Orally administrated acetate inhibits atherosclerosis progression through AMPK activation via GPR43 in plaque macrophages.

BACKGROUND AND AIMS

Oral administration of acetic acid, a short-chain fatty acid, has been shown to efficiently reduce obesity and insulin resistance in both experimental animals and humans. The anti-atherosclerotic effect of acetate is expected owing to its anti-inflammatory and anti-oxidative stress characteristics; however, this remains to be fully understood.

METHODS

For 12 weeks, apolipoprotein E-deficient mice were administered 0.6 % sodium acetate water or vehicle water. Plaque formation and progression were investigated using histological analysis of dissected aortic root sections. Flow cytometry and gene expression analyses were employed to assess plaque macrophage characteristics and functional states. In vitro tests were performed on mouse peritoneal primary macrophages and bone marrow-derived macrophages isolated from wild-type or GPR43-deficient mice.

RESULTS

Atherosclerotic plaque formation was inhibited in acetate-treated ApoE-deficient mice, and AMPK activation was directly validated in plaque macrophages. Acetate inhibited macrophage proliferation, reactive oxygen species production, and pro-inflammatory molecule expression, all of which were reversed by AMPK inhibition. Bone marrow transplantation study revealed the role of GPR43-mediated AMPK activation by acetic acid in anti-atherosclerotic effect.

CONCLUSIONS

Oral acetate administration suppressed arteriosclerosis formation and progression in ApoE-deficient mice. Acetate inhibited macrophage proliferation, inflammatory cytokine release, and reactive oxygen species production via GPR43-mediated AMPK activation in macrophages, ameliorating plaque formation and progression.