Review

Authors: Michele Alves-Bezerra, David E Cohen

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

Review

Authors: Rudolf Zechner, Robert Zimmermann, Thomas O Eichmann...

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

Review

Authors: Edward T Chouchani, Shingo Kajimura

Adipose tissue possesses the remarkable capacity to control its size and function in response to a variety of internal and external cues, such as nutritional status and temperature. The regulatory circuits of fuel storage and oxidation in white adipocytes and thermogenic adipocytes (brown and beige adipocytes) play a central role in systemic energy homeostasis, whereas dysregulation of the pathways is closely associated with metabolic disorders and adipose tissue malfunction, including obesity, insulin resistance, chronic inflammation, mitochondrial dysfunction, and fibrosis. Recent studies have uncovered new regulatory elements that control the above parameters and provide new mechanistic opportunities to reprogram fat cell fate and function. In this Review, we provide an overview of the current understanding of adipocyte metabolism in physiology and disease and also discuss possible strategies to alter fuel utilization in fat cells to improve metabolic health.

Topics: Adaptation, Physiological; Adipocytes, Beige; Adipose Tissue; Animals; Cellular Reprogramming; Energy Metabolism; Humans; Lipolysis; Mitochondria; Thermogenesis

PubMed: 31903450
DOI: 10.1038/s42255-018-0021-8

Review

Authors: Robin E Duncan, Maryam Ahmadian, Kathy Jaworski...

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

Review

Authors: Alexander Yang, Emilio P Mottillo

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

Authors: Haikuo Li, Eryn E Dixon, Haojia Wu...

The underlying cellular events driving kidney fibrogenesis and metabolic dysfunction are incompletely understood. Here, we employed single-cell combinatorial indexing RNA sequencing to analyze 24 mouse kidneys from two fibrosis models. We profiled 309,666 cells in one experiment, representing 50 cell types/states encompassing epithelial, endothelial, immune, and stromal populations. Single-cell analysis identified diverse injury states of the proximal tubule, including two distinct early-phase populations with dysregulated lipid and amino acid metabolism, respectively. Lipid metabolism was defective in the chronic phase but was transiently activated in the very early stages of ischemia-induced injury, where we discovered increased lipid deposition and increased fatty acid β-oxidation. Perilipin 2 was identified as a surface marker of intracellular lipid droplets, and its knockdown in vitro disrupted cell energy state maintenance during lipid accumulation. Surveying epithelial cells across nephron segments identified shared and unique injury responses. Stromal cells exhibited high heterogeneity and contributed to fibrogenesis by epithelial-stromal crosstalk.

Topics: Animals; Mice; Lipolysis; Fibrosis; Kidney; Lipids

PubMed: 36265491
DOI: 10.1016/j.cmet.2022.09.026

Authors: Gencer Sancar, Sihao Liu, Emanuel Gasser...

Inexorable increases in insulin resistance, lipolysis, and hepatic glucose production (HGP) are hallmarks of type 2 diabetes. Previously, we showed that peripheral delivery of exogenous fibroblast growth factor 1 (FGF1) has robust anti-diabetic effects mediated by the adipose FGF receptor (FGFR) 1. However, its mechanism of action is not known. Here, we report that FGF1 acutely lowers HGP by suppressing adipose lipolysis. On a molecular level, FGF1 inhibits the cAMP-protein kinase A axis by activating phosphodiesterase 4D (PDE4D), which separates it mechanistically from the inhibitory actions of insulin via PDE3B. We identify Ser44 as an FGF1-induced regulatory phosphorylation site in PDE4D that is modulated by the feed-fast cycle. These findings establish the FGF1/PDE4 pathway as an alternate regulator of the adipose-HGP axis and identify FGF1 as an unrecognized regulator of fatty acid homeostasis.

Topics: Diabetes Mellitus, Type 2; Fibroblast Growth Factor 1; Humans; Insulin; Insulin Resistance; Lipolysis

PubMed: 34986332
DOI: 10.1016/j.cmet.2021.12.004

Review

Authors: Ines Katrin Cerk, Lisa Wechselberger, Monika Oberer...

Adipose triglyceride lipase (ATGL) is the key-enzyme for the release of fatty acids (FAs) from triacylglycerol (TG) stores during intracellular lipolysis producing FAs used for energy production. There is growing evidence that the products and intermediates from lipolytic breakdown during the FA mobilization process also have fundamental regulatory functions affecting cell signaling, gene expression, metabolism, cell growth, cell death, and lipotoxicity. Regulation of ATGL is therefore vital for maintaining a defined balance between lipid storage and mobilization. This review addresses the regulation of ATGL activity at the post-translational level with special emphasis on protein-mediated interaction at the site of hydrolytic action, namely to the lipid droplet.

Topics: Animals; Fatty Acids; Humans; Lipase; Lipid Metabolism; Lipids; Lipolysis; Molecular Structure; Protein Conformation; Signal Transduction; Triglycerides

PubMed: 28925902
DOI: 10.2174/1389203718666170918160110

Review

Authors: Carole Sztalryd, Dawn L Brasaemle

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

Authors: Brett A Shook, Renee R Wasko, Omer Mano...

Mature adipocytes store fatty acids and are a common component of tissue stroma. Adipocyte function in regulating bone marrow, skin, muscle, and mammary gland biology is emerging, but the role of adipocyte-derived lipids in tissue homeostasis and repair is poorly understood. Here, we identify an essential role for adipocyte lipolysis in regulating inflammation and repair after injury in skin. Genetic mouse studies revealed that dermal adipocytes are necessary to initiate inflammation after injury and promote subsequent repair. We find through histological, ultrastructural, lipidomic, and genetic experiments in mice that adipocytes adjacent to skin injury initiate lipid release necessary for macrophage inflammation. Tamoxifen-inducible genetic lineage tracing of mature adipocytes and single-cell RNA sequencing revealed that dermal adipocytes alter their fate and generate ECM-producing myofibroblasts within wounds. Thus, adipocytes regulate multiple aspects of repair and may be therapeutic for inflammatory diseases and defective wound healing associated with aging and diabetes.

Topics: Adipocytes; Animals; Lipolysis; Macrophages; Mice; Myofibroblasts; Skin

PubMed: 32302523
DOI: 10.1016/j.stem.2020.03.013