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Nature Metabolism Nov 2021The perception that intracellular lipolysis is a straightforward process that releases fatty acids from fat stores in adipose tissue to generate energy has experienced... (Review)
Review
The perception that intracellular lipolysis is a straightforward process that releases fatty acids from fat stores in adipose tissue to generate energy has experienced major revisions over the last two decades. The discovery of new lipolytic enzymes and coregulators, the demonstration that lipophagy and lysosomal lipolysis contribute to the degradation of cellular lipid stores and the characterization of numerous factors and signalling pathways that regulate lipid hydrolysis on transcriptional and post-transcriptional levels have revolutionized our understanding of lipolysis. In this review, we focus on the mechanisms that facilitate intracellular fatty-acid mobilization, drawing on canonical and noncanonical enzymatic pathways. We summarize how intracellular lipolysis affects lipid-mediated signalling, metabolic regulation and energy homeostasis in multiple organs. Finally, we examine how these processes affect pathogenesis and how lipolysis may be targeted to potentially prevent or treat various diseases.
Topics: Adipose Tissue; Animals; Biomarkers; Disease Management; Disease Susceptibility; Energy Metabolism; Fatty Acids; Gene Expression Regulation, Enzymologic; Humans; Lipid Mobilization; Lipolysis; Metabolic Networks and Pathways; Molecular Targeted Therapy; Protein Processing, Post-Translational; Triglycerides
PubMed: 34799702
DOI: 10.1038/s42255-021-00493-6 -
Cell Metabolism Mar 2012Lipolysis is defined as the catabolism of triacylglycerols stored in cellular lipid droplets. Recent discoveries of essential lipolytic enzymes and characterization of... (Review)
Review
Lipolysis is defined as the catabolism of triacylglycerols stored in cellular lipid droplets. Recent discoveries of essential lipolytic enzymes and characterization of numerous regulatory proteins and mechanisms have fundamentally changed our perception of lipolysis and its impact on cellular metabolism. New findings that lipolytic products and intermediates participate in cellular signaling processes and that "lipolytic signaling" is particularly important in many nonadipose tissues unveil a previously underappreciated aspect of lipolysis, which may be relevant for human disease.
Topics: Animals; Humans; Lipase; Lipid Metabolism; Lipolysis; Signal Transduction
PubMed: 22405066
DOI: 10.1016/j.cmet.2011.12.018 -
Annual Review of Nutrition 2007Lipolysis of white adipose tissue triacylglycerol stores results in the liberation of glycerol and nonesterified fatty acids that are released into the vasculature for... (Review)
Review
Lipolysis of white adipose tissue triacylglycerol stores results in the liberation of glycerol and nonesterified fatty acids that are released into the vasculature for use by other organs as energy substrates. In response to changes in nutritional state, lipolysis rates are precisely regulated through hormonal and biochemical signals. These signals modulate the activity of lipolytic enzymes and accessory proteins, allowing for maximal responsiveness of adipose tissue to changes in energy requirements and availability. Recently, a number of novel adipocyte triacylglyceride lipases have been identified, including desnutrin/ATGL, greatly expanding our understanding of adipocyte lipolysis. We have also begun to better appreciate the role of a number of nonenzymatic proteins that are critical to triacylglyceride breakdown. This review provides an overview of key mediators of lipolysis and the regulation of this process by changes in nutritional status and nutrient intakes.
Topics: Adipocytes; Animals; Hormones; Humans; Lipase; Lipolysis; Nutritional Status; Signal Transduction; Triglycerides
PubMed: 17313320
DOI: 10.1146/annurev.nutr.27.061406.093734 -
The Biochemical Journal Mar 2020Fatty acids (FAs) are stored safely in the form of triacylglycerol (TAG) in lipid droplet (LD) organelles by professional storage cells called adipocytes. These lipids... (Review)
Review
Fatty acids (FAs) are stored safely in the form of triacylglycerol (TAG) in lipid droplet (LD) organelles by professional storage cells called adipocytes. These lipids are mobilized during adipocyte lipolysis, the fundamental process of hydrolyzing TAG to FAs for internal or systemic energy use. Our understanding of adipocyte lipolysis has greatly increased over the past 50 years from a basic enzymatic process to a dynamic regulatory one, involving the assembly and disassembly of protein complexes on the surface of LDs. These dynamic interactions are regulated by hormonal signals such as catecholamines and insulin which have opposing effects on lipolysis. Upon stimulation, patatin-like phospholipase domain containing 2 (PNPLA2)/adipocyte triglyceride lipase (ATGL), the rate limiting enzyme for TAG hydrolysis, is activated by the interaction with its co-activator, alpha/beta hydrolase domain-containing protein 5 (ABHD5), which is normally bound to perilipin 1 (PLIN1). Recently identified negative regulators of lipolysis include G0/G1 switch gene 2 (G0S2) and PNPLA3 which interact with PNPLA2 and ABHD5, respectively. This review focuses on the dynamic protein-protein interactions involved in lipolysis and discusses some of the emerging concepts in the control of lipolysis that include allosteric regulation and protein turnover. Furthermore, recent research demonstrates that many of the proteins involved in adipocyte lipolysis are multifunctional enzymes and that lipolysis can mediate homeostatic metabolic signals at both the cellular and whole-body level to promote inter-organ communication. Finally, adipocyte lipolysis is involved in various diseases such as cancer, type 2 diabetes and fatty liver disease, and targeting adipocyte lipolysis is of therapeutic interest.
Topics: Adipocytes; Animals; Diabetes Mellitus; Energy Metabolism; Enzyme Inhibitors; Humans; Lipolysis; Neoplasms; Non-alcoholic Fatty Liver Disease; Protein Interaction Domains and Motifs
PubMed: 32168372
DOI: 10.1042/BCJ20190468 -
Biochimica Et Biophysica Acta.... Oct 2017Lipid droplets in chordates are decorated by two or more members of the perilipin family of lipid droplet surface proteins. The perilipins sequester lipids by protecting... (Review)
Review
Lipid droplets in chordates are decorated by two or more members of the perilipin family of lipid droplet surface proteins. The perilipins sequester lipids by protecting lipid droplets from lipase action. Their relative expression and protective nature is adapted to the balance of lipid storage and utilization in specific cells. Most cells of the body have tiny lipid droplets with perilipins 2 and 3 at the surfaces, whereas specialized fat-storing cells with larger lipid droplets also express perilipins 1, 4, and/or 5. Perilipins 1, 2, and 5 modulate lipolysis by controlling the access of lipases and co-factors of lipases to substrate lipids stored within lipid droplets. Although perilipin 2 is relatively permissive to lipolysis, perilipins 1 and 5 have distinct control mechanisms that are altered by phosphorylation. Here we evaluate recent progress toward understanding functions of the perilipins with a focus on their role in regulating lipolysis and autophagy. This article is part of a Special Issue entitled: Recent Advances in Lipid Droplet Biology edited by Rosalind Coleman and Matthijs Hesselink.
Topics: Animals; Autophagy; Humans; Lipid Droplets; Lipolysis; Perilipin-1; Phosphorylation
PubMed: 28754637
DOI: 10.1016/j.bbalip.2017.07.009 -
Current Opinion in Genetics &... Dec 2023White adipose tissue stores fatty acid (FA) as triglyceride in the lipid droplet organelle of highly specialized cells known as fat cells or adipocytes. Depending on the... (Review)
Review
White adipose tissue stores fatty acid (FA) as triglyceride in the lipid droplet organelle of highly specialized cells known as fat cells or adipocytes. Depending on the nutritional state and energy demand, hormonal and biochemical signals converge on activating an elegant and fundamental process known as lipolysis, which involves triglyceride hydrolysis to FAs. Almost six decades of work have vastly expanded our knowledge of lipolysis from enzymatic processes to complex protein assembly, disassembly, and post-translational modification. Research in recent decades ushered in the discovery of new lipolytic enzymes and coregulators and the characterization of numerous factors and signaling pathways that regulate lipid hydrolysis on transcriptional and post-transcriptional levels. This review will discuss recent developments with particular emphasis on the past two years in enzymatic lipolytic pathways and transcriptional regulation of lipolysis. We will summarize the positive and negative regulators of lipolysis, the adipose tissue microenvironment in lipolysis, and the systemic effects of lipolysis. The dynamic nature of adipocyte lipolysis is emerging as an essential regulator of metabolism and energy balance, and we will discuss recent developments in this area.
Topics: Lipolysis; Lipid Metabolism; Adipose Tissue; Adipocytes; Triglycerides
PubMed: 37738733
DOI: 10.1016/j.gde.2023.102114 -
Cell Reports Jun 2022In hepatocytes, peroxisome proliferator-activated receptor α (PPARα) orchestrates a genomic and metabolic response required for homeostasis during fasting. This...
In hepatocytes, peroxisome proliferator-activated receptor α (PPARα) orchestrates a genomic and metabolic response required for homeostasis during fasting. This includes the biosynthesis of ketone bodies and of fibroblast growth factor 21 (FGF21). Here we show that in the absence of adipose triglyceride lipase (ATGL) in adipocytes, ketone body and FGF21 production is impaired upon fasting. Liver gene expression analysis highlights a set of fasting-induced genes sensitive to both ATGL deletion in adipocytes and PPARα deletion in hepatocytes. Adipose tissue lipolysis induced by activation of the β-adrenergic receptor also triggers such PPARα-dependent responses not only in the liver but also in brown adipose tissue (BAT). Intact PPARα activity in hepatocytes is required for the cross-talk between adipose tissues and the liver during fat mobilization.
Topics: Adipose Tissue; Adipose Tissue, Brown; Adipose Tissue, White; Hepatocytes; Ketone Bodies; Lipolysis; PPAR alpha
PubMed: 35675775
DOI: 10.1016/j.celrep.2022.110910 -
Nature Communications Jul 2022β-Adrenergic signaling is a core regulator of brown adipocyte function stimulating both lipolysis and transcription of thermogenic genes, thereby expanding the capacity...
β-Adrenergic signaling is a core regulator of brown adipocyte function stimulating both lipolysis and transcription of thermogenic genes, thereby expanding the capacity for oxidative metabolism. We have used pharmacological inhibitors and a direct activator of lipolysis to acutely modulate the activity of lipases, thereby enabling us to uncover lipolysis-dependent signaling pathways downstream of β-adrenergic signaling in cultured brown adipocytes. Here we show that induction of lipolysis leads to acute induction of several gene programs and is required for transcriptional regulation by β-adrenergic signals. Using machine-learning algorithms to infer causal transcription factors, we show that PPARs are key mediators of lipolysis-induced activation of genes involved in lipid metabolism and thermogenesis. Importantly, however, lipolysis also activates the unfolded protein response and regulates the core circadian transcriptional machinery independently of PPARs. Our results demonstrate that lipolysis generates important metabolic signals that exert profound pleiotropic effects on transcription and function of cultured brown adipocytes.
Topics: Adipocytes, Brown; Adipose Tissue, Brown; Adrenergic Agents; Lipolysis; Peroxisome Proliferator-Activated Receptors; Thermogenesis
PubMed: 35803907
DOI: 10.1038/s41467-022-31525-8 -
Radiology Apr 2023
Topics: Humans; Lipolysis; Adipose Tissue
PubMed: 36692403
DOI: 10.1148/radiol.221947 -
Comprehensive Physiology Dec 2017Triglyceride molecules represent the major form of storage and transport of fatty acids within cells and in the plasma. The liver is the central organ for fatty acid... (Review)
Review
Triglyceride molecules represent the major form of storage and transport of fatty acids within cells and in the plasma. The liver is the central organ for fatty acid metabolism. Fatty acids accrue in liver by hepatocellular uptake from the plasma and by de novo biosynthesis. Fatty acids are eliminated by oxidation within the cell or by secretion into the plasma within triglyceride-rich very low-density lipoproteins. Notwithstanding high fluxes through these pathways, under normal circumstances the liver stores only small amounts of fatty acids as triglycerides. In the setting of overnutrition and obesity, hepatic fatty acid metabolism is altered, commonly leading to the accumulation of triglycerides within hepatocytes, and to a clinical condition known as nonalcoholic fatty liver disease (NAFLD). In this review, we describe the current understanding of fatty acid and triglyceride metabolism in the liver and its regulation in health and disease, identifying potential directions for future research. Advances in understanding the molecular mechanisms underlying the hepatic fat accumulation are critical to the development of targeted therapies for NAFLD. © 2018 American Physiological Society. Compr Physiol 8:1-22, 2018.
Topics: Biological Transport; Fatty Acids; Humans; Lipid Metabolism; Lipogenesis; Lipolysis; Liver; Non-alcoholic Fatty Liver Disease; Triglycerides
PubMed: 29357123
DOI: 10.1002/cphy.c170012