Metabolic crosstalk between the heart and liver impacts familial hypertrophic cardiomyopathy

EMBO Molecular Medicine

Jason A Magida¹ 

[1] Department of Molecular, Cellular and Developmental Biology, BioFrontiers Institute, University of Colorado at Boulder, Boulder, CO, USA

关键词: cardiomyopathy;    glucose;    lipoproteins;    liver;   

DOI  :  10.1002/emmm.201302852

来源: Wiley

【 摘 要 】

Abstract

Familial hypertrophic cardiomyopathy (HCM) is largely caused by dominant mutations in genes encoding cardiac sarcomeric proteins, and it is etiologically distinct from secondary cardiomyopathies resulting from pressure/volume overload and neurohormonal or inflammatory stimuli. Here, we demonstrate that decreased left ventricular contractile function in male, but not female, HCM mice is associated with reduced fatty acid translocase (CD36) and AMP-activated protein kinase (AMPK) activity. As a result, the levels of myocardial ATP and triglyceride (TG) content are reduced, while the levels of oleic acid and TG in circulating very low density lipoproteins (VLDLs) and liver are increased. With time, these metabolic changes culminate in enhanced glucose production in male HCM mice. Remarkably, restoration of ventricular TG and ATP deficits via AMPK agonism as well as inhibition of gluconeogenesis improves ventricular architecture and function. These data underscore the importance of the systemic effects of a primary genetic heart disease to other organs and provide insight into potentially novel therapeutic interventions for HCM.

Synopsis

A primary cardiac myocyte defect leads to aberrant lipid accumulation and signaling in the liver. The resulting hepatic phenotype impacts cardiac function. Normalization of heart lipid delivery or inhibition of gluconeogenesis improves ventricular function.

• Genetic heart disease causes metabolic abnormalities in the liver.
• There is reduced triglyceride clearance by the HCM heart.
• Accumulating plasma triglycerides are sequestered by hepatocytes.
• Activation of gluconeogenesis exacerbates cardiac pathology.

【 授权许可】

CC BY   
© 2014 The Authors.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.