A novel mouse model of lipotoxic cardiomyopathy

TLDR

Inherited and acquired cardiomyopathies are linked to marked intracellular lipid accumulation in the heart, and the long‑chain acyl‑CoA synthetase protein plays a key role in vectorial fatty acid transport across the plasma membrane. The study tests whether a mismatch between myocardial fatty acid uptake and utilization causes cardiotoxic lipid accumulation and establishes a transgenic mouse model (MHC‑ACS) overexpressing long‑chain acyl‑CoA synthetase to investigate the role of lipid metabolism perturbations in heart failure. The authors created transgenic mice (MHC‑ACS) that overexpress long‑chain acyl‑CoA synthetase specifically in cardiac tissue. MHC‑ACS mice exhibit cardiac‑restricted transgene expression, marked triglyceride accumulation, initial hypertrophy progressing to left‑ventricular dysfunction and premature death, with evidence of lipid‑induced programmed cell death, demonstrating that fatty‑acid uptake/utilization mismatch leads to toxic lipid accumulation in cardiomyocytes.

Abstract

Inherited and acquired cardiomyopathies are associated with marked intracellular lipid accumulation in the heart. To test the hypothesis that mismatch between myocardial fatty acid uptake and utilization leads to the accumulation of cardiotoxic lipid species, and to establish a mouse model of metabolic cardiomyopathy, we generated transgenic mouse lines that overexpress long-chain acyl-CoA synthetase in the heart (MHC-ACS). This protein plays an important role in vectorial fatty acid transport across the plasma membrane. MHC-ACS mice demonstrate cardiac-restricted expression of the transgene and marked cardiac myocyte triglyceride accumulation. Lipid accumulation is associated with initial cardiac hypertrophy, followed by the development of left-ventricular dysfunction and premature death. Terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling staining and cytochrome c release in transgenic hearts suggest that cardiac myocyte death occurs, in part, by lipid-induced programmed cell death. Taken together, our data demonstrate that fatty acid uptake/utilization mismatch in the heart leads to accumulation of lipid species toxic to cardiac myocytes. This novel mouse model will provide insight into the role of perturbations in myocardial lipid metabolism in the pathogenesis of inherited and acquired forms of heart failure.