ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-α and PGC-1

By G. Haemmerle, T. Moustafa, G. Woelkart, S. Büttner, A. Schmidt, T. van de Weijer, M. Hesselink, Doris Jaeger, P. Kienesberger, Kathrin A. Zierler and 25 more. Nature Medicine, 2011

730 citations recorded by the source corpus.

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate genes involved in energy metabolism and inflammation. For biological activity, PPARs require cognate lipid ligands, heterodimerization with retinoic X receptors, and coactivation by PPAR-γ coactivator-1α or PPAR-γ coactivator-1β (PGC-1α or PGC-1β, encoded by Ppargc1a and Ppargc1b, respectively). Here we show that lipolysis of cellular triglycerides by adipose triglyceride lipase (patatin-like phospholipase domain containing protein 2, encoded by Pnpla2; hereafter referred to as Atgl) generates essential mediator(s) involved in the generation of lipid ligands for PPAR activation. Atgl deficiency in mice decreases mRNA levels of PPAR-α and PPAR-δ target genes. In the heart, this leads to decreased PGC-1α and PGC-1β expression and severely disrupted mitochondrial substrate oxidation and respiration; this is followed by excessive lipid accumulation, cardiac insufficiency and lethal cardiomyopathy. Reconstituting normal PPAR target gene expression by pharmacological treatment of Atgl-deficient mice with PPAR-α agonists completely reverses the mitochondrial defects, restores normal heart function and prevents premature death. These findings reveal a potential treatment for the excessive cardiac lipid accumulation and often-lethal cardiomyopathy in people with neutral lipid storage disease, a disease marked by reduced or absent ATGL activity.

Subfields: Biochemistry, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/b9bc19febfe062a716f3bb9279305d25588eb939

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Citations in the corpus

Effect of dietary bile acids on growth, body composition, lipid metabolism and microbiota in grass carp (Ctenopharyngodon idella) (2018, background): “…of pparα in fish fed the 7L+BA diet, because PPARα is a nuclear receptor that stimulate the expression of genes related with fatty acid transport and oxidation (Haemmerle et al., 2011), whereas in the liver, PPARα is a key regulator governing hepatic fatty acid oxidation (Pineda et al., 2003).”
What We Talk About When We Talk About Fat (2014, positive): “Interestingly, lipolysis is required for the generation of endogenous PPARa ligands, as fatty acids imported from the blood or synthesized endogenously cannot activate this nuclear receptor until they have undergone a cycle of esterification and hydrolysis (Haemmerle et al., 2011).”
Integrated physiology and systems biology of PPARα (2014, background): “[45] Haemmerle, G.”
Cardiac Metabolism and Its Interactions with Contraction, Growth, and Survival of the Cardiomyocte (2013, background): “lation and severe cardiomyopathy associated with decreased FAO.(63,64) However, cardiac-specific overexpression of adipose”
Fatty acid trafficking in starved cells: regulation by lipid droplet lipolysis, autophagy and mitochondrial fusion dynamics (2015, background): “In line with this, a recent report demonstrated that lipid-dependent peroxisome proliferator-activated receptor (PPAR) signaling specifically requires cytoplasmic lipase-catalyzed hydrolysis of intracellular triglyceride stores, but not FAs from other sources, to build a functional signaling complex”
Memory CD8+ T cells use cell intrinsic lipolysis to support the metabolic programming necessary for development (2014, background): “Although FA derived from lipolysis can fuel OXPHOS, lipolysis is also required for the production of lipid signaling molecules, such as lipid ligands that activate the peroxisome proliferator-activated receptor (PPAR) pathway (Haemmerle et al., 2011).”