid-poor apoproteins like apoAI or ApoE. 4 As cholesterol efflux from macrophages results in decreased cellular lipid accumulation, macrophage ABCA1 expression has been suggested to protect against atherosclerosis. Information on the critical role of macrophage ABCA1 in lesion formation and progression was provided by bone marrow transplantation studies, using mostly LDL receptor (LDLr) KO mice as recipients with ABCA1 KO mice or ABCA1 overexpressor mice as donors leading to the anticipated induction and inhibition of lesion formation, respectively. [5][6][7] More recently, in macrophages a second ABC-transporter, ABCG1, was identified as a transporter for cholesterol from cells to HDL. 8 -10 Because, similarly to ABCA1, ABCG1 is highly induced in lipid-laden macrophages and able to facilitate efflux of cholesterol from macrophages, 8,9 it was anticipated that ABCG1 would add to the protective function of ABCA1 in lesion formation. This hypothesis was strengthened by data from Kennedy et al who showed th...