Cardioprotective Role of Beta Hydroxybutyrate in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

Abstract

Background: Cardiovascular disease (CVD) is the leading cause of mortality in metabolic dysfunction-associated steatotic liver disease (MASLD). Beta hydroxybutyrate (BHOB), a liver metabolite, is the major ketone that serves as an alternative fuel source in the body. Previously, we observed cardiovascular dysfunction that was associated with reduced circulating BHOB in hepatocyte-specific PPARα knockout mice (PparaHEPKO), a mouse model that exhibits hepatic steatosis independent of obesity and insulin resistance. Hypothesis: We hypothesize that restoring plasma BHOB levels will attenuate the mechanisms underlying hepatic steatosis-induced cardiovascular dysfunction and improve cardiovascular function in PparaHEPKO mice.Aims: To determine the cardioprotective role of increased plasma levels of BHOB in CVDs induced by MASLD. Methods: 30 week old male PparaHEPKO mice were given 1,3 butanediol (20% in drinking water) (PparaHEPKO+ 1,3 butanediol) or vehicle (PparaHEPKO) (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). Mean arterial blood pressure was measured by radio telemetry. Cardiac lipid accumulation was determined by Oil Red O (ORO) and cardiac triglyceride levels. Cardiac apoptosis and fibrosis were determined by TUNEL and picrosirius red staining, further confirmed by western blot. Cardiac natriuretic peptides were determined by real-time PCR. Liver fat was determined by EchoMRI, ORO staining and hepatic triglyceride levels.Results: After 6 weeks of 1,3 butanediol treatment, PparaHEPKO 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 cardiac output (13.8 ± 0.8 vs. 11.1 ± 0.7mL/min), stroke volume (31.1 ± 2.1 vs. 23.4 ± 1.3μL), and isovolumic relaxation time (18.7 ± 0.8 vs. 20.6 ± 0.9ms). 1,3 butanediol treatment also attenuated vascular stiffness, cardiac lipid (0.7 ± 0.27 vs. 1.5 ± 0.17), ANP (1.1 ± 0.03 vs. 1.3 ± 0.03), COL1A1 (0.9 ± 0.1 vs. 9.0 ± 0.5), and cleaved caspase-3 (1.8 ± 0.3 vs. 3.7 ± 0.7). Interestingly, 1,3 butanediol 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 increasing plasma BHOB level improves arterial blood pressure, exercise tolerance, systolic, diastolic, and vascular functions in MASLD-induced CVD. Furthermore, BHOB attenuates cardiac lipid, apoptosis and fibrosis. However, BHOB did not alleviate hepatic steatosis suggesting that BHOB improves cardiovascular functions in PparaHEPKO mice independent of hepatic fat content. This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Grant 1R01DK121748-01A1 (D.E. Stec), the National Institute of General Medical Sciences Grant P20GM104357-02, P30GM149404 and P20GM144041 (D.E. Stec), and by American Heart Association Postdoctoral Award (23POST1020493, O.O. Badmus). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.