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      A New Targeted Lipidomics Approach Reveals Lipid Droplets in Liver, Muscle and Heart as a Repository for Diacylglycerol and Ceramide Species in Non-Alcoholic Fatty Liver

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          Abstract

          Obesity is frequently associated with excessive accumulation of lipids in ectopic tissue and presents a major risk factor for type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). Diacylglycerols (DAGs) and ceramides (CERs) were identified as key players in lipid-induced insulin resistance, typical for such diseases. Recent results suggest that the subcellular distribution of these lipids affects their lipotoxic properties. However, the subcellular dynamics of these lipids and the role of lipid droplets (LDs) as a potential storage site is not understood. Here, we developed a liquid chromatography triple quadrupole mass spectrometry (LC-MS/MS)-method for the rapid and simultaneous quantification of DAG and CER species in tissue sample fractions. The assay is characterized by excellent recovery of analytes, limit of quantification, accuracy and precision. We established a fractionation protocol that allows the separation of subcellular tissue fractions. This method was subsequently tested to measure the concentration of DAGs and CERs in subcellular fractions of human muscle and several mouse tissues. In a mouse model of NAFLD, application of this method revealed a prominent role for LDs as repository for lipotoxic DAG and CER species. In conclusion, the new method proved as a valuable tool to analyse the subcellular dynamics of lipotoxins, related to the pathogenesis of insulin resistance, T2D and NAFLD.

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          Regulation of lipolysis in adipocytes.

          Robin Duncan, Maryam Ahmadian, Kathy Jaworski … (2007)
          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.
          Article 0 comments Cited 305 times – based on 0 reviews     Review now
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            Triacylglycerol synthesis enzymes mediate lipid droplet growth by relocalizing from the ER to lipid droplets.

            Florian Wilfling, Huajin Wang, Joel T. Haas … (2013)
            Lipid droplets (LDs) store metabolic energy and membrane lipid precursors. With excess metabolic energy, cells synthesize triacylglycerol (TG) and form LDs that grow dramatically. It is unclear how TG synthesis relates to LD formation and growth. Here, we identify two LD subpopulations: smaller LDs of relatively constant size, and LDs that grow larger. The latter population contains isoenzymes for each step of TG synthesis. Glycerol-3-phosphate acyltransferase 4 (GPAT4), which catalyzes the first and rate-limiting step, relocalizes from the endoplasmic reticulum (ER) to a subset of forming LDs, where it becomes stably associated. ER-to-LD targeting of GPAT4 and other LD-localized TG synthesis isozymes is required for LD growth. Key features of GPAT4 ER-to-LD targeting and function in LD growth are conserved between Drosophila and mammalian cells. Our results explain how TG synthesis is coupled with LD growth and identify two distinct LD subpopulations based on their capacity for localized TG synthesis. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study.

              M Krššák, K Falk Petersen, A Dresner … (1999)
              Recent muscle biopsy studies have shown a relation between intramuscular lipid content and insulin resistance. The aim of this study was to test this relation in humans by using a novel proton nuclear magnetic resonance (1H NMR) spectroscopy technique, which enables non-invasive and rapid (approximately 45 min) determination of intramyocellular lipid (IMCL) content. Normal weight non-diabetic adults (n = 23, age 29+/-2 years. BMI = 24.1+/-0.5 kg/m2) were studied using cross-sectional analysis. Insulin sensitivity was assessed by a 2-h hyperinsulinaemic (approximately 450 pmol/l)-euglycaemic (approximately 5 mmol/l) clamp test. Intramyocellular lipid concentrations were determined by using localized 1H NMR spectroscopy of soleus muscle. Simple linear regression analysis showed an inverse correlation (r = -0.579, p = 0.0037) [corrected] between intramyocellular lipid content and M-value (100-120 min of clamp) as well as between fasting plasma non-esterified fatty acid concentration and M-value (r = -0.54, p = 0.0267). Intramyocellular lipid content was not related to BMI, age and fasting plasma concentrations of triglycerides, non-esterified fatty acids, glucose or insulin. These results show that intramyocellular lipid concentration, as assessed non invasively by localized 1H NMR spectroscopy, is a good indicator of whole body insulin sensitivity in non-diabetic, non-obese humans.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cells
                Journal ID (iso-abbrev): Cells
                Journal ID (publisher-id): cells
                Title: Cells
                Publisher: MDPI
                ISSN (Electronic): 2073-4409
                Publication date (Electronic): 22 March 2019
                Publication date Collection: March 2019
                Volume: 8
                Issue: 3
                Electronic Location Identifier: 277
                Affiliations
                [1 ]Institute for Clinical Diabetology, German Diabetes Center, c/o Auf’m Hennekamp 65, D-40225 Düsseldorf, Germany; Christina.Preuss@ 123456ddz.de (C.P.); Tomas.Jelenik@ 123456ddz.de (T.J.); Kalman.Bodis@ 123456ddz.de (K.B.); Karsten.Muessig@ 123456ddz.de (K.M.); Volker.Burkart@ 123456ddz.de (V.B.); Julia.Szendroedi@ 123456ddz.de (J.S.); Michael.Roden@ 123456ddz.de (M.R.)
                [2 ]German Center for Diabetes Research (DZD e.V.), D-85764 München, Neuherberg, Germany
                [3 ]Division of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University, D-40225 Düsseldorf, Germany
                Author notes
                Article
                Publisher ID: cells-08-00277
                DOI: 10.3390/cells8030277
                PMC ID: 6468791
                PubMed ID: 30909521
                SO-VID: e18880e3-e595-43a7-a1a0-20a2f4a938ca
                Copyright © © 2019 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 30 January 2019
                Date accepted : 19 March 2019
                Categories
                Subject: Article

                Keywords: non-alcoholic fatty liver,lipid-induced insulin resistance,diacylglycerol,ceramide,lipid droplet,type 2 diabetes
                Data availability:
                Keywords: non-alcoholic fatty liver, lipid-induced insulin resistance, diacylglycerol, ceramide, lipid droplet, type 2 diabetes

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