Butyrate from pectin fermentation inhibits intestinal cholesterol absorption and attenuates atherosclerosis in apolipoprotein E-deficient mice

Short-chain fatty acids (SCFAs), the major products of dietary fiber fermentation by intestinal microflora, exert beneficial effects on pathogenesis of multiple metabolic diseases. The aim of this study was to determine whether SCFAs from fermentation of pectin (PE), a soluble dietary fiber, prevent the development of atherosclerosis in apolipoprotein E-deficient (apoE−/−) mice. Male apoE−/− mice (8-week-old) were fed a high-fat, high-cholesterol diet (HCD; 21% wt/wt fat, 0.15% wt/wt cholesterol) or HCD supplemented with 20% wt/wt PE (HCD+PE) alone or with antibiotics (HCD+PE + A) in drinking water for 12 weeks. Serum lipids and SCFAs concentrations, atherosclerotic lesion area, and intestinal morphology and function were measured. Caco-2 cells were treated with SCFAs to determine whether they affected the expression of genes involved in cholesterol absorption. HCD+PE-treated mice exhibited decreased serum total and low-density lipoprotein cholesterol, and reduced atherosclerotic lesion area compared with HCD mice. These beneficial effects of PE were not observed in the HCD+PE+A group. Incubation of Caco-2 cells with butyrate, but not acetate and propionate, down-regulated the expression of Niemann-Pick C1-Like 1 but up-regulated the ATP-binding cassette transporters G5 and G8 (ABCG5 and G8) at the mRNA level. Butyrate treatment also increased transcriptional activity of liver X receptor in Caco-2 cells. Our data suggest that butyrate from PE intestinal fermentation protects mice from the progression of diet-induced atherosclerosis in apoE−/− mice. These findings suggest a novel mechanism by which dietary fiber may prevent the development of atherosclerosis.