Abstract 14039: Therapeutic Potential of Beta Hydroxybutyrate in Nonalcoholic Fatty Liver Disease (NAFLD)-Induced Cardiovascular Disease

Abstract

Background: Cardiovascular disease (CVD) is the leading cause of mortality in non-alcoholic fatty liver disease (NAFLD). Beta hydroxybutyrate (BHOB), a liver metabolite, is the major ketone that serves as an alternative fuel source in the body. Our previous studies show that hepatocyte peroxisome proliferator activator receptor-α knockout (Ppara HEPKO ) mice, model of NAFLD-induced CVD, exhibit reduced circulating levels of BHOB. Hypothesis: We hypothesized that restoring plasma BHOB levels will improve cardiovascular function in Ppara HEPKO mice. Aims: To determine the therapeutic role of BHOB in NAFLD-induced CVD. Methods: 30 weeks old male Ppara HEPKO mice were given 1,3 butanediol (20% in drinking water) (Ppara HEPKO + BHOB) or vehicle (Ppara HEPKO ) (n=6) for 6 weeks. Plasma BHOB was measured at baseline and after treatment. Cardiac structure and function were measured by high resolution ultrasound echocardiography (VEVO 3100), using the B-mode, M-mode, pulse wave and tissue doppler at baseline and after treatment. Mean arterial blood pressure was measured by radiotelemetry. Liver fat was determined by EchoMRI, Oil Red O staining and hepatic triglyceride levels. Results: After 6 weeks of BHOB treatment, Ppara HEPKO exhibit increased plasma BHOB compared to baseline (0.5 ± 0.01 vs. 0.2 ± 0.02mmol/L), attenuated arterial blood pressure compared to control (109 ± 3 vs. 121 ± 4mmHg), improved systolic function: cardiac output (13.8 ± 0.8 vs. 11.1 ± 0.7ml/min), stroke volume (31.1 ± 2.1 vs. 23.4 ± 1.3ml/min), improved diastolic function: isovolumic relaxation time (18.7 ± 0.8 vs. 20.6 ± 0.9m/sec), E/e’ (-29.6 ± 0.9 vs. -32.4 ± 1.4), and attenuated vascular stiffness. Interestingly, BHOB did not alleviate hepatic fat compared to control as demonstrated by EchoMRI (0.8 ± 0.3 vs. 0.7 ± 0.3), hepatic triglyceride (1.4 ± 0.3 vs. 1.3 ± 0.2mM) and Oil Red O staining. Conclusion: Our findings indicate that BHOB treatment improves arterial blood pressure, systolic, diastolic, and vascular function in, Ppara HEPKO knockout mice. However, BHOB did not alleviate hepatic steatosis suggesting that BHOB improves cardiovascular function in Ppara HEPKO mice independent of changes in hepatic fat content.