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

Abstract

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 × 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.

Perilipins 2 and 3 lack a carboxy-terminal domain present in perilipin 1 involved in sequestering ABHD5 and suppressing basal lipolysis

“…In striking contrast to this highly dynamic regulation of lipolysis, recent stable isotope studies in human skeletal muscle have suggested that basal lipolytic rates in muscle are relatively high and that free fatty acids entering the myocytes necessarily traffic via the intramyocellular TAG stored within LDs before being oxidized (7). Concordant observations were also recently reported in cardiomyocytes, hepatocytes, and islets (8)(9)(10). How, then, are these important functional differences mediated?…”

“…The situation in the liver is more complex, because here neutral lipids can be repackaged into lipoproteins for subsequent export (6). Intriguing work by several groups has recently suggested that fatty acids traffic via the LDs in myocytes (7), cardiomyocytes (8), hepatocytes (9), and pancreatic islets (10). These studies also imply and, in some cases (7) actually demonstrate, that this is a somewhat more constitutive process than in adipocytes, raising the question of exactly how lipolysis is coordinated in these cells, which under normal circumstances do not express perilipin 1.…”

Increased lipolysis and altered lipid homeostasis protect γ-synuclein–null mutant mice from diet-induced obesity

“…Conversely, adipose-selective disruption of ATGL leads to increased adiposity and a more WAT-like phenotype in BAT (17). The lipolytic action of ATGL has been shown to be important for inducing the expression of genes favoring lipid oxidation genes in hepatocytes, macrophages, cardiac muscle, and BAT, as well as increased thermogenesis in the latter (17)(18)(19)(20). As γ-synuclein is clearly detectable in BAT and appears able to regulate ATGL function, activation of ATGL in the BAT of γ-synuclein −/− mice may also increase lipolysis in this tissue and drive the increased lipid oxidation profile we observe.…”

The role of triacylglycerol in cardiac energy provision

“…phospholipid) and signalling (e.g. DAG) functions [111], and mTAG-derived FAs may be metabolic signals/PPAR ligands [112] (Fig. 1).…”

“…Moreover, PPA' PPA' in rodent ATGL deficiency [112], presumably due to decreased FA-PPAR ligands [135,136], and this is associated with impaired mitochondrial oxidation [112], supporting the role of mTAG-derived FAs as oxidative substrates together with significant shuttling of incoming FAs through the LD-TAG pool prior to lipolysis and FA release for -oxidation [120,126,138]. Heart-specific ATGL overexpression decreased mTAG, and surprisingly, decreased cardiac FA oxidation, supporting a role for a mTAG pool to facilitate FA flux to mitochondria.…”