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A special issue of Biology (ISSN 2079-7737).

Deadline for manuscript submissions: closed (30 September 2014) | Viewed by 130205

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Prof. Dr. Annette Graham

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Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow G4 0BA, UK
Interests: intracellular lipid transport in health and disease; lipid and lipoprotein metabolism; vascular contributions to diabetes and Alzheimer’s disease

Special Issue Information

Dear Colleagues,

It is becoming increasingly evident that intracellular proteins can specifically regulate the direction of lipid transport within cells, thereby influencing the storage, synthesis and export of lipids, and the activity of nuclear receptor transcription factors involved in lipid and lipoprotein metabolism. Defective intracellular lipid transport may also contribute to a number of disease states, including metabolic disorders and tumorigenesis.
For this special issue, we invite research articles on aspects of lipid transport within cells and tissues, and particularly those which contribute to our understanding of the role of intracellular lipid transporters in pathological conditions.

Prof. Annette Graham
Guest Editor

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Published Papers (12 papers)

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Research

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121 KiB

Open AccessArticle

Effect of Different Omega-6/Omega-3 Polyunsaturated Fatty Acid Ratios on the Formation of Monohydroxylated Fatty Acids in THP-1 Derived Macrophages

by Kathrin Keeren, Dan Huang, Christopher Smyl, Andreas Fischer, Michael Rothe and Karsten-H. Weylandt

Biology 2015, 4(2), 314-326; https://doi.org/10.3390/biology4020314 - 09 Apr 2015

Cited by 3 | Viewed by 6582

Abstract

Omega-6 and omega-3 polyunsaturated fatty acids (n-6 and n-3 PUFA) can modulate inflammatory processes. In western diets, the content of n-6 PUFA is much higher than that of n-3 PUFA, which has been suggested to promote a pro-inflammatory phenotype. The aim of this study was to analyze the effect of modulating the n-6/n-3 PUFA ratio on the formation of monohydroxylated fatty acid (HO-FAs) derived from the n-6 PUFA arachidonic acid (AA) and the n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in THP-1 macrophages by means of LC-MS. Lipid metabolites were measured in THP-1 macrophage cell pellets. The concentration of AA-derived hydroxyeicosatetraenoic acids (HETEs) was not significantly changed when incubated THP-1 macrophages in a high AA/(EPA+DHA) ratio of 19/1 vs. a low ratio AA/(EPA+DHA) of 1/1 (950.6 ± 110 ng/mg vs. 648.2 ± 92.4 ng/mg, p = 0.103). Correspondingly, the concentration of EPA-derived hydroxyeicosapentaenoic acids (HEPEs) and DHA-derived hydroxydocosahexaenoic acids (HDHAs) were significantly increased (63.9 ± 7.8 ng/mg vs. 434.4 ± 84.3 ng/mg, p = 0.012 and 84.9 ± 18.3 ng/mg vs. 439.4 ± 82.7 ng/mg, p = 0.014, respectively). Most notable was the strong increase of 18-hydroxyeicosapentaenoic acid (18-HEPE) formation in THP-1 macrophages, with levels of 170.9 ± 40.2 ng/mg protein in the high n-3 PUFA treated cells. Thus our data indicate that THP-1 macrophages prominently utilize EPA and DHA for monohydroxylated metabolite formation, in particular 18-HEPE, which has been shown to be released by macrophages to prevent pressure overload-induced maladaptive cardiac remodeling. Full article

(This article belongs to the Special Issue Lipid Metabolism)

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1654 KiB

Open AccessArticle

MALDI Mass Spectrometry Imaging of Lipids and Gene Expression Reveals Differences in Fatty Acid Metabolism between Follicular Compartments in Porcine Ovaries

by Svetlana Uzbekova, Sebastien Elis, Ana-Paula Teixeira-Gomes, Alice Desmarchais, Virginie Maillard and Valerie Labas

Biology 2015, 4(1), 216-236; https://doi.org/10.3390/biology4010216 - 06 Mar 2015

Cited by 35 | Viewed by 9917

Abstract

In mammals, oocytes develop inside the ovarian follicles; this process is strongly supported by the surrounding follicular environment consisting of cumulus, granulosa and theca cells, and follicular fluid. In the antral follicle, the final stages of oogenesis require large amounts of energy that is produced by follicular cells from substrates including glucose, amino acids and fatty acids (FAs). Since lipid metabolism plays an important role in acquiring oocyte developmental competence, the aim of this study was to investigate site-specificity of lipid metabolism in ovaries by comparing lipid profiles and expression of FA metabolism-related genes in different ovarian compartments. Using MALDI Mass Spectrometry Imaging, images of porcine ovary sections were reconstructed from lipid ion signals for the first time. Cluster analysis of ion spectra revealed differences in spatial distribution of lipid species among ovarian compartments, notably between the follicles and interstitial tissue. Inside the follicles analysis differentiated follicular fluid, granulosa, theca and the oocyte-cumulus complex. Moreover, by transcript quantification using real time PCR, we showed that expression of five key genes in FA metabolism significantly varied between somatic follicular cells (theca, granulosa and cumulus) and the oocyte. In conclusion, lipid metabolism differs between ovarian and follicular compartments. Full article

(This article belongs to the Special Issue Lipid Metabolism)

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573 KiB

Open AccessArticle

StAR Protein Stability in Y1 and Kin-8 Mouse Adrenocortical Cells

by Barbara J. Clark and Elizabeth A. Hudson

Biology 2015, 4(1), 200-215; https://doi.org/10.3390/biology4010200 - 04 Mar 2015

Cited by 8 | Viewed by 5669

Abstract

The steroidogenic acute regulatory protein (STAR) protein expression is required for cholesterol transport into mitochondria to initiate steroidogenesis in the adrenal and gonads. STAR is synthesized as a 37 kDa precursor protein which is targeted to the mitochondria and imported and processed to an intra-mitochondrial 30 kDa protein. Tropic hormone stimulation of the cAMP-dependent protein kinase A (PKA) signaling pathway is the major contributor to the transcriptional and post-transcriptional regulation of STAR synthesis. Many studies have focused on the mechanisms of cAMP-PKA mediated control of STAR synthesis while there are few reports on STAR degradation pathways. The objective of this study was to determine the effect of cAMP-PKA-dependent signaling on STAR protein stability. We have used the cAMP-PKA responsive Y1 mouse adrenocortical cells and the PKA-deficient Kin-8 cells to measure STAR phosphorylation and protein half-life. Western blot analysis and standard radiolabeled pulse-chase experiments were used to determine STAR phosphorylation status and protein half-life, respectively. Our data demonstrate that PKA-dependent STAR phosphorylation does not contribute to 30 kDa STAR protein stability in the mitochondria. We further show that inhibition of the 26S proteasome does not block precursor STAR phosphorylation or steroid production in Y1 cells. These data suggest STAR can maintain function and promote steroidogenesis under conditions of proteasome inhibition. Full article

(This article belongs to the Special Issue Lipid Metabolism)

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Open AccessArticle

The Human ABCG1 Transporter Mobilizes Plasma Membrane and Late Endosomal Non-Sphingomyelin-Associated-Cholesterol for Efflux and Esterification

by Edward B. Neufeld, Katherine O'Brien, Avram D. Walts, John A. Stonik, Daniela Malide, Christian A. Combs and Alan T. Remaley

Biology 2014, 3(4), 866-891; https://doi.org/10.3390/biology3040866 - 04 Dec 2014

Cited by 17 | Viewed by 7389

Abstract

We have previously shown that GFP-tagged human ABCG1 on the plasma membrane (PM) and in late endosomes (LE) mobilizes sterol on both sides of the membrane lipid bilayer, thereby increasing cellular cholesterol efflux to lipid surfaces. In the present study, we examined ABCG1-induced changes in membrane cholesterol distribution, organization, and mobility. ABCG1-GFP expression increased the amount of mobile, non-sphingomyelin(SM)-associated cholesterol at the PM and LE, but not the amount of SM-associated-cholesterol or SM. ABCG1-mobilized non-SM-associated-cholesterol rapidly cycled between the PM and LE and effluxed from the PM to extracellular acceptors, or, relocated to intracellular sites of esterification. ABCG1 increased detergent-soluble pools of PM and LE cholesterol, generated detergent-resistant, non-SM-associated PM cholesterol, and increased resistance to both amphotericin B-induced (cholesterol-mediated) and lysenin-induced (SM-mediated) cytolysis, consistent with altered organization of both PM cholesterol and SM. ABCG1 itself resided in detergent-soluble membrane domains. We propose that PM and LE ABCG1 residing at the phase boundary between ordered (L_o) and disordered (L_d) membrane lipid domains alters SM and cholesterol organization thereby increasing cholesterol flux between L_o and L_d, and hence, the amount of cholesterol available for removal by acceptors on either side of the membrane bilayer for either efflux or esterification. Full article

(This article belongs to the Special Issue Lipid Metabolism)

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1968 KiB

Open AccessArticle

Cellular Localization and Trafficking of the Human ABCG1 Transporter

by Edward B. Neufeld, Katherine O'Brien, Avram D. Walts, John A. Stonik, Steven J. Demosky, Jr., Daniela Malide, Christian A. Combs and Alan T. Remaley

Biology 2014, 3(4), 781-800; https://doi.org/10.3390/biology3040781 - 14 Nov 2014

Cited by 23 | Viewed by 6877

Abstract

We have developed a suitable heterologous cell expression system to study the localization, trafficking, and site(s) of function of the human ABCG1 transporter. Increased plasma membrane (PM) and late endosomal (LE) cholesterol generated by ABCG1 was removed by lipoproteins and liposomes, but not apoA-I. Delivery of ABCG1 to the PM and LE was required for ABCG1-mediated cellular cholesterol efflux. ABCG1 LEs frequently contacted the PM, providing a collisional mechanism for transfer of ABCG1-mobilized cholesterol, similar to ABCG1-mediated PM cholesterol efflux to lipoproteins. ABCG1-mobilized LE cholesterol also trafficked to the PM by a non-vesicular pathway. Transfer of ABCG1-mobilized cholesterol from the cytoplasmic face of LEs to the PM and concomitant removal of cholesterol from the outer leaflet of the PM bilayer by extracellular acceptors suggests that ABCG1 mobilizes cholesterol on both sides of the lipid bilayer for removal by acceptors. ABCG1 increased uptake of HDL into LEs, consistent with a potential ABCG1-mediated cholesterol efflux pathway involving HDL resecretion. Thus, ABCG1 at the PM mobilizes PM cholesterol and ABCG1 in LE/LYS generates mobile pools of cholesterol that can traffic by both vesicular and non-vesicular pathways to the PM where it can also be transferred to extracellular acceptors with a lipid surface. Full article

(This article belongs to the Special Issue Lipid Metabolism)

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335 KiB

Open AccessArticle

Genetic Risk Scores Associated with Baseline Lipoprotein Subfraction Concentrations Do Not Associate with Their Responses to Fenofibrate

by Alexis C. Frazier-Wood, Mary K. Wojczynski, Ingrid B. Borecki, Paul N. Hopkins, Chao-Qiang Lai, Jose M. Ordovas, Robert J. Straka, Micheal Y. Tsai, Hemant K. Tiwari and Donna K. Arnett

Biology 2014, 3(3), 536-550; https://doi.org/10.3390/biology3030536 - 25 Aug 2014

Cited by 1 | Viewed by 6338

Abstract

Lipoprotein subclass concentrations are modifiable markers of cardiovascular disease risk. Fenofibrate is known to show beneficial effects on lipoprotein subclasses, but little is known about the role of genetics in mediating the responses of lipoprotein subclasses to fenofibrate. A recent genomewide association study (GWAS) associated several single nucleotide polymorphisms (SNPs) with lipoprotein measures, and validated these associations in two independent populations. We used this information to construct genetic risk scores (GRSs) for fasting lipoprotein measures at baseline (pre-fenofibrate), and aimed to examine whether these GRSs also associated with the responses of lipoproteins to fenofibrate. Fourteen lipoprotein subclass measures were assayed in 817 men and women before and after a three week fenofibrate trial. We set significance at a Bonferroni corrected alpha <0.05 (p < 0.004). Twelve subclass measures changed with fenofibrate administration (each p = 0.003 to <0.0001). Mixed linear models which controlled for age, sex, body mass index (BMI), smoking status, pedigree and study-center, revealed that GRSs were associated with eight baseline lipoprotein measures (p < 0.004), however no GRS was associated with fenofibrate response. These results suggest that the mechanisms for changes in lipoprotein subclass concentrations with fenofibrate treatment are not mediated by the genetic risk for fasting levels. Full article

(This article belongs to the Special Issue Lipid Metabolism)

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Review

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134 KiB

Open AccessReview

Stearoyl-CoA Desaturase-1: Is It the Link between Sulfur Amino Acids and Lipid Metabolism?

by Soraia Poloni, Henk J. Blom and Ida V. D. Schwartz

Biology 2015, 4(2), 383-396; https://doi.org/10.3390/biology4020383 - 03 Jun 2015

Cited by 31 | Viewed by 9894

Abstract

An association between sulfur amino acids (methionine, cysteine, homocysteine and taurine) and lipid metabolism has been described in several experimental and population-based studies. Changes in the metabolism of these amino acids influence serum lipoprotein concentrations, although the underlying mechanisms are still poorly understood. However, recent evidence has suggested that the enzyme stearoyl-CoA desaturase-1 (SCD-1) may be the link between these two metabolic pathways. SCD-1 is a key enzyme for the synthesis of monounsaturated fatty acids. Its main substrates C16:0 and C18:0 and products palmitoleic acid (C16:1) and oleic acid (C18:1) are the most abundant fatty acids in triglycerides, cholesterol esters and membrane phospholipids. A significant suppression of SCD-1 has been observed in several animal models with disrupted sulfur amino acid metabolism, and the activity of SCD-1 is also associated with the levels of these amino acids in humans. This enzyme also appears to be involved in the etiology of metabolic syndromes because its suppression results in decreased fat deposits (regardless of food intake), improved insulin sensitivity and higher basal energy expenditure. Interestingly, this anti-obesogenic phenotype has also been described in humans and animals with sulfur amino acid disorders, which is consistent with the hypothesis that SCD-1 activity is influenced by these amino acids, in particularly cysteine, which is a strong and independent predictor of SCD-1 activity and fat storage. In this narrative review, we discuss the evidence linking sulfur amino acids, SCD-1 and lipid metabolism. Full article

(This article belongs to the Special Issue Lipid Metabolism)

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Open AccessReview

Oncostatin M Modulation of Lipid Storage

by Carrie M. Elks and Jacqueline M. Stephens

Biology 2015, 4(1), 151-160; https://doi.org/10.3390/biology4010151 - 13 Feb 2015

Cited by 13 | Viewed by 7709

Abstract

Oncostatin M (OSM) is a cytokine belonging to the gp130 family, whose members serve pleiotropic functions. However, several actions of OSM are unique from those of other gp130 cytokines, and these actions may have critical roles in inflammatory mechanisms influencing several metabolic and biological functions of insulin-sensitive tissues. In this review, the actions of OSM in adipose tissue and liver are discussed, with an emphasis on lipid metabolism. Full article

(This article belongs to the Special Issue Lipid Metabolism)

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954 KiB

Open AccessReview

Lipids around the Clock: Focus on Circadian Rhythms and Lipid Metabolism

by Davide Gnocchi, Matteo Pedrelli, Eva Hurt-Camejo and Paolo Parini

Biology 2015, 4(1), 104-132; https://doi.org/10.3390/biology4010104 - 05 Feb 2015

Cited by 72 | Viewed by 15927

Abstract

Disorders of lipid and lipoprotein metabolism and transport are responsible for the development of a large spectrum of pathologies, ranging from cardiovascular diseases, to metabolic syndrome, even to tumour development. Recently, a deeper knowledge of the molecular mechanisms that control our biological clock and circadian rhythms has been achieved. From these studies it has clearly emerged how the molecular clock tightly regulates every aspect of our lives, including our metabolism. This review analyses the organisation and functioning of the circadian clock and its relevance in the regulation of physiological processes. We also describe metabolism and transport of lipids and lipoproteins as an essential aspect for our health, and we will focus on how the circadian clock and lipid metabolism are greatly interconnected. Finally, we discuss how a deeper knowledge of this relationship might be useful to improve the recent spread of metabolic diseases. Full article

(This article belongs to the Special Issue Lipid Metabolism)

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850 KiB

Open AccessReview

Will Lipidation of ApoA1 through Interaction with ABCA1 at the Intestinal Level Affect the Protective Functions of HDL?

by Eric J. Niesor

Biology 2015, 4(1), 17-38; https://doi.org/10.3390/biology4010017 - 06 Jan 2015

Cited by 18 | Viewed by 15042

Abstract

The relationship between levels of high-density lipoprotein cholesterol (HDL-C) and cardiovascular (CV) risk is well recognized; however, in recent years, large-scale phase III studies with HDL-C-raising or -mimicking agents have failed to demonstrate a clinical benefit on CV outcomes associated with raising HDL-C, casting doubt on the “HDL hypothesis.” This article reviews potential reasons for the observed negative findings with these pharmaceutical compounds, focusing on the paucity of translational models and relevant biomarkers related to HDL metabolism that may have confounded understanding of in vivo mechanisms. A unique function of HDL is its ability to interact with the ATP-binding cassette transporter (ABC) A1 via apolipoprotein (Apo) A1. Only recently, studies have shown that this process may be involved in the intestinal uptake of dietary sterols and antioxidants (vitamin E, lutein and zeaxanthin) at the basolateral surface of enterocytes. This parameter should be assessed for HDL-raising drugs in addition to the more documented reverse cholesterol transport (RCT) from peripheral tissues to the liver. Indeed, a single mechanism involving the same interaction between ApoA1 and ABCA1 may encompass two HDL functions previously considered as separate: antioxidant through the intestinal uptake of antioxidants and RCT through cholesterol efflux from loaded cells such as macrophages. Full article

(This article belongs to the Special Issue Lipid Metabolism)

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670 KiB

Open AccessReview

Hepatitis C Virus Life Cycle and Lipid Metabolism

by Costin-Ioan Popescu, Laura Riva, Ovidiu Vlaicu, Rayan Farhat, Yves Rouillé and Jean Dubuisson

Biology 2014, 3(4), 892-921; https://doi.org/10.3390/biology3040892 - 15 Dec 2014

Cited by 84 | Viewed by 22507

Abstract

Hepatitis C Virus (HCV) infects over 150 million people worldwide. In most cases HCV infection becomes chronic, causing liver disease ranging from fibrosis to cirrhosis and hepatocellular carcinoma. HCV affects the cholesterol homeostasis and at the molecular level, every step of the virus life cycle is intimately connected to lipid metabolism. In this review, we present an update on the lipids and apolipoproteins that are involved in the HCV infectious cycle steps: entry, replication and assembly. Moreover, the result of the assembly process is a lipoviroparticle, which represents a peculiarity of hepatitis C virion. This review illustrates an example of an intricate virus-host interaction governed by lipid metabolism. Full article

(This article belongs to the Special Issue Lipid Metabolism)

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Open AccessReview

Glycerophosphate/Acylglycerophosphate Acyltransferases

by Atsushi Yamashita, Yasuhiro Hayashi, Naoki Matsumoto, Yoko Nemoto-Sasaki, Saori Oka, Takashi Tanikawa and Takayuki Sugiura

Biology 2014, 3(4), 801-830; https://doi.org/10.3390/biology3040801 - 19 Nov 2014

Cited by 95 | Viewed by 14346

Abstract

Acyl-CoA:glycerol-3-phosphate acyltransferase (GPAT) and acyl-CoA: 1-acyl-glycerol-3-phosphate acyltransferase (AGPAT) are involved in the de novo synthesis of triacylglycerol (TAG) and glycerophospholipids. Many enzymes belonging to the GPAT/AGPAT family have recently been identified and their physiological or pathophysiological roles have been proposed. The roles of GPAT/AGPAT in the synthesis of TAG and obesity-related diseases were revealed through the identification of causative genes of these diseases or analyses of genetically manipulated animals. Recent studies have suggested that some isoforms of GPAT/AGPAT family enzymes are involved in the fatty acid remodeling of phospholipids. The enzymology of GPAT/AGPAT and their physiological/ pathological roles in the metabolism of glycerolipids have been described and discussed in this review. Full article

(This article belongs to the Special Issue Lipid Metabolism)

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