Special Issue "Lipid Droplets in Disease"

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (31 January 2019)

Special Issue Editor

Guest Editor
Assoc. Prof. Paul Dalhaimer

Department of Chemical and Biomolecular Engineering, University of Tennessee, Knoxville, Knoxville, United States
Website | E-Mail
Interests: lipid droplets; metabolism; nanotechnology

Special Issue Information

Dear Colleagues,

High levels of freely-diffusing fatty acids are toxic to cells. Thus, cells have evolved to convert free fatty acids into more soluble molecules and isolate them from the rest of the cell in dynamic compartments. A rapidly growing area of cell biology research is the study of the conversion of free fatty acids to neutral lipids. This initially occurs in or on the endoplasmic reticulum (ER) membrane by the action of neutral lipid synthesizing enzymes. Once formed, it is postulated that the neutral lipids change the local geometry of the ER membrane. This causes the formation of a lens of neutral lipids, which continues to grow in size and causes the budding of a nascent organelle called a lipid droplet. It is unknown if lipid droplets completely separate from the ER or if they remain attached via their formation stem or form a persistent contact over their surfaces with the outer leaflet of the ER membrane. Once formed, factors such as FSP27 facilitate their fusion. It is at this point that droplet(s) can occupy vast volumes of cells. This is most often observed in adipocytes, and hepatocytes in fatty livers. These observations have led researchers to call lipid droplets the “obesity organelle.” Indeed, excessive sizes and numbers of cellular lipid droplets are one of the hallmarks of obesity. This Special Issue of Cells will improve our understanding of how lipid droplets form from the ER, fuse, and ultimately affect cellular metabolism. Since all eukaryotes have the machinery to produce lipid droplets, submissions are welcome from those studying model organisms.

Assoc. Prof. Paul Dalhaimer
Guest Editor

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Keywords

  • Lipid droplet
  • Neutral lipid
  • Endoplasmic reticulum
  • Metabolic imbalance

Published Papers (11 papers)

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Research

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Open AccessArticle
Characterization of Lipid and Lipid Droplet Metabolism in Human HCC
Received: 9 May 2019 / Revised: 20 May 2019 / Accepted: 21 May 2019 / Published: 27 May 2019
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Abstract
Human hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and the most common cause of death in people with cirrhosis. While previous metabolic studies of HCC have mainly focused on the glucose metabolism (Warburg effect), less attention [...] Read more.
Human hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and the most common cause of death in people with cirrhosis. While previous metabolic studies of HCC have mainly focused on the glucose metabolism (Warburg effect), less attention has been paid to tumor-specific features of the lipid metabolism. Here, we applied a computational approach to analyze major pathways of fatty acid utilization in individual HCC. To this end, we used protein intensity profiles of eleven human HCCs to parameterize tumor-specific kinetic models of cellular lipid metabolism including formation, enlargement, and degradation of lipid droplets (LDs). Our analysis reveals significant inter-tumor differences in the lipid metabolism. The majority of HCCs show a reduced uptake of fatty acids and decreased rate of β-oxidation, however, some HCCs display a completely different metabolic phenotype characterized by high rates of β-oxidation. Despite reduced fatty acid uptake in the majority of HCCs, the content of triacylglycerol is significantly enlarged compared to the tumor-adjacent tissue. This is due to tumor-specific expression profiles of regulatory proteins decorating the surface of LDs and controlling their turnover. Our simulations suggest that HCCs characterized by a very high content of triglycerides comprise regulatory peculiarities that render them susceptible to selective drug targeting without affecting healthy tissue. Full article
(This article belongs to the Special Issue Lipid Droplets in Disease)
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Open AccessArticle
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
Received: 30 January 2019 / Revised: 14 March 2019 / Accepted: 19 March 2019 / Published: 22 March 2019
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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, [...] Read more.
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. Full article
(This article belongs to the Special Issue Lipid Droplets in Disease)
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Open AccessArticle
Ursodeoxycholic Acid Regulates Hepatic Energy Homeostasis and White Adipose Tissue Macrophages Polarization in Leptin-Deficiency Obese Mice
Received: 31 January 2019 / Revised: 12 March 2019 / Accepted: 13 March 2019 / Published: 16 March 2019
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Abstract
Obesity has been shown to play a role in the pathogenesis of several forms of metabolic syndrome, including non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes. Ursodeoxycholic acid (UDCA) has been shown to possess antioxidant and anti-inflammatory properties and prevents mitochondrial dysfunction [...] Read more.
Obesity has been shown to play a role in the pathogenesis of several forms of metabolic syndrome, including non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes. Ursodeoxycholic acid (UDCA) has been shown to possess antioxidant and anti-inflammatory properties and prevents mitochondrial dysfunction in the progression of obesity-associated diseases. The aim of the study was to evaluate the mechanisms of UDCA during obesity-linked hepatic mitochondrial dysfunction and obesity-associated adipose tissue macrophage-induced inflammation in obese mice. UDCA significantly decreased lipid droplets, reduced free fatty acids (FFA) and triglycerides (TG), improved mitochondrial function, and enhanced white adipose tissue browning in ob/ob mice. This is associated with increased hepatic energy expenditure, mitochondria biogenesis, and incorporation of bile acid metabolism (Abca1, Abcg1 mRNA and BSEP, FGFR4, and TGR5 protein). In addition, UDCA downregulated NF-κB and STAT3 phosphorylation by negative regulation of the expression of SOCS1 and SOCS3 signaling. These changes were accompanied by decreased angiogenesis, as shown by the downregulation of VEGF, VCAM, and TGF-βRII expression. Importantly, UDCA is equally effective in reducing whole body adiposity. This is associated with decreased adipose tissue expression of macrophage infiltration (CD11b, CD163, and CD206) and lipogenic capacity markers (lipofuscin, SREBP-1, and CD36). Furthermore, UDCA significantly upregulated adipose browning in association with upregulation of SIRT-1-PGC1-α signaling in epididymis adipose tissue (EWAT). These results suggest that multi-targeted therapies modulate glucose and lipid biosynthesis fluxes, inflammatory response, angiogenesis, and macrophage differentiation. Therefore, it may be suggested that UDCA treatment may be a novel therapeutic agent for obesity. Full article
(This article belongs to the Special Issue Lipid Droplets in Disease)
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Open AccessArticle
Apolipoprotein E4 Alters Astrocyte Fatty Acid Metabolism and Lipid Droplet Formation
Received: 30 January 2019 / Revised: 15 February 2019 / Accepted: 19 February 2019 / Published: 20 February 2019
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Abstract
Lipid droplets (LDs) serve as energy rich reservoirs and have been associated with apolipoprotein E (APOE) and neurodegeneration. The E4 allele of APOE (E4) is the strongest genetic risk factor for the development of late onset Alzheimer’s disease (AD). Since both [...] Read more.
Lipid droplets (LDs) serve as energy rich reservoirs and have been associated with apolipoprotein E (APOE) and neurodegeneration. The E4 allele of APOE (E4) is the strongest genetic risk factor for the development of late onset Alzheimer’s disease (AD). Since both E4 carriers and individuals with AD exhibit a state of cerebral lipid dyshomeostasis, we hypothesized that APOE may play a role in regulating LD metabolism. We found that astrocytes expressing E4 accumulate significantly more and smaller LDs compared to E3 astrocytes. Accordingly, expression of perilipin-2, an essential LD protein component, was higher in E4 astrocytes. We then probed fatty acid (FA) metabolism and found E4 astrocytes to exhibit decreased uptake of palmitate, and decreased oxidation of exogenously supplied oleate and palmitate. We then measured oxygen consumption rate, and found E4 astrocytes to consume more oxygen for endogenous FA oxidation and accumulate more LD-derived metabolites due to incomplete oxidation. Lastly, we found that E4 astrocytes are more sensitive to carnitine palmitoyltransferase-1 inhibition than E3 astrocytes. These findings offer the potential for further studies investigating the link between astrocyte lipid storage, utilization, and neurodegenerative disease as a function of APOE genotype. Full article
(This article belongs to the Special Issue Lipid Droplets in Disease)
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Open AccessArticle
ETF-QO Mutants Uncoupled Fatty Acid β-Oxidation and Mitochondrial Bioenergetics Leading to Lipid Pathology
Received: 11 December 2018 / Revised: 24 January 2019 / Accepted: 28 January 2019 / Published: 31 January 2019
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Abstract
The electron-transfer flavoprotein dehydrogenase gene (ETFDH) that encodes the ETF-ubiquinone oxidoreductase (ETF-QO) has been reported to be the major cause of multiple acyl-CoA dehydrogenase deficiency (MADD). ETF-QO is an electron carrier that mainly functions in mitochondrial fatty acid β-oxidation and the [...] Read more.
The electron-transfer flavoprotein dehydrogenase gene (ETFDH) that encodes the ETF-ubiquinone oxidoreductase (ETF-QO) has been reported to be the major cause of multiple acyl-CoA dehydrogenase deficiency (MADD). ETF-QO is an electron carrier that mainly functions in mitochondrial fatty acid β-oxidation and the delivery of electrons to the ubiquinone pool in the mitochondrial respiratory chain. A high frequency of c.250G>A has been found in Taiwanese patients with late-onset MADD. We postulated that the ETFDH c.250G>A mutation may concomitantly impair fatty acid β-oxidation and mitochondrial function. Using MADD patient-derived lymphoblastoid cells and specifically overexpressed ETFDH c.92C>T, c.250G>A, or coexisted c.92C>T and c.250G>A (c.92C>T + c.250G>A) mutated lymphoblastoid cells, we addressed the genotype-phenotype relationship of ETFDH variation in the pathogenesis of MADD. The decreased adenosine triphosphate synthesis, dissipated mitochondrial membrane potentials, reduced mitochondrial bioenergetics, and increased neutral lipid droplets and lipid peroxides were found in the MADD patient-derived lymphoblastoid cells. Riboflavin and/or coenzyme Q10 supplementation rescued cells from lipid droplet accumulation. All three mutant types, c.92C>T, c.250G>A, or c.92C>T + c.250G>A, had increased lipid droplet accumulation after treatment with palmitic acid. These results help to clarify the molecular pathogenesis of MADD as a result of the high frequency of the ETFDH c.250G>A and c.92C>T mutations. Full article
(This article belongs to the Special Issue Lipid Droplets in Disease)
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Open AccessArticle
Decreasing Phosphatidylcholine on the Surface of the Lipid Droplet Correlates with Altered Protein Binding and Steatosis
Cells 2018, 7(12), 230; https://doi.org/10.3390/cells7120230
Received: 1 November 2018 / Revised: 19 November 2018 / Accepted: 22 November 2018 / Published: 24 November 2018
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Abstract
Alcoholic fatty liver disease (AFLD) is characterized by an abnormal accumulation of lipid droplets (LDs) in the liver. Here, we explore the composition of hepatic LDs in a rat model of AFLD. Five to seven weeks of alcohol consumption led to significant increases [...] Read more.
Alcoholic fatty liver disease (AFLD) is characterized by an abnormal accumulation of lipid droplets (LDs) in the liver. Here, we explore the composition of hepatic LDs in a rat model of AFLD. Five to seven weeks of alcohol consumption led to significant increases in hepatic triglyceride mass, along with increases in LD number and size. Additionally, hepatic LDs from rats with early alcoholic liver injury show a decreased ratio of surface phosphatidylcholine (PC) to phosphatidylethanolamine (PE). This occurred in parallel with an increase in the LD association of perilipin 2, a prominent LD protein. To determine if changes to the LD phospholipid composition contributed to differences in protein association with LDs, we constructed liposomes that modeled the LD PC:PE ratios in AFLD and control rats. Reducing the ratio of PC to PE increased the binding of perilipin 2 to liposomes in an in vitro experiment. Moreover, we decreased the ratio of LD PC:PE in NIH 3T3 and AML12 cells by culturing these cells in choline-deficient media. We again detected increased association of specific LD proteins, including perilipin 2. Taken together, our experiments suggest an important link between LD phospholipids, protein composition, and lipid accumulation. Full article
(This article belongs to the Special Issue Lipid Droplets in Disease)
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Review

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Open AccessReview
Lipid Droplets: A Significant but Understudied Contributor of Host–Bacterial Interactions
Received: 10 March 2019 / Revised: 5 April 2019 / Accepted: 12 April 2019 / Published: 15 April 2019
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Abstract
Lipid droplets (LDs) are cytosolic lipid storage organelles that are important for cellular lipid metabolism, energy homeostasis, cell signaling, and inflammation. Several bacterial, viral and protozoal pathogens exploit host LDs to promote infection, thus emphasizing the importance of LDs at the host–pathogen interface. [...] Read more.
Lipid droplets (LDs) are cytosolic lipid storage organelles that are important for cellular lipid metabolism, energy homeostasis, cell signaling, and inflammation. Several bacterial, viral and protozoal pathogens exploit host LDs to promote infection, thus emphasizing the importance of LDs at the host–pathogen interface. In this review, we discuss the thus far reported relation between host LDs and bacterial pathogens including obligate and facultative intracellular bacteria, and extracellular bacteria. Although there is less evidence for a LD–extracellular bacterial interaction compared to interactions with intracellular bacteria, in this review, we attempt to compare the bacterial mechanisms that target LDs, the host signaling pathways involved and the utilization of LDs by these bacteria. Many intracellular bacteria employ unique mechanisms to target host LDs and potentially obtain nutrients and lipids for vacuolar biogenesis and/or immune evasion. However, extracellular bacteria utilize LDs to either promote host tissue damage or induce host death. We also identify several areas that require further investigation. Along with identifying LD interactions with bacteria besides the ones reported, the precise mechanisms of LD targeting and how LDs benefit pathogens should be explored for the bacteria discussed in the review. Elucidating LD–bacterial interactions promises critical insight into a novel host–pathogen interaction. Full article
(This article belongs to the Special Issue Lipid Droplets in Disease)
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Open AccessReview
Skeletal Muscle Lipid Droplets and the Athlete’s Paradox
Received: 28 January 2019 / Revised: 7 March 2019 / Accepted: 12 March 2019 / Published: 15 March 2019
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Abstract
The lipid droplet (LD) is an organelle enveloped by a monolayer phospholipid membrane with a core of neutral lipids, which is conserved from bacteria to humans. The available evidence suggests that the LD is essential to maintaining lipid homeostasis in almost all organisms. [...] Read more.
The lipid droplet (LD) is an organelle enveloped by a monolayer phospholipid membrane with a core of neutral lipids, which is conserved from bacteria to humans. The available evidence suggests that the LD is essential to maintaining lipid homeostasis in almost all organisms. As a consequence, LDs also play an important role in pathological metabolic processes involving the ectopic storage of neutral lipids, including type 2 diabetes mellitus (T2DM), atherosclerosis, steatosis, and obesity. The degree of insulin resistance in T2DM patients is positively correlated with the size of skeletal muscle LDs. Aerobic exercise can reduce the occurrence and development of various metabolic diseases. However, trained athletes accumulate lipids in their skeletal muscle, and LD size in their muscle tissue is positively correlated with insulin sensitivity. This phenomenon is called the athlete’s paradox. This review will summarize previous studies on the relationship between LDs in skeletal muscle and metabolic diseases and will discuss the paradox at the level of LDs. Full article
(This article belongs to the Special Issue Lipid Droplets in Disease)
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Open AccessReview
CIDE Proteins in Human Health and Disease
Received: 19 February 2019 / Revised: 7 March 2019 / Accepted: 9 March 2019 / Published: 13 March 2019
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Abstract
Cell death-Inducing DNA Fragmentation Factor Alpha (DFFA)-like Effector (CIDE) proteins have emerged as lipid droplet-associated proteins that regulate fat metabolism. There are three members in the CIDE protein family—CIDEA, CIDEB, and CIDEC (also known as fat-specific protein 27 (FSP27)). CIDEA and FSP27 are [...] Read more.
Cell death-Inducing DNA Fragmentation Factor Alpha (DFFA)-like Effector (CIDE) proteins have emerged as lipid droplet-associated proteins that regulate fat metabolism. There are three members in the CIDE protein family—CIDEA, CIDEB, and CIDEC (also known as fat-specific protein 27 (FSP27)). CIDEA and FSP27 are primarily expressed in adipose tissue, while CIDEB is expressed in the liver. Originally, based upon their homology with DNA fragmentation factors, these proteins were identified as apoptotic proteins. However, recent studies have changed the perception of these proteins, redefining them as regulators of lipid droplet dynamics and fat metabolism, which contribute to a healthy metabolic phenotype in humans. Despite various studies in humans and gene-targeting studies in mice, the physiological roles of CIDE proteins remains elusive. This review will summarize the known physiological role and metabolic pathways regulated by the CIDE proteins in human health and disease. Full article
(This article belongs to the Special Issue Lipid Droplets in Disease)
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Open AccessReview
Neutral Lipid Storage Diseases as Cellular Model to Study Lipid Droplet Function
Received: 24 January 2019 / Revised: 14 February 2019 / Accepted: 19 February 2019 / Published: 21 February 2019
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Abstract
Neutral lipid storage disease with myopathy (NLSDM) and with ichthyosis (NLSDI) are rare autosomal recessive disorders caused by mutations in the PNPLA2 and in the ABHD5/CGI58 genes, respectively. These genes encode the adipose triglyceride lipase (ATGL) and α-β hydrolase domain 5 (ABHD5) proteins, [...] Read more.
Neutral lipid storage disease with myopathy (NLSDM) and with ichthyosis (NLSDI) are rare autosomal recessive disorders caused by mutations in the PNPLA2 and in the ABHD5/CGI58 genes, respectively. These genes encode the adipose triglyceride lipase (ATGL) and α-β hydrolase domain 5 (ABHD5) proteins, which play key roles in the function of lipid droplets (LDs). LDs, the main cellular storage sites of triacylglycerols and sterol esters, are highly dynamic organelles. Indeed, LDs are critical for both lipid metabolism and energy homeostasis. Partial or total PNPLA2 or ABHD5/CGI58 knockdown is characteristic of the cells of NLSD patients; thus, these cells are natural models with which one can unravel LD function. In this review we firstly summarize genetic and clinical data collected from NLSD patients, focusing particularly on muscle, skin, heart, and liver damage due to impaired LD function. Then, we discuss how NLSD cells were used to investigate and expand the current structural and functional knowledge of LDs. Full article
(This article belongs to the Special Issue Lipid Droplets in Disease)
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Other

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Open AccessPerspective
Retinoids Issued from Hepatic Stellate Cell Lipid Droplet Loss as Potential Signaling Molecules Orchestrating a Multicellular Liver Injury Response
Received: 3 September 2018 / Revised: 11 September 2018 / Accepted: 13 September 2018 / Published: 13 September 2018
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Abstract
Hepatic stellate cells (HSCs) serve as the main body storage compartment for vitamin A through retinyl ester (RE)-filled lipid droplets (LDs). Upon liver injury, HSCs adopt a myofibroblastic phenotype characterized by an elevated expression of extracellular matrix proteins and a concomitant loss of [...] Read more.
Hepatic stellate cells (HSCs) serve as the main body storage compartment for vitamin A through retinyl ester (RE)-filled lipid droplets (LDs). Upon liver injury, HSCs adopt a myofibroblastic phenotype characterized by an elevated expression of extracellular matrix proteins and a concomitant loss of LDs. On the one hand, LD breakdown has been suggested to provide the energy required for HSC activation into myofibroblast-like cells. On the other hand, this process could mitigate HSC activation following the transformation of released REs into retinoic acids (RAs), ligands for nuclear receptors exerting antifibrotic transcriptional regulatory activities in HSCs. Importantly, RAs may also constitute a means for HSCs to orchestrate the liver response to injury by triggering transcriptional effects in multiple additional surrounding liver cell populations. We envision that new approaches, such as single-cell technologies, will allow to better define how RAs are issued from LD loss in HSCs exert a multicellular control of the liver (patho)physiology. Full article
(This article belongs to the Special Issue Lipid Droplets in Disease)
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