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.
Lysosomes are crucial cellular organelles for human health that function in digestion and recycling of extracellular and intracellular macromolecules. We describe a signaling role for lysosomes that affects aging. In the worm, Caenorhabditis elegans, the lysosomal acid lipase LIPL-4 triggered nuclear translocalization of a lysosomal lipid chaperone LBP-8, consequently promoting longevity by activating the nuclear hormone receptors NHR-49 and NHR-80. We used high-throughput metabolomic analysis to identify several lipids whose abundance was increased in worms constitutively over-expressing LIPL-4. Among them, oleoylethanolamide directly bound to LBP-8 and NHR-80 proteins, activated transcription of target genes of NHR-49 and NHR-80, and promoted longevity in C. elegans. These findings reveal a lysosome-to-nucleus signaling pathway that promotes longevity and suggest a function of lysosomes as signaling organelles in metazoans.
SUMMARY Numerous studies in humans link a nonsynonymous genetic polymorphism (I148M) in adiponutrin (ADPN) to various forms of fatty liver disease and liver cirrhosis. Despite its high clinical relevance, the molecular function of ADPN and the mechanism by which I148M variant affects hepatic metabolism are unclear. Here we show that ADPN promotes cellular lipid synthesis by converting lysophosphatidic acid (LPA) into phosphatidic acid. The ADPN-catalyzed LPA acyltransferase (LPAAT) reaction is specific for LPA and long-chain acyl-CoAs. Wild-type mice receiving a high-sucrose diet exhibit substantial upregulation of Adpn in the liver and a concomitant increase in LPAAT activity. In Adpn-deficient mice, this diet-induced increase in hepatic LPAAT activity is reduced. Notably, the I148M variant of human ADPN exhibits increased LPAAT activity leading to increased cellular lipid accumulation. This gain of function provides a plausible biochemical mechanism for the development of liver steatosis in subjects carrying the I148M variant.
Lipid droplets (LDs) are found in nearly all eukaryotic cells, and each consists of a neutral lipid core enveloped by a phospholipid monolayer and surface proteins ( 1 ). The main lipids found in the cores of LDs are triacylglycerols (TGs) and sterol esters (SEs). Whether TGs are required for the formation of LDs is unknown. The major known enzymes that catalyze TG synthesis in mammals are the acyl CoA:diacylglycerol acyltransferases (DGAT; Fig. 1A ) ( 2 ), which catalyze the covalent addition of a fatty acyl chain to diacylglycerol. Genetic deletion of DGAT1 in mice revealed that this enzyme is not essential and that DGAT1 knockout (DGAT1 KO) mice have reductions in TG levels in many tissues, including adipose tissue, when fed a high-fat diet ( 3 ). Deletion of DGAT2 revealed that this enzyme is essential: mice lacking DGAT2 have severe reductions in TG levels and die shortly after birth ( 4 ). Nevertheless, newborn DGAT2 KO mice do have some TG, which may be due to DGAT1 activity. Given that enzymes in both the DGAT1 (MBOAT, 16 family members) and DGAT2 (7 members) families possess many different lipid acyltransferase activities ( 5, 6 ), and that several of these Abstract The total contribution of the acyl CoA:diacylglycerol acyltransferase (DGAT) enzymes, DGAT1 and DGAT2, to mammalian triacylglycerol (TG) synthesis has not been determined. Similarly, whether DGAT enzymes are required for lipid droplet (LD) formation is unknown. In this study, we examined the requirement for DGAT enzymes in TG synthesis and LDs in differentiated adipocytes with genetic deletions of DGAT1 and DGAT2. Adipocytes with a single deletion of either enzyme were capable of TG synthesis and LD formation. In contrast, adipocytes with deletions of both DGATs were severely lacking in TG and did not have LDs, indicating that DGAT1 and DGAT2 account for nearly all TG synthesis in adipocytes and appear to be required for LD formation during adipogenesis. DGAT enzymes were not absolutely required for LD formation in mammalian cells, however; macrophages defi cient in both DGAT enzymes were able to form LDs when incubated with cholesterolrich lipoproteins. Although adipocytes lacking both DGATs had no TG or LDs, they were fully differentiated by multiple criteria.Our fi ndings show that DGAT1 and DGAT2 account for the vast majority of TG synthesis in mice, and DGAT function is required for LDs in adipocytes, but not in all cell
Beige and brown adipocytes generate heat in response to reductions in ambient temperature. When warmed, both beige and brown adipocytes exhibit morphological "whitening," but it is unknown whether or to what extent this represents a true shift in cellular identity. Using cell-type-specific profiling in vivo, we uncover a unique paradigm of temperature-dependent epigenomic plasticity of beige, but not brown, adipocytes, with conversion from a brown to a white chromatin state. Despite this profound shift in cellular identity, warm whitened beige adipocytes retain an epigenomic memory of prior cold exposure defined by an array of poised enhancers that prime thermogenic genes for rapid response during a second bout of cold exposure. We further show that a transcriptional cascade involving glucocorticoid receptor and Zfp423 can drive warm-induced whitening of beige adipocytes. These studies identify the epigenomic and transcriptional bases of an extraordinary example of cellular plasticity in response to environmental signals.
Comparative gene identification-58 (CGI-58), also designated as ␣/-hydrolase domain containing-5 (ABHD-5), is a lipid droplet-associated protein that activates adipose triglyceride lipase (ATGL) and acylates lysophosphatidic acid. Activation of ATGL initiates the hydrolytic catabolism of cellular triacylglycerol (TG) stores to glycerol and nonesterified fatty acids. Mutations in both ATGL and CGI-58 cause "neutral lipid storage disease" characterized by massive accumulation of TG in various tissues. The analysis of CGI-58-deficient (Cgi-58 ؊/؊ ) mice, presented in this study, reveals a dual function of CGI-58 in lipid metabolism. First, systemic TG accumulation and severe hepatic steatosis in newborn Cgi-58 ؊/؊ mice establish a limiting role for CGI-58 in ATGL-mediated TG hydrolysis and supply of nonesterified fatty acids as energy substrate. Second, a severe skin permeability barrier defect uncovers an essential ATGLindependent role of CGI-58 in skin lipid metabolism. The neonatal lethal skin barrier defect is linked to an impaired hydrolysis of epidermal TG. As a consequence, sequestration of fatty acids in TG prevents the synthesis of acylceramides, which are essential lipid precursors for the formation of a functional skin permeability barrier. This mechanism may also underlie the pathogenesis of ichthyosis in neutral lipid storage disease patients lacking functional CGI-58.Fatty acids (FA) 3 are major energy substrates and essential components of membrane lipids as well as of numerous bioactive lipid species. Because excessive cellular concentrations of nonesterified FA are toxic, eukaryotic cells detoxify them by esterification to triacylglycerols (TG), which are subsequently stored in cellular lipid droplets (LD). Adipose tissue is the major storage organ for TG. However, some LD are found in essentially all cell types and tissues. Depending on the nutritional status and the energy demand of an organism, TG are synthesized (lipogenesis) or catabolized (lipolysis). Defects in the control of the finely regulated balance between lipogenesis and lipolysis result in the development of metabolic disorders such as obesity, type II diabetes, lipodystrophy, and neutral lipid storage disease (NLSD) (1-6).Hydrolysis of TG is mediated by the enzymatic activity of adipose triglyceride lipase (ATGL) (7-9) and hormone-sensitive lipase (10, 11). Whereas hormone-sensitive lipase-deficient mice exhibit a relatively benign phenotype (12, 13), mice lacking ATGL massively accumulate TG in multiple tissues, exhibit a severe defect in energy metabolism, and die prematurely due to cardiac dysfunction (14). Similarly, humans with mutations in the ATGL gene lacking normal enzyme function develop NLSD associated with skeletal and cardiac myopathy (15). In severe cases, cardiomyopathy necessitates heart transplantation (16).Studies in this laboratory and by others demonstrated that both human and murine ATGL are stimulated by a protein designated as CGI-58 (comparative gene identification-58) (17, 18) or ABHD5 (␣/-hydrolase domain...
Background: Adipose triglyceride lipase (ATGL) degrades triacylglycerol to diacylglycerol (DAG). The stereo/regioselectivity of ATGL is unknown. Results: ATGL specifically generates sn-1,3 and, in the presence of its co-activator CGI-58, sn-1,3 and sn-2,3 DAG. Conclusion: ATGL generates distinct DAG isoforms that cannot directly enter phospholipid synthesis or activate protein kinase C. Significance: Elucidation of the stereo/regioselectivity of ATGL is crucial to understand cellular DAG metabolism and signaling.
Obesity and the metabolic syndrome are major contributors to morbidity and mortality from a variety of diseases affecting virtually all organ systems ( 1 ). Obesity is essentially a disorder of lipid accumulation, primarily in the form of triacylglycerols (TAGs) in adipose tissue. TAGs serve as a critical reservoir for lipid metabolites involved not only in energy homeostasis but also other essential cellular processes including membrane synthesis and cell signaling. In the context of chronic energy excess and/or impaired lipid metabolism, TAGs accumulate in metabolically relevant nonadipose tissues such as liver, where they are associated with cellular and systemic Abstract PNPLA3 (adiponutrin, calcium-independent phospholipase A 2 epsilon [iPLA 2 ]) is an adipose-enriched, nutritionally regulated protein that belongs to the patatinlike phospholipase domain containing (PNPLA) family of lipid metabolizing proteins. Genetic variations in the human PNPLA3 gene (i.e., the rs738409 I148M allele) has been strongly and repeatedly associated with fatty liver disease. Although human PNPLA3 has triacylglycerol (TAG) hydrolase and transacylase activities in vitro, its in vivo function and physiological relevance remain controversial. The objective of this study was to determine the metabolic consequences of global targeted deletion of the Pnpla3 gene in mice. We found that Pnpla3 mRNA expression is altered in adipose tissue and liver in response to acute and chronic nutritional challenges. However, global targeted deletion of the Pnpla3 gene in mice did not affect TAG hydrolysis, nor did it infl uence energy/glucose/lipid homoeostasis or hepatic steatosis/injury. Experimental interventions designed to increase Pnpla3 expression (refeeding, high-sucrose diet, diet-induced obesity, and liver X receptor agonism) likewise failed to reveal differences in the above-mentioned metabolic phenotypes. Expression of the Pnpla3 paralog, Pnpla5 , was increased in adipose tissue but not in liver of Pnpla3 -defi cient mice, but compensatory regulation of genes involved in TAG metabolism was not identifi ed. Together these data argue against a role for Pnpla3 loss-of-function in fatty liver disease or metabolic syndrome in mice. -Basantani,
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.