Adipose triglyceride lipase (ATGL) was recently identified as an important triacylglycerol (TG) hydrolase promoting the catabolism of stored fat in adipose and nonadipose tissues. We now demonstrate that efficient ATGL enzyme activity requires activation by CGI-58. Mutations in the human CGI-58 gene are associated with Chanarin-Dorfman Syndrome (CDS), a rare genetic disease where TG accumulates excessively in multiple tissues. CGI-58 interacts with ATGL, stimulating its TG hydrolase activity up to 20-fold. Alleles of CGI-58 carrying point mutations associated with CDS fail to activate ATGL. Moreover, CGI-58/ATGL coexpression attenuates lipid accumulation in COS-7 cells. Antisense RNA-mediated reduction of CGI-58 expression in 3T3-L1 adipocytes inhibits TG mobilization. Finally, expression of functional CGI-58 in CDS fibroblasts restores lipolysis and reverses the abnormal TG accumulation typical for CDS. These data establish an important biochemical function for CGI-58 in the lipolytic degradation of fat, implicating this lipolysis activator in the pathogenesis of CDS.
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.
Fatty acids (FAs) are essential components of all lipid classes and pivotal substrates for energy production in all vertebrates. Additionally, they act directly or indirectly as signaling molecules and, when bonded to amino acid side chains of peptides, anchor proteins in biological membranes. In vertebrates, FAs are predominantly stored in the form of triacylglycerol (TG) within lipid droplets of white adipose tissue. Lipid droplet-associated TGs are also found in most nonadipose tissues, including liver, cardiac muscle, and skeletal muscle. The mobilization of FAs from all fat depots depends on the activity of TG hydrolases. Currently, three enzymes are known to hydrolyze TG, the well-studied hormone-sensitive lipase (HSL) and monoglyceride lipase (MGL), discovered more than 40 years ago, as well as the relatively recently identified adipose triglyceride lipase (ATGL). The phenotype of HSL-and ATGL-deficient mice, as well as the disease pattern of patients with defective ATGL activity (due to mutation in ATGL or in the enzymeʼs activator, CGI-58), suggest that the consecutive action of ATGL, HSL, and MGL is responsible for the complete hydrolysis of a TG molecule. The complex regulation of these enzymes by numerous, partially uncharacterized effectors creates the "lipolysome," a complex metabolic network that contributes to the control of lipid and energy homeostasis. This review focuses on the structure, function, and regulation of lipolytic enzymes with a special emphasis on ATGL.-Zechner, R., P. C. Kienesberger, G. Haemmerle, R. Zimmermann, and A. Lass. Adipose triglyceride lipase and the lipolytic catabolism of cellular fat stores. J. Lipid Res. 2009. 50: 3-21.Supplementary key words lipolysis • hydrolase • neutral lipid storage disease Lipid homeostasis reflects a balance of processes, designed to generate fatty acids (FAs) and lipids, deliver them from their site of origin to target tissues, and catabolize them for metabolic purposes. Innumerable genes and signal components are responsible for an integrated communication network between many tissues and organs, including adipose tissue, liver, muscles, the digestive tract, pancreas, and the nervous system. This network ultimately accounts for the accurate regulation of lipid and energy homeostasis. Despite the central physiological importance of these processes for human health, many basic mechanisms regulating the synthesis, uptake, storage, and utilization of lipids remain insufficiently characterized.FAs are vital components of essentially all known organisms. They are important substrates for oxidation and the production of cellular energy. FAs are essential precursors for all lipid classes, including those forming biological membranes. Finally, they are important for protein function in acylated proteins and as ligands for nuclear receptor transcription factors. In contrast to these "beneficial" characteristics, unesterified FAs can become deleterious for cells when present even at relatively low concentrations. The chronic exposure of nona...
The human genome expresses nine patatin-like phospholipase domain containing proteins (PNPLA1-9). Members of this family share a protein domain discovered initially in patatin, the most abundant protein of the potato tuber. Patatin is a lipid hydrolase with an unusual folding topology that differs from classical lipases. Mammalian PNPLAs include lipid hydrolases with specificities for diverse substrates such as triacylglycerols, phospholipids, and retinol esters. Analysis of induced mutant mouse models and the clinical phenotype of patients with mutations revealed important insights into the physiological role of several members of the PNPLA family. This review aims to summarize current knowledge of PNPLA proteins and to document their emerging importance in lipid and energy homeostasis.-Kienesberger, P. C., M. Oberer, A. Lass, and R. Zechner. Mammalian patatin domain containing proteins: a family with diverse lipolytic activities involved in multiple biological functions. J. Lipid Res. 2009. 50: S63-S68. Supplementary key wordsThe large group of lipid hydrolases, diverse enzymes involved in the hydrolysis of ester and amide bonds of fatty acids (FA) in lipid molecules, include triacylglycerol (TG) hydrolases (lipases), phospholipases, ceraminidases as well as cholesterol ester, and retinol ester (RE) hydrolases. These enzymes are generally important to a plethora of intra-and extracellular processes, including maintenance of membrane integrity, lipid signaling, and regulation of energy homeostasis. In recent years, a mammalian family of lipid hydrolases, designated patatin-like phospholipase domain containing (PNPLA), has attracted attention, as its members were found to serve critical roles in diverse aspects of lipid metabolism and signaling. Several gain-and loss-offunction mouse models revealed important implications for PNPLA proteins in physiological processes. Moreover, the phenotypic consequences of mutations and gene polymorphisms in humans identified enzyme family members as key players in disease states linked to energy homeostasis, neuronal integrity, and age-related bone morphology.As the name implies, PNPLA proteins are members of the patatin family (Pfam01734). The eponym of this protein family, potato patatin, harbors the evolutionarily conserved consensus serine lipase motif Gly-X-Ser-X-Gly and exhibits nonspecific acyl-hydrolase activity (1). The 3-D structure of Pat17, an isoenzyme of potato patatin, localized the active site of the enzyme to the so-called patatinlike phospholipase domain (2). The name of this domain as well as the nomenclature of the PNPLA family is, unfortunately, somewhat misleading, because several of the subsequently discovered mammalian proteins exhibit hydrolase but not phospholipase activity. The patatin-like phospholipase domain is characterized by a three-layer a/b/a architecture employing a catalytic Ser-Asp catalytic dyad instead of the classical catalytic triad (2). The observed folding topology and the 3-D arrangement of the catalytic site of patatin (o...
Maintenance of circadian alignment between an organism and its environment is essential to ensure metabolic homeostasis. Synchrony is achieved by cell autonomous circadian clocks. Despite a growing appreciation of the integral relation between clocks and metabolism, little is known regarding the direct influence of a peripheral clock on cellular responses to fatty acids. To address this important issue, we utilized a genetic model of disrupted clock function specifically in cardiomyocytes in vivo (termed cardiomyocyte clock mutant (CCM)). CCM mice exhibited altered myocardial response to chronic high fat feeding at the levels of the transcriptome and lipidome as well as metabolic fluxes, providing evidence that the cardiomyocyte clock regulates myocardial triglyceride metabolism. Time-of-day-dependent oscillations in myocardial triglyceride levels, net triglyceride synthesis, and lipolysis were markedly attenuated in CCM hearts. Analysis of key proteins influencing triglyceride turnover suggest that the cardiomyocyte clock inactivates hormone-sensitive lipase during the active/awake phase both at transcriptional and post-translational (via AMP-activated protein kinase) levels. Consistent with increased net triglyceride synthesis during the end of the active/awake phase, high fat feeding at this time resulted in marked cardiac steatosis. These data provide evidence for direct regulation of triglyceride turnover by a peripheral clock and reveal a potential mechanistic explanation for accelerated metabolic pathologies after prevalent circadian misalignment in Western society.Striking time-of-day-dependent oscillations are observed in multiple cardiometabolic parameters in both animal models and humans. These parameters range from levels of circulating nutrients and endocrine factors, neural activity, glucose tolerance, insulin sensitivity, feeding behavior, and energy metabolism (both at the individual tissue and whole body levels) to cardiovascular function (1-5). Significant alterations in many of these oscillations are observed in metabolic disease states (e.g. obesity, diabetes mellitus, and cardiovascular disease), suggesting that circadian misalignment may play an important role in the etiology of multiple pathologies (5, 6). Recent molecular/ genetic-based studies reinforce such a concept and suggest that intrinsic cellular circadian clocks play a pivotal role in mediating many, if not all, biological rhythms. Circadian clocks are transcriptionally based molecular mechanisms that generate self-sustained positive and negative feedback loops with a free running period of ϳ24 h (7); this molecular mechanism has been identified within essentially all mammalian cells (both central and peripheral). Circadian clocks confer the selective advantage of anticipation. In doing so molecular clocks enable the cell to prepare for an external stimulus before its onset, thereby maintaining optimal synchrony with the environment. Given marked time-of-day-dependent rhythms in energy supply (e.g. dietary nutrient intake) and de...
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