Role of hepatokines in hypertension and cardiac dysfunction - the rates of metabolic dysfunction-associated steatotic liver disease (MASLD) have dramatically increased to 25% of the population in…

Role of hepatokines in hypertension and cardiac dysfunction - the rates of metabolic dysfunction-associated steatotic liver disease (MASLD) have dramatically increased to 25% of the population in the U.S., reflecting the increase in obesity in the general population. Cardiovascular disease (CVD) is a significant complication of MASLD. More MASLD patients DIE from CVD than from liver disease. Many factors can contribute to the development of CVD in patients with MASLD as this condition is often associated with obesity, type II diabetes, and dyslipidemia. All of these factors can significantly contribute to the development of CVD. However, the contribution of hepatic steatosis to the development of CVD in MASLD is unknown. Our lab has developed a unique model to determine the role of hepatic steatosis in developing CVD independent of obesity and metabolic dysfunction, such as insulin resistance and dyslipidemia. We have exciting data showing that hepatocyte-specific deletion of peroxisome proliferator-activated receptor Α (PPARAHEPKO) results in significant hepatic steatosis even on mice maintained on a standard laboratory diet. PPARAHEPKO mice develop hypertension, cardiac systolic and diastolic dysfunction, and increased vascular stiffness. This proposal will test the central hypothesis that MASLD suppresses liver-derived nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), which promote healthy cardiovascular function. This proposal will use a combination of whole animal integrative physiology and molecular techniques to address the aims:aim 1 will determine if increasing plasma NGF levels reverses hypertension and cardiovascular remodeling to improve cardiac function in PPARAHEPKO mice. Aim 2 will determine whether increasing BDNF in the plasma of the PPARAHEPKO mice reverses hypertension and cardiovascular remodeling to improve cardiac function in PPARAHEPKO mice. This project will utilize state-of-the-art pamgene kinome chip technology to determine which signaling mechanisms are impacted by increases in the plasma levels of these hepatokines. Our investigations will identify novel targets for the treatment of MASLD- derived CVD. This project is the first systematic investigation of the role of hepatic steatosis in the development of CVD in MASLD.