Butyrate protects against high‐fat diet‐induced atherosclerosis via up‐regulating ABCA1 expression in apolipoprotein E‐deficiency mice

Abstract

Background and Purpose The gut microbial metabolite butyrate is linked to the modulation of metabolic disease. The mechanism by which butyrate effects in atherosclerosis is unknown. Hence, the present investigation into effects of butyrate on high‐fat diet‐fed ApoE−/− mice after 16 weeks' administration. Experimental Approach Gut microbiota composition was analysed via 16S rRNA gene sequencing of caecal contents. The effects of butyrate on atherosclerosis were evaluated in vivo using the ApoE−/− mice model. Serum lipids and glucose were analysed for physiological changes and differentially expressed genes in liver samples were identified by hepatic transcriptome profiling. The proteins involved in reverse cholesterol transport were quantified by Western blot and immunohistochemical staining. Finally, the up‐regulatory effects of butyrate on ATP‐binding cassette sub‐family A member 1 (ABCA1) were further evaluated in RAW 264.7 cells along with role of specificity protein 1 by inhibition and silencing. Key Results Oral gavage of butyrate altered microbiota composition and enhanced gut microbial diversity that was decreased by high fat diet (HFD). Butyrate treatment significantly inhibited the HFD‐induced atherosclerosis as well as hepatic steatosis without changing body weight gain in ApoE−/− mice. Butyrate had metabolic effects on the liver by regulation of gene expression involved in lipid/glucose metabolism. Furthermore, ABCA1 was significantly induced by butyrate in vivo, ex vivo and in vitro and Sp1 pathway was identified as a potential mechanism. Conclusion and Implications Butyrate ameliorates HFD‐induced atherosclerosis in ApoE−/− mice via ABCA1‐mediated cholesterol efflux in macrophages, which suggesting a promising therapeutic strategy for protecting against atherosclerosis.

Implication of Gut Microbiota in Cardiovascular Diseases

“…Kasahara and his colleagues demonstrated that Roseburia intestinalis is capable of ameliorating atherosclerosis by shaping gene expression, enhancing fatty acid metabolism, and reducing the inflammatory response [ 77 ]. However, treatment with butyrate markedly mitigates the formation of atherosclerotic plaques via the upregulation of ABCA1 and subsequent cholesterol efflux [ 78 ]. In contrast, the production of TMAO by gut microbiota yields negative effects on atherosclerosis [ 79 ].…”

A small-molecule inhibitor of PCSK9 transcription ameliorates atherosclerosis through the modulation of FoxO1/3 and HNF1α

“…4). A group of mice treated with 15 mg/kg atorvastatin was applied as a positive control for the en face analysis, and atorvastatin effectively decreased atherosclerotic plaque accumulation in whole aorta with no differences in serum cholesterol levels as in our previous studies [40] (Suppl Fig. 6).…”

Unraveling Host-Gut Microbiota Dialogue and Its Impact on Cholesterol Levels

“…In vivo, supplementation of a cholesterol-rich diet with acetate in rats resulted in a lower increase of TC levels associated with lower hepatic HMGCS and increased conversion of cholesterol into BAs due to the upregulation of Cyp7a (Fushimi et al, 2006). A similar rise in Cyp7a was observed in Apoe-deficient mice fed with a cholesterolrich diet supplemented with butyrate, with additional beneficial effects on the "reverse cholesterol transport" (RCT) (Du et al, 2019). The connection between SCFAs and BAs metabolism was further reported in Syrian hamsters (Zhao et al, 2017).…”