Effect of 3-hydroxyisobutyrate in vivo administration on cardiometabolic disease in ApoE-/- mouse model

The valine catabolite 3-hydroxyisobutyrate (3-HIB) is suggested to mediate the uptake of extracellular fatty acids into the cells, thus regulating intracellular lipid metabolism, although the direct mechanism remains unclear. In this study, we assessed the effects of long-term 3-HIB treatment on the development and progression of complex atherosclerotic lesions, lipid metabolism and liver injury in vivo in ApoE-/- mouse model fed Western Diet (WD). Results show that 3-HIB treatment is associated with a significant reduction in weight and serum lipid content, reduced aortic mean plaque area and improvement of liver functions. Mechanistically, 3-HIB treatment mainly affects the modulation of genes involved in circadian rhythm and liver fatty acid oxidation. Experiments in hepatocyte HepG2 cells, confirm the link between 3-HIB treatment and circadian genes and show the increase of intracellular acetyl-CoA levels that, in turn, may improve fatty acid oxidation rates and ATP generation. In conclusion, despite previous evidence that elevated endogenous 3-HIB serum levels may represent a biomarker for metabolic and cardiovascular diseases, our results suggest that in ApoE-/- mice, enhanced fatty acid oxidation induced by 3-HIB treatment protects against atherosclerosis, at least in part through the modulation of circadian genes. Our results highlight the potential of new 3-HIB-based therapeutic strategy to slow the progression of cardiovascular diseases.