Novel liver-mediated mechanisms in hypertension and cardiac dysfunction

Obesity and metabolic diseases such as type II diabetes are at an all-time high. The rates of nonalcoholic fatty liver disease (NAFLD) or recently renamed 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 NAFLD. In fact, more NAFLD patients die from CVD than from liver disease. There are many factors that can contribute to the development of CVD in patients with NAFLD as this condition is often associated with obesity, type II diabetes, and dyslipidemia. All of which can significantly contribute to the development of CVD. However, the contribution of hepatic steatosis itself to the development of CVD in NAFLD is not known. There is a subgroup of NAFLD patients who develop hepatic steatosis independently of obesity and metabolic disease so called “lean” NAFLD patients. Interstingly, these patients are also at greater risk for the development of CVD. We have developed a unique model to determine the role of hepatic steatosis in the development of 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. We also found that PparaHEPKO mice exhibit reduced hepatic ketone β-hydroxybutyrate (βOHB) production and PPARα-regulated hepatic-derived hormones in their plasma compared to littermates. This proposal will test the central hypothesis that NAFLD reduces βOHB production and suppresses PPARα-regulated hepatokines that promote healthy cardiovascular function. Aim 1 of the proposal will determine if increasing plasma βOHB levels reverses hypertension and cardiovascular remodeling to improve cardiac function in PparaHEPKO mice. In addition, we will use state-of-the-art Pamgene kinome chip technology to determine which signaling mechanisms are impacted by increasing βOHB levels in PparaHEPKO mice. Aim 2 will determine whether increasing PPARα-regulated hepatic-derived hormones in the plasma of the PparaHEPKO mice reduces cardiovascular complications. We will increase the levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in PparaHEPKO mice to determine if increasing the plasma levels of these hepatokines revereses hypertension and cardiovascular remodeling to improve cardiac function in PparaHEPKO mice. We will also use 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 treatment of NAFLD-derived CVD. Collectively, this project is the first systematic investigation of the role of hepatic steatosis in the development of CVD in NAFLD.