Cardiac dysfunction in adipose triglyceride lipase deficiency: treatment with a PPARα agonist

Br J Pharmacol. 2012 Jan;165(2):380-9. doi: 10.1111/j.1476-5381.2011.01490.x.


Background and purpose: Adipose triglyceride lipase (ATGL) has been identified as a rate-limiting enzyme of mammalian triglyceride catabolism. Deletion of the ATGL gene in mice results in severe lipid accumulation in a variety of tissues including the heart. In the present study we investigated cardiac function in ATGL-deficient mice and the potential therapeutic effects of the PPARα and γ agonists Wy14,643 and rosiglitazone, respectively.

Experimental approach: Hearts isolated from wild-type (WT) mice and ATGL(-/-) mice treated with Wy14,643 (PPARα agonist), rosiglitazone (PPARγ agonist) or vehicle were perfused at a constant flow using the Langendorff technique. Left ventricular (LV) pressure-volume relationships were established, and the response to adrenergic stimulation was determined with noradrenaline (NA).

Key results: Hearts from ATGL(-/-) mice generated higher LV end-diastolic pressure and lower LV developed pressure as a function of intracardiac balloon volume compared to those from WT mice. Likewise, passive wall stress was increased and active wall stress decreased in ATGL(-/-) hearts. Contractile and microvascular responses to NA were substantially reduced in ATGL(-/-) hearts. Cardiac contractility was improved by treating ATGL(-/-) mice with the PPARα agonist Wy14,643 but not with the PPARγ agonist rosiglitazone.

Conclusions and implications: Our results indicate that lipid accumulation in mouse hearts caused by ATGL gene deletion severely affects systolic and diastolic function, as well as the response to adrenergic stimulation. The beneficial effects of Wy14,643 suggest that the cardiac phenotype of these mice is partially due to impaired PPARα signalling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticholesteremic Agents / pharmacology*
  • Body Weight / drug effects
  • Female
  • Heart / drug effects*
  • Heart / physiopathology
  • Heart Rate / drug effects
  • In Vitro Techniques
  • Lipase / deficiency
  • Lipase / genetics
  • Lipase / physiology*
  • Male
  • Mice
  • Mice, Knockout
  • Myocardium / pathology
  • Norepinephrine / pharmacology
  • Organ Size / drug effects
  • PPAR alpha / agonists*
  • PPAR gamma / agonists
  • Pyrimidines / pharmacology*
  • Rosiglitazone
  • Thiazolidinediones / pharmacology
  • Ventricular Dysfunction, Left / pathology
  • Ventricular Dysfunction, Left / physiopathology


  • Anticholesteremic Agents
  • PPAR alpha
  • PPAR gamma
  • Pyrimidines
  • Thiazolidinediones
  • Rosiglitazone
  • pirinixic acid
  • Lipase
  • PNPLA2 protein, mouse
  • Norepinephrine