TCA Cycle Dysfunction and Amino Acid Catabolism Drive Hepatic Steatosis in Mice with HFpEF
The prevalence of cardiometabolic heart failure with preserved ejection fraction (HFpEF) continues to grow worldwide, and now represents over half of current heart failure cases in the United States (1). Due to a lack of specific approved therapies, current treatment guidelines focus on the management of comorbidities related to metabolic syndrome (e.g. obesity, diabetes, hypertension) that promote HFpEF progression (1). The same comorbidities also drive cardiometabolic disease in non-cardiac tissues, and links between disease presentations in different organs are increasingly being recognized in the clinic. However, mechanistic studies examining the underlying pathophysiological connections have not kept pace, particularly in the cardio-hepatic disease axis (2). To address this, we used a recently developed and validated preclinical model of HFpEF (3) to examine how this disease impacts the liver. The development of HFpEF in mice leads to the simultaneous development of widespread hepatic steatosis that is consistent with human non-alcoholic fatty liver disease (NAFLD). Mechanistically, we show that the liver steatosis observed is driven by excess glucogenic amino acid entry into the TCA cycle, which promotes hepatic glucose production and de novo lipogenesis. Our findings suggest that HFpEF development is a multi-organ event, with implications for both preclinical and translational research.