Abstract
The association between metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular disease is well characterized; however, the underlying mechanism is incompletely understood. Interestingly, hepatocyte-specific silencing of dipeptidyl peptidase 4 (DPP4) prevents liver fibrosis and adipose tissue inflammation; however, how this affects the heart remains to be investigated. This study evaluates how diastolic function and molecular signatures of heart failure, like inflammation and fibrosis, are affected in male Dpp4+/+, Dpp4-/-, and Dpp4flox/flox mice injected with a TBG-CRE to selectively eliminate DPP4 from hepatocytes (Dpp4hep-/-) and respective controls (Dpp4GFP), aged and fed an HFHC diet for 24 weeks. Mice underwent pulsed-wave and tissue Doppler echocardiography. Further, speckle-tracking strain analysis was performed to detect diastolic dysfunction. Differential mRNA analysis using the NanoString platform and qRT-PCR were conducted using ventricular tissue to assess immunological pathway expression, as well as hypertrophy, modeling-related, senescence, and metabolism gene expression. Immunological pathway analysis of ventricular tissue revealed downregulation of 12 immune-related pathways in Dpp4hep-/- mice, including apoptosis and chemokine and cytokine signaling; however, this was not observed in Dpp4-/- mice. Further, fibrosis and ECM modeling-related genes, Col1a1, Col3a1, Ctgf, and Myh7, were significantly upregulated in Dpp4-/- mice but unchanged in Dpp4hep-/- mice, compared to controls. Interestingly, cardiac hypertrophy and systolic and diastolic function evaluated with echocardiography were unchanged. Immune-related pathways are downregulated in Dpp4hep-/- mice, while fibrosis genes are significantly upregulated in Dpp4-/- mice, compared to respective controls. Despite these molecular changes, cardiac hypertrophy and systolic and diastolic function were unchanged with systemic and organ-specific loss of Dpp4.