Cardiac-specific deletion of GCN5L1 promotes fatty liver disease in HFpEF

Bugga, P.; Mushala, B. A.; Stoner, M. W.; Manning, J. R.; Bhattarai, N.; Sharifi-Sanjani, M.; Vandevender, A.; Mooli, R. G.; Ramakrishnan, S. K.; Kaufman, B. A.; Shiva, S. S.; Happe, C. L.; Mullett, S. J.; Gelhaus, S. L.; Jurczak, M. J.; Scott, I.

doi:10.1101/2025.02.05.636634

bioRxiv · 10.1101/2025.02.05.636634

Cardiac-specific deletion of GCN5L1 promotes fatty liver disease in HFpEF

Bugga, P.·Mushala, B. A.·Stoner, M. W.·Manning, J. R.·Bhattarai, N.·Sharifi-Sanjani, M.·Vandevender, A.·Mooli, R. G.·Ramakrishnan, S. K.·Kaufman, B. A.·Shiva, S. S.·Happe, C. L.·Mullett, S. J.·Gelhaus, S. L.·Jurczak, M. J.·Scott, I.

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Abstract

The prevalence of cardiometabolic heart failure with preserved ejection fraction (HFpEF) continues to grow, representing over half of heart failure cases in the United States. As no specific medication for HFpEF exists, treatment guidelines focus on the management of comorbidities related to metabolic syndrome (e.g. obesity, diabetes, hypertension) that promote the disease1. These same comorbidities also drive pathology in non-cardiac tissues, and the links between cardiometabolic disease presentations in different organs are increasingly being recognized. Preclinical studies on the potential crosstalk between HFpEF and metabolic disease in the liver (e.g. metabolic dysfunction-associated liver disease; MASLD) have focused on how liver dysfunction may affect the heart, particularly through the release of secreted liver proteins. This may reflect the situation in the clinic, where incident MASLD is a risk factor for future HFpEF development. Here, in contrast to this developing paradigm of liver-initiated cardiac disease, we report for the first time a defect in cardiac metabolism related to the mitochondrial metabolic protein GCN5L1 that drives hepatic steatosis and MASLD in HFpEF.

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Bugga, P., Mushala, B. A., Stoner, M. W., Manning, J. R., Bhattarai, N., Sharifi-Sanjani, M., Vandevender, A., Mooli, R. G., Ramakrishnan, S. K., Kaufman, B. A., Shiva, S. S., Happe, C. L., Mullett, S. J., Gelhaus, S. L., Jurczak, M. J., Scott, I.. 2025-02-08. Cardiac-specific deletion of GCN5L1 promotes fatty liver disease in HFpEF. https://doi.org/10.1101/2025.02.05.636634

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