PPARg-induced cardiolipotoxicity in mice is ameliorated by PPARa deficiency
despite increases in fatty acid oxidation.
Authors Son NH, Yu S, Tuinei J, Arai K, Hamai H, Homma S, Shulman GI, Abel ED, Goldberg
Submitted By Ira Goldberg on 11/8/2010
Status Published
Journal The Journal of clinical investigation
Year 2010
Date Published 10/1/2010
Volume : Pages 120 : 3443 - 3454
PubMed Reference 20852389
Abstract Excess lipid accumulation in the heart is associated with decreased cardiac
function in humans and in animal models. The reasons are unclear, but this is
generally believed to result from either toxic effects of intracellular lipids
or excessive fatty acid oxidation (FAO). PPAR? expression is increased in the
hearts of humans with metabolic syndrome, and use of PPAR? agonists is
associated with heart failure. Here, mice with dilated cardiomyopathy due to
cardiomyocyte PPAR? overexpression were crossed with PPARa-deficient mice.
Surprisingly, this cross led to enhanced expression of several PPAR-regulated
genes that mediate fatty acid (FA) uptake/oxidation and triacylglycerol (TAG)
synthesis. Although FA oxidation and TAG droplet size were increased, heart
function was preserved and survival improved. There was no marked decrease in
cardiac levels of triglyceride or the potentially toxic lipids diacylglycerol
(DAG) and ceramide. However, long-chain FA coenzyme A (LCCoA) levels were
increased, and acylcarnitine content was decreased. Activation of PKCa and PKCd,
apoptosis, ROS levels, and evidence of endoplasmic reticulum stress were also
reduced. Thus, partitioning of lipid to storage and oxidation can reverse
cardiolipotoxicity despite increased DAG and ceramide levels, suggesting a role
for other toxic intermediates such as acylcarnitines in the toxic effects of
lipid accumulation in the heart.

Investigators with authorship
E. Dale AbelUniversity of Iowa
Ira GoldbergNew York University School of Medicine