Cardioprotective Effects of 1,3 Butanediol in MASLD via Reversal of Cardiac Lipid Accumulation and Suppression of Cardiac Fibrosis

Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly associated with the development of cardiovascular disease (CVD); however, the mechanisms responsible are currently unknown. We have developed a model of MASLD due to the loss of hepatocyte peroxisome proliferator-activated receptor α (PPARαHEPKO). We found that plasma beta-hydroxybutyrate (BHOB) levels were significantly reduced in PPARαHEPKO mice and aimed to investigate the therapeutic potential of restoring BHOB levels in the development of CVD in these mice. Thirty-week-old PPARαHEPKO and control PPARαFL/FL mice were randomized to receive 1,3 butanediol (1,3-BDO), a precursor of BHOB, in drinking water for 6 weeks. 1,3-BDO treatment resulted in a significant increase in plasma BHOB levels, a significant decrease in mean arterial blood pressure, improvement in systolic and diastolic function, a decrease in vascular stiffness, and improved exercise performance in PPARαHEPKO mice. 1,3-BDO treatment did not alleviate hepatic steatosis in PPARαHEPKO mice; however, it improved plasma cholesterol levels and decreased cardiac lipid accumulation, fibrosis, and apoptosis. 1,3-BDO treatment also resulted in a significant increase in cardiac AMP-activated protein kinase (AMPK) levels. Increasing plasma BHOB levels reverses CVD in our mouse model of MASLD. A similar approach could be an effective strategy for preventing the development of CVD in patients with human MASLD.