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Quan J, Zhang C, Chen X, Cai X, Luo X. Lipid droplet - organelle crosstalk and its implication in cancer. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2025; 197:11-20. [PMID: 40381741 DOI: 10.1016/j.pbiomolbio.2025.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2025] [Revised: 04/15/2025] [Accepted: 05/06/2025] [Indexed: 05/20/2025]
Abstract
Lipid droplets (LDs) store lipids in cells, provide phospholipids for membrane synthesis, and maintain the intracellular balance of energy and lipid metabolism. Undoubtedly, the crosstalk between LDs and other organelles is the foundation for performing functions. Many studies indicate that LDs promote tumor progression. LD accumulation has been observed in a variety of cancers, and high LD content is associated with malignant phenotype and poor prognosis of cancers. In this paper, we summarized the intimate crosstalk between LDs and intracellular organelles, including endoplasmic reticulum (ER), mitochondria, lysosomes and peroxisomes, and addressed the effects of LD-organelle crosstalk on cancer initiation and progression. We also integrated the changes of LD-organelle interactions in cancers to provide an insightful knowledge for cancer therapeutics.
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Affiliation(s)
- Jing Quan
- Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, PR China; Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, PR China
| | - Chunhong Zhang
- Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, PR China; Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, PR China
| | - Xue Chen
- Early Clinical Trial Center, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, PR China
| | - Xinfei Cai
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, PR China
| | - Xiangjian Luo
- Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, PR China; Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, PR China; Key Laboratory of Biological Nanotechnology of National Health Commission, Central South University, Changsha, Hunan, 410078, PR China.
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2
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Thorlacius A, Rulev M, Sundberg O, Sundborger-Lunna A. Peripheral membrane protein endophilin B1 probes, perturbs and permeabilizes lipid bilayers. Commun Biol 2025; 8:182. [PMID: 39910321 PMCID: PMC11799418 DOI: 10.1038/s42003-025-07610-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 01/27/2025] [Indexed: 02/07/2025] Open
Abstract
Bin/Amphiphysin/Rvs167 (BAR) domain containing proteins are peripheral membrane proteins that regulate intracellular membrane curvature. BAR protein endophilin B1 plays a key role in multiple cellular processes critical for oncogenesis, including autophagy and apoptosis. Amphipathic regions in endophilin B1 drive membrane association and tubulation through membrane scaffolding. Our understanding of exactly how BAR proteins like endophilin B1 promote highly diverse intracellular membrane remodeling events in the cell is severely limited due to lack of high-resolution structural information. Here we present the highest resolution cryo-EM structure of a BAR protein to date and the first structures of a BAR protein bound to a lipid bicelle. Using neural networks, we can effectively sort particle species of different stoichiometries, revealing the tremendous flexibility of post-membrane binding, pre-polymer BAR dimer organization and membrane deformation. We also show that endophilin B1 efficiently permeabilizes negatively charged liposomes that contain mitochondria-specific lipid cardiolipin and propose a new model for Bax-mediated cell death.
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Affiliation(s)
- Arni Thorlacius
- Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden
| | - Maksim Rulev
- Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden
| | - Oscar Sundberg
- Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden
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3
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Zhang L, Zhou Y, Yang Z, Jiang L, Yan X, Zhu W, Shen Y, Wang B, Li J, Song J. Lipid droplets in central nervous system and functional profiles of brain cells containing lipid droplets in various diseases. J Neuroinflammation 2025; 22:7. [PMID: 39806503 PMCID: PMC11730833 DOI: 10.1186/s12974-025-03334-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Accepted: 01/02/2025] [Indexed: 01/16/2025] Open
Abstract
Lipid droplets (LDs), serving as the convergence point of energy metabolism and multiple signaling pathways, have garnered increasing attention in recent years. Different cell types within the central nervous system (CNS) can regulate energy metabolism to generate or degrade LDs in response to diverse pathological stimuli. This article provides a comprehensive review on the composition of LDs in CNS, their generation and degradation processes, their interaction mechanisms with mitochondria, the distribution among different cell types, and the roles played by these cells-particularly microglia and astrocytes-in various prevalent neurological disorders. Additionally, we also emphasize the paradoxical role of LDs in post-cerebral ischemia inflammation and explore potential underlying mechanisms, aiming to identify novel therapeutic targets for this disease.
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Affiliation(s)
- Longxiao Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Yunfei Zhou
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Zhongbo Yang
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Liangchao Jiang
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Xinyang Yan
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Wenkai Zhu
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Yi Shen
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Bolong Wang
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Jiaxi Li
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
| | - Jinning Song
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
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4
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Gianazza E, Papaianni GG, Brocca L, Banfi C, Mallia A. Omics Approaches to Study Perilipins and Their Significant Biological Role in Cardiometabolic Disorders. Int J Mol Sci 2025; 26:557. [PMID: 39859272 PMCID: PMC11765208 DOI: 10.3390/ijms26020557] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/07/2025] [Accepted: 01/08/2025] [Indexed: 01/27/2025] Open
Abstract
Lipid droplets (LDs), highly dynamic cellular organelles specialized in lipid storage and maintenance of lipid homeostasis, contain several proteins on their surface, among which the perilipin (Plin) family stands out as the most abundant group of LD-binding proteins. They play a pivotal role in influencing the behavior and functionality of LDs, regulating lipase activity, and preserving a balance between lipid synthesis and degradation, which is crucial in the development of obesity and abnormal accumulation of fat in non-adipose tissues, causing negative adverse biological effects, such as insulin resistance, mitochondrial dysfunction, and inflammation. The expression levels of Plins are often associated with various diseases, such as hepatic steatosis and atherosclerotic plaque formation. Thus, it becomes of interest to investigate the Plin roles by using appropriate "omics" approaches that may provide additional insight into the mechanisms through which these proteins contribute to cellular and tissue homeostasis. This review is intended to give an overview of the most significant omics studies focused on the characterization of Plin proteins and the identification of their potential targets involved in the development and progression of cardiovascular and cardiometabolic complications, as well as their interactors that could be useful for more efficient therapeutic and preventive approaches for patients.
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Affiliation(s)
| | | | | | - Cristina Banfi
- Unit of Functional Proteomics, Metabolomics and Network Analysis, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy; (E.G.); (G.G.P.); (L.B.); (A.M.)
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5
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Li Y, Gao R, Yang Z, Zong H, Li Y. Liraglutide modulates lipid metabolism via ZBTB20-LPL pathway. Life Sci 2025; 360:123267. [PMID: 39608448 DOI: 10.1016/j.lfs.2024.123267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 11/15/2024] [Accepted: 11/19/2024] [Indexed: 11/30/2024]
Abstract
OBJECTIVE To investigate the mechanism of liraglutide affecting lipid metabolism by regulating lipolysis and lipogenesis in cells and ob/ob mice. METHODS 3 T3-L1 cells were treated with liraglutide in vitro, and differentially expressed genes were screened by RNA sequencing. Gene Ontology (GO) and KEGG (Kvoto Encyclopedia of Genes and Genomes) enrichment analyses identified target genes for lipid regulation of liraglutide. 3 T3-L1 preadipocytes were induced to differentiate into adipocytes using a "cocktail method". Western blot and immunofluorescence were used to detect the expression of target genes and the lipid regulatory effect of liraglutide. 3 T3-L1 preadipocytes were transfected with lentivirus overexpressing Zbtb20 to study its role in adipogenesis, and gene expression was analyzed by RT-qPCR and Western blot. In vivo, ob/ob mice were subcutaneously injected with liraglutide or saline for 4 weeks. Blood lipids, adipose tissue volume and adipocyte size were detected. Immunohistochemical analysis and RT-qPCR were used to detect the expression of target genes in adipose tissue. RESULTS Liraglutide reduced lipid droplets and TG levels and altered the expression of genes related to fatty acid metabolism, lipogenesis, fatty acid oxidation, and adipocyte browning. The results of PCR, Western blot and immunofluorescence confirmed that liraglutide could regulate the adipogenesis by downregulating the transcriptional suppressor ZBTB20, and overexpression of Zbtb20 inhibited the expression of LPL, the key enzyme for lipohydrolysis. CONCLUSIONS Liraglutide regulates lipid metabolism through ZBTB20-LPL pathway to reveal its molecular mechanism.
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Affiliation(s)
- Yue Li
- Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan- Hospital, Jinan, Shandong, China; Department of Medicine, Qilu Institute of Technology, Jinan, China.
| | - Rui Gao
- Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan- Hospital, Jinan, Shandong, China.
| | - Zhiyan Yang
- Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan- Hospital, Jinan, Shandong, China; Department of Pharmacy, Jining No.1 People's Hospital, Jining, China.
| | - Huiying Zong
- Department of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China.
| | - Yan Li
- Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan- Hospital, Jinan, Shandong, China.
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Dias Araújo AR, Bello AA, Bigay J, Franckhauser C, Gautier R, Cazareth J, Kovács D, Brau F, Fuggetta N, Čopič A, Antonny B. Surface tension-driven sorting of human perilipins on lipid droplets. J Cell Biol 2024; 223:e202403064. [PMID: 39297796 PMCID: PMC11413419 DOI: 10.1083/jcb.202403064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 08/13/2024] [Accepted: 08/21/2024] [Indexed: 09/26/2024] Open
Abstract
Perilipins (PLINs), the most abundant proteins on lipid droplets (LDs), display similar domain organization including amphipathic helices (AH). However, the five human PLINs bind different LDs, suggesting different modes of interaction. We established a minimal system whereby artificial LDs covered with defined polar lipids were transiently deformed to promote surface tension. Binding of purified PLIN3 and PLIN4 AH was strongly facilitated by tension but was poorly sensitive to phospholipid composition and to the presence of diacylglycerol. Accordingly, LD coverage by PLIN3 increased as phospholipid coverage decreased. In contrast, PLIN1 bound readily to LDs fully covered by phospholipids; PLIN2 showed an intermediate behavior between PLIN1 and PLIN3. In human adipocytes, PLIN3/4 were found in a soluble pool and relocated to LDs upon stimulation of fast triglyceride synthesis, whereas PLIN1 and PLIN2 localized to pre-existing LDs, consistent with the large difference in LD avidity observed in vitro. We conclude that the PLIN repertoire is adapted to handling LDs with different surface properties.
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Affiliation(s)
- Ana Rita Dias Araújo
- Université Côte d’Azur, CNRS and Inserm, Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, Sophia Antipolis, France
| | - Abdoul Akim Bello
- Université Côte d’Azur, CNRS and Inserm, Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, Sophia Antipolis, France
| | - Joëlle Bigay
- Université Côte d’Azur, CNRS and Inserm, Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, Sophia Antipolis, France
| | - Céline Franckhauser
- Centre de Recherche en Biologie Cellulaire de Montpellier-CRBM, Université de Montpellier, CNRS, UMR 5237, Montpellier, France
| | - Romain Gautier
- Université Côte d’Azur, CNRS and Inserm, Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, Sophia Antipolis, France
| | - Julie Cazareth
- Université Côte d’Azur, CNRS and Inserm, Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, Sophia Antipolis, France
| | - Dávid Kovács
- Université Côte d’Azur, CNRS and Inserm, Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, Sophia Antipolis, France
| | - Frédéric Brau
- Université Côte d’Azur, CNRS and Inserm, Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, Sophia Antipolis, France
| | - Nicolas Fuggetta
- Centre de Recherche en Biologie Cellulaire de Montpellier-CRBM, Université de Montpellier, CNRS, UMR 5237, Montpellier, France
| | - Alenka Čopič
- Centre de Recherche en Biologie Cellulaire de Montpellier-CRBM, Université de Montpellier, CNRS, UMR 5237, Montpellier, France
| | - Bruno Antonny
- Université Côte d’Azur, CNRS and Inserm, Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, Sophia Antipolis, France
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Yu Y, Fu R, Jin C, Gao H, Han L, Fu B, Qi M, Li Q, Suo Z, Leng J. Regulation of Milk Fat Synthesis: Key Genes and Microbial Functions. Microorganisms 2024; 12:2302. [PMID: 39597692 PMCID: PMC11596427 DOI: 10.3390/microorganisms12112302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 11/04/2024] [Accepted: 11/07/2024] [Indexed: 11/29/2024] Open
Abstract
Milk is rich in a variety of essential nutrients, including fats, proteins, and trace elements that are important for human health. In particular, milk fat has an alleviating effect on diseases such as heart disease and diabetes. Fatty acids, the basic units of milk fat, play an important role in many biological reactions in the body, including the involvement of glycerophospholipids and sphingolipids in the formation of cell membranes. However, milk fat synthesis is a complex biological process involving multiple organs and tissues, and how to improve milk fat of dairy cows has been a hot research issue in the industry. There exists a close relationship between milk fat synthesis, genes, and microbial functions, as a result of the organic integration between the different tissues of the cow's organism and the external environment. This review paper aims (1) to highlight the synthesis and regulation of milk fat by the first and second genomes (gastrointestinal microbial genome) and (2) to discuss the effects of ruminal microorganisms and host metabolites on milk fat synthesis. Through exploring the interactions between the first and second genomes, and discovering the relationship between microbial and host metabolite in the milk fat synthesis pathway, it may become a new direction for future research on the mechanism of milk fat synthesis in dairy cows.
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Affiliation(s)
- Ye Yu
- Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (Y.Y.); (R.F.); (C.J.); (H.G.); (L.H.); (B.F.); (M.Q.); (Q.L.); (Z.S.)
- Key Laboratory of Animal Nutrition and Feed Science of Yunnan Province, Yunnan Agricultural University, Kunming 650201, China
| | - Runqi Fu
- Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (Y.Y.); (R.F.); (C.J.); (H.G.); (L.H.); (B.F.); (M.Q.); (Q.L.); (Z.S.)
- Key Laboratory of Animal Nutrition and Feed Science of Yunnan Province, Yunnan Agricultural University, Kunming 650201, China
| | - Chunjia Jin
- Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (Y.Y.); (R.F.); (C.J.); (H.G.); (L.H.); (B.F.); (M.Q.); (Q.L.); (Z.S.)
- Key Laboratory of Animal Nutrition and Feed Science of Yunnan Province, Yunnan Agricultural University, Kunming 650201, China
| | - Huan Gao
- Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (Y.Y.); (R.F.); (C.J.); (H.G.); (L.H.); (B.F.); (M.Q.); (Q.L.); (Z.S.)
- Key Laboratory of Animal Nutrition and Feed Science of Yunnan Province, Yunnan Agricultural University, Kunming 650201, China
| | - Lin Han
- Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (Y.Y.); (R.F.); (C.J.); (H.G.); (L.H.); (B.F.); (M.Q.); (Q.L.); (Z.S.)
- Key Laboratory of Animal Nutrition and Feed Science of Yunnan Province, Yunnan Agricultural University, Kunming 650201, China
| | - Binlong Fu
- Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (Y.Y.); (R.F.); (C.J.); (H.G.); (L.H.); (B.F.); (M.Q.); (Q.L.); (Z.S.)
- Key Laboratory of Animal Nutrition and Feed Science of Yunnan Province, Yunnan Agricultural University, Kunming 650201, China
| | - Min Qi
- Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (Y.Y.); (R.F.); (C.J.); (H.G.); (L.H.); (B.F.); (M.Q.); (Q.L.); (Z.S.)
| | - Qian Li
- Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (Y.Y.); (R.F.); (C.J.); (H.G.); (L.H.); (B.F.); (M.Q.); (Q.L.); (Z.S.)
- Key Laboratory of Animal Nutrition and Feed Science of Yunnan Province, Yunnan Agricultural University, Kunming 650201, China
| | - Zhuo Suo
- Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (Y.Y.); (R.F.); (C.J.); (H.G.); (L.H.); (B.F.); (M.Q.); (Q.L.); (Z.S.)
- Key Laboratory of Animal Nutrition and Feed Science of Yunnan Province, Yunnan Agricultural University, Kunming 650201, China
| | - Jing Leng
- Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (Y.Y.); (R.F.); (C.J.); (H.G.); (L.H.); (B.F.); (M.Q.); (Q.L.); (Z.S.)
- Key Laboratory of Animal Nutrition and Feed Science of Yunnan Province, Yunnan Agricultural University, Kunming 650201, China
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8
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Bjørnestad SA, Solbakken MH, Krokene P, Thiede B, Hylland K, Jakobsen KS, Jentoft S, Bakke O, Progida C. The Atlantic Cod MHC I compartment has the properties needed for cross-presentation in the absence of MHC II. Sci Rep 2024; 14:25404. [PMID: 39455705 PMCID: PMC11511864 DOI: 10.1038/s41598-024-76225-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 10/11/2024] [Indexed: 10/28/2024] Open
Abstract
Atlantic cod has a peculiar immune system, characterized by the loss of Major Histocompatibility Complex (MHC) class II pathway, and an extreme expansion of the MHC class I gene repertoire. This has led to the hypothesis that some of the MHC I variants have replaced MHC II by presenting exogenous-peptides in a process similar to cross-presentation. In mammals, MHC I loads endogenous antigens in the endoplasmic reticulum, but we recently found that different Atlantic cod MHC I gene variants traffic to endolysosomes. There, they colocalize with Tapasin and other components of the peptide-loading complex, indicating a plausible peptide-loading system outside the endoplasmic reticulum. In this study, we further characterize the identity of the Atlantic cod MHC I compartment (cMIC). We found that, similarly to mammalian MHC II compartment, cMIC contains late endosomal markers such as Rab7, LAMP1 and CD63. Furthermore, we identified Hsp90b1 (also known as grp94) and LRP1 (also known as CD91) as interactors of MHC I by mass spectrometry. As these two proteins are involved in cross-presentation in mammals, this further suggests that Atlantic cod MHC I might use a similar mechanism to present exogenous peptides, thus, compensating for the absence of MHC II.
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Affiliation(s)
| | - Monica Hongrø Solbakken
- Department of Biosciences, University of Oslo, Oslo, Norway
- Norwegian University of Life Sciences, Ås, Norway
| | - Pia Krokene
- Department of Biosciences, University of Oslo, Oslo, Norway
| | - Bernd Thiede
- Department of Biosciences, University of Oslo, Oslo, Norway
| | - Ketil Hylland
- Department of Biosciences, University of Oslo, Oslo, Norway
| | | | - Sissel Jentoft
- Department of Biosciences, University of Oslo, Oslo, Norway
| | - Oddmund Bakke
- Department of Biosciences, University of Oslo, Oslo, Norway
| | - Cinzia Progida
- Department of Biosciences, University of Oslo, Oslo, Norway.
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9
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Farías MA, Diethelm-Varela B, Kalergis AM, González PA. Interplay between lipid metabolism, lipid droplets and RNA virus replication. Crit Rev Microbiol 2024; 50:515-539. [PMID: 37348003 DOI: 10.1080/1040841x.2023.2224424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 09/20/2022] [Accepted: 01/29/2023] [Indexed: 06/24/2023]
Abstract
Lipids play essential roles in the cell as components of cellular membranes, signaling molecules, and energy storage sources. Lipid droplets are cellular organelles composed of neutral lipids, such as triglycerides and cholesterol esters, and are also considered as cellular energy reserves, yet new functions have been recently associated with these structures, such as regulators of oxidative stress and cellular lipotoxicity, as well as modulators of pathogen infection through immune regulation. Lipid metabolism and lipid droplets participate in the infection process of many RNA viruses and control their replication and assembly, among others. Here, we review and discuss the contribution of lipid metabolism and lipid droplets over the replication cycle of RNA viruses, altogether pointing out potentially new pharmacological antiviral targets associated with lipid metabolism.
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Affiliation(s)
- Mónica A Farías
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Benjamín Diethelm-Varela
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alexis M Kalergis
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
- Departamento de Endocrinología, Facultad de Medicina, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Pablo A González
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
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10
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Pei J, Zou D, Li L, Kang L, Sun M, Li X, Chen Q, Chen D, Qu B, Gao X, Lin Z. Senp7 deficiency impairs lipid droplets maturation in white adipose tissues via Plin4 deSUMOylation. J Biol Chem 2024; 300:107319. [PMID: 38677512 PMCID: PMC11134554 DOI: 10.1016/j.jbc.2024.107319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 04/08/2024] [Accepted: 04/10/2024] [Indexed: 04/29/2024] Open
Abstract
Lipid metabolism is important for the maintenance of physiological homeostasis. Several members of the small ubiquitin-like modifier (SUMO)-specific protease (SENP) family have been reported as the regulators of lipid homeostasis. However, the function of Senp7 in lipid metabolism remains unclear. In this study, we generated both conventional and adipocyte-specific Senp7 KO mice to characterize the role of Senp7 in lipid metabolism homeostasis. Both Senp7-deficient mice displayed reduced white adipose tissue mass and decreased size of adipocytes. By analyzing the lipid droplet morphology, we demonstrated that the lipid droplet size was significantly smaller in Senp7-deficient adipocytes. Mechanistically, Senp7 could deSUMOylate the perilipin family protein Plin4 to promote the lipid droplet localization of Plin4. Our results reveal an important role of Senp7 in the maturation of lipid droplets via Plin4 deSUMOylation.
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Affiliation(s)
- Jingwen Pei
- State Key Laboratory of Pharmaceutical Biotechnology, Ministry of Education Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, National Resource Center for Mutant Mice of China, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Dayuan Zou
- State Key Laboratory of Pharmaceutical Biotechnology, Ministry of Education Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, National Resource Center for Mutant Mice of China, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China; Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-Related Diseases, First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
| | - Lu Li
- State Key Laboratory of Pharmaceutical Biotechnology, Ministry of Education Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, National Resource Center for Mutant Mice of China, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Lulu Kang
- State Key Laboratory of Pharmaceutical Biotechnology, Ministry of Education Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, National Resource Center for Mutant Mice of China, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Minli Sun
- State Key Laboratory of Pharmaceutical Biotechnology, Ministry of Education Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, National Resource Center for Mutant Mice of China, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Xu Li
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Qianyue Chen
- State Key Laboratory of Pharmaceutical Biotechnology, Ministry of Education Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, National Resource Center for Mutant Mice of China, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Danning Chen
- State Key Laboratory of Pharmaceutical Biotechnology, Ministry of Education Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, National Resource Center for Mutant Mice of China, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Bin Qu
- Biophysics, Center for Integrative Physiology and Molecular Medicine (CIPMM), School of Medicine, Saarland University, Homburg, Germany
| | - Xiang Gao
- State Key Laboratory of Pharmaceutical Biotechnology, Ministry of Education Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, National Resource Center for Mutant Mice of China, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China.
| | - Zhaoyu Lin
- State Key Laboratory of Pharmaceutical Biotechnology, Ministry of Education Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, National Resource Center for Mutant Mice of China, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China.
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11
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Umar AW, Ahmad N, Xu M. Reviving Natural Rubber Synthesis via Native/Large Nanodiscs. Polymers (Basel) 2024; 16:1468. [PMID: 38891415 PMCID: PMC11174458 DOI: 10.3390/polym16111468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 04/28/2024] [Accepted: 05/17/2024] [Indexed: 06/21/2024] Open
Abstract
Natural rubber (NR) is utilized in more than 40,000 products, and the demand for NR is projected to reach $68.5 billion by 2026. The primary commercial source of NR is the latex of Hevea brasiliensis. NR is produced by the sequential cis-condensation of isopentenyl diphosphate (IPP) through a complex known as the rubber transferase (RTase) complex. This complex is associated with rubber particles, specialized organelles for NR synthesis. Despite numerous attempts to isolate, characterize, and study the RTase complex, definitive results have not yet been achieved. This review proposes an innovative approach to overcome this longstanding challenge. The suggested method involves isolating the RTase complex without using detergents, instead utilizing the native membrane lipids, referred to as "natural nanodiscs", and subsequently reconstituting the complex on liposomes. Additionally, we recommend the adaptation of large nanodiscs for the incorporation and reconstitution of the RTase complex, whether it is in vitro transcribed or present within the natural nanodiscs. These techniques show promise as a viable solution to the current obstacles. Based on our experimental experience and insights from published literature, we believe these refined methodologies can significantly enhance our understanding of the RTase complex and its role in in vitro NR synthesis.
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Affiliation(s)
- Abdul Wakeel Umar
- BNU-HKUST Laboratory of Green Innovation, Advanced Institute of Natural Sciences, Beijing Normal University at Zhuhai (BNUZ), Zhuhai 519087, China
| | - Naveed Ahmad
- Joint Center for Single Cell Biology, Shanghai Collaborative Innovation Center of Agri-Seeds, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China;
| | - Ming Xu
- BNU-HKUST Laboratory of Green Innovation, Advanced Institute of Natural Sciences, Beijing Normal University at Zhuhai (BNUZ), Zhuhai 519087, China
- Guangdong-Hong Kong Joint Laboratory for Carbon Neutrality, Jiangmen Laboratory of Carbon Science and Technology, Jiangmen 529199, China
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12
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Griseti E, Bello AA, Bieth E, Sabbagh B, Iacovoni JS, Bigay J, Laurell H, Čopič A. Molecular mechanisms of perilipin protein function in lipid droplet metabolism. FEBS Lett 2024; 598:1170-1198. [PMID: 38140813 DOI: 10.1002/1873-3468.14792] [Citation(s) in RCA: 22] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 11/27/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023]
Abstract
Perilipins are abundant lipid droplet (LD) proteins present in all metazoans and also in Amoebozoa and fungi. Humans express five perilipins, which share a similar domain organization: an amino-terminal PAT domain and an 11-mer repeat region, which can fold into amphipathic helices that interact with LDs, followed by a structured carboxy-terminal domain. Variations of this organization that arose during vertebrate evolution allow for functional specialization between perilipins in relation to the metabolic needs of different tissues. We discuss how different features of perilipins influence their interaction with LDs and their cellular targeting. PLIN1 and PLIN5 play a direct role in lipolysis by regulating the recruitment of lipases to LDs and LD interaction with mitochondria. Other perilipins, particularly PLIN2, appear to protect LDs from lipolysis, but the molecular mechanism is not clear. PLIN4 stands out with its long repetitive region, whereas PLIN3 is most widely expressed and is used as a nascent LD marker. Finally, we discuss the genetic variability in perilipins in connection with metabolic disease, prominent for PLIN1 and PLIN4, underlying the importance of understanding the molecular function of perilipins.
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Affiliation(s)
- Elena Griseti
- Institut des Maladies Métaboliques et Cardiovasculaires - I2MC, Université de Toulouse, Inserm, Université Toulouse III - Paul Sabatier (UPS), France
| | - Abdoul Akim Bello
- Institut de Pharmacologie Moléculaire et Cellulaire - IPMC, Université Côte d'Azur, CNRS, Valbonne, France
| | - Eric Bieth
- Institut des Maladies Métaboliques et Cardiovasculaires - I2MC, Université de Toulouse, Inserm, Université Toulouse III - Paul Sabatier (UPS), France
- Departement de Génétique Médicale, Centre Hospitalier Universitaire de Toulouse, France
| | - Bayane Sabbagh
- Centre de Recherche en Biologie Cellulaire de Montpellier - CRBM, Université de Montpellier, CNRS, France
| | - Jason S Iacovoni
- Institut des Maladies Métaboliques et Cardiovasculaires - I2MC, Université de Toulouse, Inserm, Université Toulouse III - Paul Sabatier (UPS), France
| | - Joëlle Bigay
- Institut de Pharmacologie Moléculaire et Cellulaire - IPMC, Université Côte d'Azur, CNRS, Valbonne, France
| | - Henrik Laurell
- Institut des Maladies Métaboliques et Cardiovasculaires - I2MC, Université de Toulouse, Inserm, Université Toulouse III - Paul Sabatier (UPS), France
| | - Alenka Čopič
- Centre de Recherche en Biologie Cellulaire de Montpellier - CRBM, Université de Montpellier, CNRS, France
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13
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Kuroiwa F, Suda H, Yabuki M, Atsuzawa K, Yamaguchi H, Toyota M, Kaneko Y, Yamashita S, Takahashi S, Tozawa Y. Cell-free translation system with artificial lipid-monolayer particles as a unique tool for characterizing lipid-monolayer binding proteins. Biosci Biotechnol Biochem 2024; 88:555-560. [PMID: 38444196 DOI: 10.1093/bbb/zbae026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 02/20/2024] [Indexed: 03/07/2024]
Abstract
Methods for functional analysis of proteins specifically localizing to lipid monolayers such as rubber particles and lipid droplets are limited. We have succeeded in establishing a system in which artificially prepared lipid monolayer particles are added to a cell-free translation system to confirm the properties of proteins that specifically bind to lipid monolayers in a translation-coupled manner.
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Affiliation(s)
- Fu Kuroiwa
- Graduate School of Science and Engineering, Saitama University, Saitama, Japan
| | - Hiraku Suda
- Graduate School of Science and Engineering, Saitama University, Saitama, Japan
| | - Maho Yabuki
- Graduate School of Science and Engineering, Saitama University, Saitama, Japan
| | - Kimie Atsuzawa
- Comprehensive Analysis Center for Science, Saitama University, Saitama, Japan
| | | | - Masatsugu Toyota
- Graduate School of Science and Engineering, Saitama University, Saitama, Japan
| | - Yasuko Kaneko
- Department of Natural Science in the Faculty of Education, Saitama University, Saitama, Japan
| | - Satoshi Yamashita
- Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa, Japan
| | - Seiji Takahashi
- Graduate School of Engineering, Tohoku University, Sendai, Miyagi, Japan
| | - Yuzuru Tozawa
- Graduate School of Science and Engineering, Saitama University, Saitama, Japan
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14
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Cinato M, Andersson L, Miljanovic A, Laudette M, Kunduzova O, Borén J, Levin MC. Role of Perilipins in Oxidative Stress-Implications for Cardiovascular Disease. Antioxidants (Basel) 2024; 13:209. [PMID: 38397807 PMCID: PMC10886189 DOI: 10.3390/antiox13020209] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Revised: 01/12/2024] [Accepted: 02/01/2024] [Indexed: 02/25/2024] Open
Abstract
Oxidative stress is the imbalance between the production of reactive oxygen species (ROS) and antioxidants in a cell. In the heart, oxidative stress may deteriorate calcium handling, cause arrhythmia, and enhance maladaptive cardiac remodeling by the induction of hypertrophic and apoptotic signaling pathways. Consequently, dysregulated ROS production and oxidative stress have been implicated in numerous cardiac diseases, including heart failure, cardiac ischemia-reperfusion injury, cardiac hypertrophy, and diabetic cardiomyopathy. Lipid droplets (LDs) are conserved intracellular organelles that enable the safe and stable storage of neutral lipids within the cytosol. LDs are coated with proteins, perilipins (Plins) being one of the most abundant. In this review, we will discuss the interplay between oxidative stress and Plins. Indeed, LDs and Plins are increasingly being recognized for playing a critical role beyond energy metabolism and lipid handling. Numerous reports suggest that an essential purpose of LD biogenesis is to alleviate cellular stress, such as oxidative stress. Given the yet unmet suitability of ROS as targets for the intervention of cardiovascular disease, the endogenous antioxidant capacity of Plins may be beneficial.
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Affiliation(s)
- Mathieu Cinato
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, 41345 Gothenburg, Sweden; (M.C.); (L.A.); (A.M.); (M.L.); (J.B.)
| | - Linda Andersson
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, 41345 Gothenburg, Sweden; (M.C.); (L.A.); (A.M.); (M.L.); (J.B.)
| | - Azra Miljanovic
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, 41345 Gothenburg, Sweden; (M.C.); (L.A.); (A.M.); (M.L.); (J.B.)
| | - Marion Laudette
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, 41345 Gothenburg, Sweden; (M.C.); (L.A.); (A.M.); (M.L.); (J.B.)
| | - Oksana Kunduzova
- Institute of Metabolic and Cardiovascular Diseases (I2MC), National Institute of Health and Medical Research (INSERM) 1297, Toulouse III University—Paul Sabatier, 31432 Toulouse, France;
| | - Jan Borén
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, 41345 Gothenburg, Sweden; (M.C.); (L.A.); (A.M.); (M.L.); (J.B.)
| | - Malin C. Levin
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, 41345 Gothenburg, Sweden; (M.C.); (L.A.); (A.M.); (M.L.); (J.B.)
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15
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Yang C, Li Q, Lin Y, Wang Y, Shi H, Xiang H, Zhu J. Diacylglycerol acyltransferase 2 promotes the adipogenesis of intramuscular preadipocytes in goat. Anim Biotechnol 2023; 34:2376-2383. [PMID: 35749715 DOI: 10.1080/10495398.2022.2091586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
Diacylglycerol acyltransferase 2 (DGAT2) is the key enzyme that catalyzes the last step of triglyceride synthesis. However, its role in intramuscular fat (IMF) deposition in goat remains unclear. The purpose of this study was to explore the role of DGAT2 in regulating goat IMF deposition. In the present study, the expression of DGAT2 was highest in goat triceps brachii, and highest on the first day after oleic acid induction in goat intramuscular preadipocytes. The overexpression of DGAT2 promoted the accumulation of lipid droplets and triglyceride synthesis, accompanied by the expression upregulation of DGAT1, TIP47, ACC and ACOX1 significantly, and expression downregulation of AGPAT6, LPIN1, LPL, HSL, ATGL and ADRP significantly. In contrast, the silencing of DGAT2 decreased the accumulation of lipid droplets, inhibited the expression of DGAT1, GPAM, ADRP, AGPAT6, LPL, HSL, ATGL, ACC, FASN, ACOX1 significantly, and enhanced that of TIP47 significantly. Overall, these data underscore DGAT2 may play a potentially important role in lipid droplets formation and triglyceride accumulation, so as to maintain intramuscular fat deposition, beyond triglyceride synthesis in goat.
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Affiliation(s)
- Changheng Yang
- Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization Key Laboratory of Sichuan Province, Southwest Minzu University, Chengdu, China
| | - Qi Li
- Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization Key Laboratory of Sichuan Province, Southwest Minzu University, Chengdu, China
| | - Yaqiu Lin
- Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization Key Laboratory of Sichuan Province, Southwest Minzu University, Chengdu, China
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China
| | - Yong Wang
- Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization Key Laboratory of Sichuan Province, Southwest Minzu University, Chengdu, China
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China
| | - Hengbo Shi
- College of Animal Science, Zhejiang University, Hangzhou, China
| | - Hua Xiang
- Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization Key Laboratory of Sichuan Province, Southwest Minzu University, Chengdu, China
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China
| | - Jiangjiang Zhu
- Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization Key Laboratory of Sichuan Province, Southwest Minzu University, Chengdu, China
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China
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16
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Stribny J, Schneiter R. Binding of perilipin 3 to membranes containing diacylglycerol is mediated by conserved residues within its PAT domain. J Biol Chem 2023; 299:105384. [PMID: 37898398 PMCID: PMC10694602 DOI: 10.1016/j.jbc.2023.105384] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 10/12/2023] [Accepted: 10/17/2023] [Indexed: 10/30/2023] Open
Abstract
Perilipins (PLINs) constitute an evolutionarily conserved family of proteins that specifically associate with the surface of lipid droplets (LDs). These proteins function in LD biogenesis and lipolysis and help to stabilize the surface of LDs. PLINs are typically composed of three different protein domains. They share an N-terminal PAT domain of unknown structure and function, a central region containing 11-mer repeats that form amphipathic helices, and a C-terminal domain that adopts a 4-helix bundle structure. How exactly these three distinct domains contribute to PLIN function remains to be determined. Here, we show that the N-terminal PAT domain of PLIN3 binds diacylglycerol (DAG), the precursor to triacylglycerol, a major storage lipid of LDs. PLIN3 and its PAT domain alone bind liposomes with micromolar affinity and PLIN3 binds artificial LDs containing low concentrations of DAG with nanomolar affinity. The PAT domain of PLIN3 is predicted to adopt an amphipathic triangular shaped structure. In silico ligand docking indicates that DAG binds to one of the highly curved regions within this domain. A conserved aspartic acid residue in the PAT domain, E86, is predicted to interact with DAG, and we found that its substitution abrogates high affinity binding of DAG as well as DAG-stimulated association with liposome and artificial LDs. These results indicate that the PAT domain of PLINs harbor specific lipid-binding properties that are important for targeting these proteins to the surface of LDs and to ER membrane domains enriched in DAG to promote LD formation.
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Affiliation(s)
- Jiri Stribny
- Department of Biology, University of Fribourg, Fribourg, Switzerland
| | - Roger Schneiter
- Department of Biology, University of Fribourg, Fribourg, Switzerland.
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17
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Bajpeyi S, Apaflo JN, Rosas V, Sepulveda-Rivera K, Varela-Ramirez A, Covington JD, Galgani JE, Ravussin E. Effect of an acute long-duration exercise bout on skeletal muscle lipid droplet morphology, GLUT 4 protein, and perilipin protein expression. Eur J Appl Physiol 2023; 123:2771-2778. [PMID: 37368137 PMCID: PMC11801175 DOI: 10.1007/s00421-023-05266-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 06/21/2023] [Indexed: 06/28/2023]
Abstract
PURPOSE Smaller lipid droplet morphology and GLUT 4 protein expression have been associated with greater muscle oxidative capacity and glucose uptake, respectively. The main purpose of this study was to determine the effect of an acute long-duration exercise bout on skeletal muscle lipid droplet morphology, GLUT4, perilipin 3, and perilipin 5 expressions. METHODS Twenty healthy men (age 24.0 ± 1.0 years, BMI 23.6 ± 0.4 kg/m2) were recruited for the study. The participants were subjected to an acute bout of exercise on a cycle ergometer at 50% VO2max until they reached a total energy expenditure of 650 kcal. The study was conducted after an overnight fast. Vastus lateralis muscle biopsies were obtained before and immediately after exercise for immunohistochemical analysis to determine lipid, perilipin 3, perilipin 5, and GLUT4 protein contents while GLUT 4 mRNA was quantified using RT-qPCR. RESULTS Lipid droplet size decreased whereas total intramyocellular lipid content tended to reduce (p = 0.07) after an acute bout of endurance exercise. The density of smaller lipid droplets in the peripheral sarcoplasmic region significantly increased (0.584 ± 0.04 to 0.638 ± 0.08 AU; p = 0.01) while larger lipid droplets significantly decreased (p < 0.05). GLUT4 mRNA tended to increase (p = 0.05). There were no significant changes in GLUT 4, perilipin 3, and perilipin 5 protein levels. CONCLUSION The study demonstrates that exercise may impact metabolism by enhancing the quantity of smaller lipid droplets over larger lipid droplets.
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Affiliation(s)
- Sudip Bajpeyi
- Metabolic, Nutrition, and Exercise Research (MiNER) Laboratory, Department of Kinesiology, The University of Texas at El Paso, 500 University Ave, El Paso, TX, 79968, USA.
| | - Jehu N Apaflo
- Metabolic, Nutrition, and Exercise Research (MiNER) Laboratory, Department of Kinesiology, The University of Texas at El Paso, 500 University Ave, El Paso, TX, 79968, USA
| | - Victoria Rosas
- Metabolic, Nutrition, and Exercise Research (MiNER) Laboratory, Department of Kinesiology, The University of Texas at El Paso, 500 University Ave, El Paso, TX, 79968, USA
| | - Keisha Sepulveda-Rivera
- Metabolic, Nutrition, and Exercise Research (MiNER) Laboratory, Department of Kinesiology, The University of Texas at El Paso, 500 University Ave, El Paso, TX, 79968, USA
| | - Armando Varela-Ramirez
- The Cellular Characterization and Biorepository (CCB) Core Facility, Border Biomedical Research Center, Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX, USA
| | - Jeffrey D Covington
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA
| | - Jose E Galgani
- Faculty of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Eric Ravussin
- Laboratory of Skeletal Muscle Physiology, Pennington Biomedical Research Center, Baton Rouge, LA, USA
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18
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Hüsler D, Stauffer P, Hilbi H. Tapping lipid droplets: A rich fat diet of intracellular bacterial pathogens. Mol Microbiol 2023; 120:194-209. [PMID: 37429596 DOI: 10.1111/mmi.15120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 06/21/2023] [Accepted: 06/22/2023] [Indexed: 07/12/2023]
Abstract
Lipid droplets (LDs) are dynamic and versatile organelles present in most eukaryotic cells. LDs consist of a hydrophobic core of neutral lipids, a phospholipid monolayer coat, and a variety of associated proteins. LDs are formed at the endoplasmic reticulum and have diverse roles in lipid storage, energy metabolism, membrane trafficking, and cellular signaling. In addition to their physiological cellular functions, LDs have been implicated in the pathogenesis of several diseases, including metabolic disorders, cancer, and infections. A number of intracellular bacterial pathogens modulate and/or interact with LDs during host cell infection. Members of the genera Mycobacterium, Legionella, Coxiella, Chlamydia, and Salmonella exploit LDs as a source of intracellular nutrients and membrane components to establish their distinct intracellular replicative niches. In this review, we focus on the biogenesis, interactions, and functions of LDs, as well as on their role in lipid metabolism of intracellular bacterial pathogens.
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Affiliation(s)
- Dario Hüsler
- Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland
| | - Pia Stauffer
- Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland
| | - Hubert Hilbi
- Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland
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19
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Zhang Y, Liang X, Lian Q, Liu L, Zhang B, Dong Z, Liu K. Transcriptional analysis of the expression and prognostic value of lipid droplet-localized proteins in hepatocellular carcinoma. BMC Cancer 2023; 23:677. [PMID: 37464334 DOI: 10.1186/s12885-023-10987-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 05/20/2023] [Indexed: 07/20/2023] Open
Abstract
The accumulation of lipid droplets (LDs) in hepatocytes is the main pathogenesis in nonalcoholic fatty liver disease (NAFLD), which is also the key risk factor for the progression of hepatocellular carcinoma (HCC). LDs behaviors are demonstrated to be associated with HCC advancement, and are tightly regulated by a subset protein localized on the surface of LDs. However, the role of LDs-localized protein in HCC has been rarely investigated. This study is focused on the transcriptional dynamic and prognostic value of LDs-localized protein in HCC. Firstly, we summarized the known LDs-localized proteins, which are demonstrated by immunofluorescence according to previous studies. Next, by the use of GEPIA/UALCAN/The Human Protein Atlas databases, we screened the transcriptional change in tumor and normal liver tissues, and found that 13 LDs-localized proteins may involve in the progression of HCC. Then we verified the transcriptional changes of 13 LDs-localized proteins by the use of HCC samples. Moreover, based on the assays of fatty liver of mice and human NAFLD liver samples, we found that the hepatic steatosis mainly contributed to the transcriptional change of selected LDs-localized proteins, indicating the involvement of these LDs-localized proteins in the negative role of NAFLD in HCC progression. Finally, we focused on the role of PLIN3 in HCC, and revealed that NAFLD status significantly promoted PLIN3 transcription in HCC tissue. Functional studies revealed that PLIN3 knockdown significantly limited the migration and chemosensitivity of hepatoma cells, suggesting the positive role of PLIN3 in HCC progression. Our study not only revealed the transcriptional change and prognostic value of lipid droplet-localized proteins in HCC, but also built the correlation between HCC and hepatic steatosis.
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Affiliation(s)
- Yize Zhang
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xue Liang
- School of Life Science, Beijing University of Chinese Medicine, Beijing, China
| | - Qinghai Lian
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Liwen Liu
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Baoyu Zhang
- Department of Neurosurgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
| | - Zihui Dong
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
- Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Kunpeng Liu
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
- School of Medicine, Guangxi University, Nanning, Guangxi, China.
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20
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Khaddaj R, Stribny J, Cottier S, Schneiter R. Perilipin 3 promotes the formation of membrane domains enriched in diacylglycerol and lipid droplet biogenesis proteins. Front Cell Dev Biol 2023; 11:1116491. [PMID: 37465010 PMCID: PMC10350540 DOI: 10.3389/fcell.2023.1116491] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 06/14/2023] [Indexed: 07/20/2023] Open
Abstract
Lipid droplets (LDs) serve as intracellular stores of energy-rich neutral lipids. LDs form at discrete sites in the endoplasmic reticulum (ER) and they remain closely associated with the ER during lipogenic growth and lipolytic consumption. Their hydrophobic neutral lipid core is covered by a monolayer of phospholipids, which harbors a specific set of proteins. This LD surface is coated and stabilized by perilipins, a family of soluble proteins that specifically target LDs from the cytosol. We have previously used chimeric fusion proteins between perilipins and integral ER membrane proteins to test whether proteins that are anchored to the ER bilayer could be dragged onto the LD monolayer. Expression of these chimeric proteins induces repositioning of the ER membrane around LDs. Here, we test the properties of membrane-anchored perilipins in cells that lack LDs. Unexpectedly, membrane-anchored perilipins induce expansion and vesiculation of the perinuclear membrane resulting in the formation of crescent-shaped membrane domains that harbor LD-like properties. These domains are stained by LD-specific lipophilic dyes, harbor LD marker proteins, and they transform into nascent LDs upon induction of neutral lipid synthesis. These ER domains are enriched in diacylglycerol (DAG) and in ER proteins that are important for early steps of LD biogenesis, including seipin and Pex30. Formation of the domains in vivo depends on DAG levels, and we show that perilipin 3 (PLIN3) binds to liposomes containing DAG in vitro. Taken together, these observations indicate that perilipin not only serve to stabilize the surface of mature LDs but that they are likely to exert a more active role in early steps of LD biogenesis at ER subdomains enriched in DAG, seipin, and neutral lipid biosynthetic enzymes.
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Affiliation(s)
- Rasha Khaddaj
- Department of Biology, University of Fribourg, Fribourg, Switzerland
| | - Jiri Stribny
- Department of Biology, University of Fribourg, Fribourg, Switzerland
| | - Stéphanie Cottier
- Department of Biology, University of Fribourg, Fribourg, Switzerland
| | - Roger Schneiter
- Department of Biology, University of Fribourg, Fribourg, Switzerland
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21
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Sun Y, Heng J, Liu F, Zhang S, Liu P. Isolation and proteomic study of fish liver lipid droplets. BIOPHYSICS REPORTS 2023; 9:120-133. [PMID: 38028150 PMCID: PMC10648235 DOI: 10.52601/bpr.2023.230004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Accepted: 06/02/2023] [Indexed: 12/01/2023] Open
Abstract
Lipid droplets (LDs) are a neutral lipid storage organelle that is conserved in almost all species. Excessive storage of neutral lipids in LDs is directly associated with many metabolic syndromes. Zebrafish is a better model animal for the study of LD biology due to its transparent embryonic stage compared to other organisms. However, the study of LDs in fish has been difficult due to the lack of specific LD marker proteins and the limitation of purification technology. In this paper, the purification and proteomic analysis of liver LDs of fish including zebrafish and Carassius auratus were performed for the first time. 259 and 267 proteins were identified respectively. Besides most of the identified proteins were reported in previous LD proteomes of mammals, indicating the similarity between mammal and fish LDs. We also identified many unique proteins of liver LDs in fish that are involved in the regulation of LD dynamics. Through morphological and biochemical analysis, we found that the marker protein Plin2 of zebrafish LD was located on LDs in Huh7 cells. These results will facilitate further study of LDs in fish and liver metabolic diseases using fish as a model animal.
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Affiliation(s)
- Yuwei Sun
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jian Heng
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute of Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
| | - Feng Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute of Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Shuyan Zhang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Pingsheng Liu
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
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22
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Choi YM, Ajjaji D, Fleming KD, Borbat PP, Jenkins ML, Moeller BE, Fernando S, Bhatia SR, Freed JH, Burke JE, Thiam AR, Airola MV. Structural insights into perilipin 3 membrane association in response to diacylglycerol accumulation. Nat Commun 2023; 14:3204. [PMID: 37268630 PMCID: PMC10238389 DOI: 10.1038/s41467-023-38725-w] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 05/12/2023] [Indexed: 06/04/2023] Open
Abstract
Lipid droplets (LDs) are dynamic organelles that contain an oil core mainly composed of triglycerides (TAG) that is surrounded by a phospholipid monolayer and LD-associated proteins called perilipins (PLINs). During LD biogenesis, perilipin 3 (PLIN3) is recruited to nascent LDs as they emerge from the endoplasmic reticulum. Here, we analyze how lipid composition affects PLIN3 recruitment to membrane bilayers and LDs, and the structural changes that occur upon membrane binding. We find that the TAG precursors phosphatidic acid and diacylglycerol (DAG) recruit PLIN3 to membrane bilayers and define an expanded Perilipin-ADRP-Tip47 (PAT) domain that preferentially binds DAG-enriched membranes. Membrane binding induces a disorder to order transition of alpha helices within the PAT domain and 11-mer repeats, with intramolecular distance measurements consistent with the expanded PAT domain adopting a folded but dynamic structure upon membrane binding. In cells, PLIN3 is recruited to DAG-enriched ER membranes, and this requires both the PAT domain and 11-mer repeats. This provides molecular details of PLIN3 recruitment to nascent LDs and identifies a function of the PAT domain of PLIN3 in DAG binding.
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Affiliation(s)
- Yong Mi Choi
- Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, 11794, USA
| | - Dalila Ajjaji
- Laboratoire de Physique de l'École normale supérieure, ENS, Université PSL, CNRS, Sorbonne Université, Université Paris Cité, F-75005, Paris, France
| | - Kaelin D Fleming
- Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, V8N 1A1, Canada
| | - Peter P Borbat
- National Biomedical Resource for Advanced Electron Spin Resonance Technology (ACERT), Cornell University, Ithaca, NY, 14853, USA
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, 14853, USA
| | - Meredith L Jenkins
- Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, V8N 1A1, Canada
| | - Brandon E Moeller
- Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, V8N 1A1, Canada
| | - Shaveen Fernando
- Department of Chemistry, Stony Brook University, Stony Brook, NY, 11794, USA
| | - Surita R Bhatia
- Department of Chemistry, Stony Brook University, Stony Brook, NY, 11794, USA
| | - Jack H Freed
- National Biomedical Resource for Advanced Electron Spin Resonance Technology (ACERT), Cornell University, Ithaca, NY, 14853, USA
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, 14853, USA
| | - John E Burke
- Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, V8N 1A1, Canada.
- Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
| | - Abdou Rachid Thiam
- Laboratoire de Physique de l'École normale supérieure, ENS, Université PSL, CNRS, Sorbonne Université, Université Paris Cité, F-75005, Paris, France.
| | - Michael V Airola
- Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, 11794, USA.
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23
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Jeon YG, Kim YY, Lee G, Kim JB. Physiological and pathological roles of lipogenesis. Nat Metab 2023; 5:735-759. [PMID: 37142787 DOI: 10.1038/s42255-023-00786-y] [Citation(s) in RCA: 92] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 03/15/2023] [Indexed: 05/06/2023]
Abstract
Lipids are essential metabolites, which function as energy sources, structural components and signalling mediators. Most cells are able to convert carbohydrates into fatty acids, which are often converted into neutral lipids for storage in the form of lipid droplets. Accumulating evidence suggests that lipogenesis plays a crucial role not only in metabolic tissues for systemic energy homoeostasis but also in immune and nervous systems for their proliferation, differentiation and even pathophysiological roles. Thus, excessive or insufficient lipogenesis is closely associated with aberrations in lipid homoeostasis, potentially leading to pathological consequences, such as dyslipidaemia, diabetes, fatty liver, autoimmune diseases, neurodegenerative diseases and cancers. For systemic energy homoeostasis, multiple enzymes involved in lipogenesis are tightly controlled by transcriptional and post-translational modifications. In this Review, we discuss recent findings regarding the regulatory mechanisms, physiological roles and pathological importance of lipogenesis in multiple tissues such as adipose tissue and the liver, as well as the immune and nervous systems. Furthermore, we briefly introduce the therapeutic implications of lipogenesis modulation.
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Affiliation(s)
- Yong Geun Jeon
- Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul, South Korea
| | - Ye Young Kim
- Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul, South Korea
| | - Gung Lee
- Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul, South Korea
| | - Jae Bum Kim
- Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul, South Korea.
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24
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Wang YD, Wu LL, Qi XY, Wang YY, Liao ZZ, Liu JH, Xiao XH. New insight of obesity-associated NAFLD: Dysregulated "crosstalk" between multi-organ and the liver? Genes Dis 2023; 10:799-812. [PMID: 37396503 PMCID: PMC10308072 DOI: 10.1016/j.gendis.2021.12.013] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 10/28/2021] [Accepted: 12/01/2021] [Indexed: 11/18/2022] Open
Abstract
Obesity plays a crucial role in the development of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanism for the pathogenesis of obesity-associated NAFLD remains largely obscure. Although the "multiple hit" theory provides a more accurate explanation of NAFLD pathogenesis, it still cannot fully explain precisely how obesity causes NAFLD. The liver is the key integrator of the body's energy needs, receiving input from multiple metabolically active organs. Thus, recent studies have advocated the "multiple crosstalk" hypothesis, highlighting that obesity-related hepatic steatosis may be the result of dysregulated "crosstalk" among multiple extra-hepatic organs and the liver in obesity. A wide variety of circulating endocrine hormones work together to orchestrate this "crosstalk". Of note, with deepening understanding of the endocrine system, the perception of hormones has gradually risen from the narrow sense (i.e. traditional hormones) to the broad sense of hormones as organokines and exosomes. In this review, we focus on the perspective of organic endocrine hormones (organokines) and molecular endocrine hormones (exosomes), summarizing systematically how the two types of new hormones mediate the dialogue between extra-hepatic organs and liver in the pathogenesis of obesity-related NAFLD.
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Affiliation(s)
- Ya-Di Wang
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Liang-Liang Wu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Xiao-Yan Qi
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Yuan-Yuan Wang
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Zhe-Zhen Liao
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Jiang-Hua Liu
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Xin-Hua Xiao
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
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25
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Jin J, Xie Y, Zhang JS, Wang JQ, Dai SJ, He WF, Li SY, Ashby CR, Chen ZS, He Q. Sunitinib resistance in renal cell carcinoma: From molecular mechanisms to predictive biomarkers. Drug Resist Updat 2023; 67:100929. [PMID: 36739809 DOI: 10.1016/j.drup.2023.100929] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 01/13/2023] [Accepted: 01/14/2023] [Indexed: 01/19/2023]
Abstract
Currently, renal cell carcinoma (RCC) is the most prevalent type of kidney cancer. Targeted therapy has replaced radiation therapy and chemotherapy as the main treatment option for RCC due to the lack of significant efficacy with these conventional therapeutic regimens. Sunitinib, a drug used to treat gastrointestinal tumors and renal cell carcinoma, inhibits the tyrosine kinase activity of a number of receptor tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), c-Kit, rearranged during transfection (RET) and fms-related receptor tyrosine kinase 3 (Flt3). Although sunitinib has been shown to be efficacious in the treatment of patients with advanced RCC, a significant number of patients have primary resistance to sunitinib or acquired drug resistance within the 6-15 months of therapy. Thus, in order to develop more efficacious and long-lasting treatment strategies for patients with advanced RCC, it will be crucial to ascertain how to overcome sunitinib resistance that is produced by various drug resistance mechanisms. In this review, we discuss: 1) molecular mechanisms of sunitinib resistance; 2) strategies to overcome sunitinib resistance and 3) potential predictive biomarkers of sunitinib resistance.
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Affiliation(s)
- Juan Jin
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, Zhejiang 310003, China
| | - Yuhao Xie
- Institute for Biotechnology, St. John's University, Queens, NY 11439, USA; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
| | - Jin-Shi Zhang
- Urology & Nephrology Center, Department of Nephrology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
| | - Jing-Quan Wang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
| | - Shi-Jie Dai
- Zhejiang Eyoung Pharmaceutical Research and Development Center, Hangzhou, Zhejiang 311258, China
| | - Wen-Fang He
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, Zhejiang 310003, China
| | - Shou-Ye Li
- Zhejiang Eyoung Pharmaceutical Research and Development Center, Hangzhou, Zhejiang 311258, China
| | - Charles R Ashby
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
| | - Zhe-Sheng Chen
- Institute for Biotechnology, St. John's University, Queens, NY 11439, USA; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
| | - Qiang He
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, Zhejiang 310003, China.
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26
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Buser DP, Spang A. Protein sorting from endosomes to the TGN. Front Cell Dev Biol 2023; 11:1140605. [PMID: 36895788 PMCID: PMC9988951 DOI: 10.3389/fcell.2023.1140605] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 02/09/2023] [Indexed: 02/23/2023] Open
Abstract
Retrograde transport from endosomes to the trans-Golgi network is essential for recycling of protein and lipid cargoes to counterbalance anterograde membrane traffic. Protein cargo subjected to retrograde traffic include lysosomal acid-hydrolase receptors, SNARE proteins, processing enzymes, nutrient transporters, a variety of other transmembrane proteins, and some extracellular non-host proteins such as viral, plant, and bacterial toxins. Efficient delivery of these protein cargo molecules depends on sorting machineries selectively recognizing and concentrating them for their directed retrograde transport from endosomal compartments. In this review, we outline the different retrograde transport pathways governed by various sorting machineries involved in endosome-to-TGN transport. In addition, we discuss how this transport route can be analyzed experimentally.
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Affiliation(s)
| | - Anne Spang
- *Correspondence: Dominik P. Buser, ; Anne Spang,
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27
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Awadh AA. The Role of Cytosolic Lipid Droplets in Hepatitis C Virus Replication, Assembly, and Release. BIOMED RESEARCH INTERNATIONAL 2023; 2023:5156601. [PMID: 37090186 PMCID: PMC10121354 DOI: 10.1155/2023/5156601] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 03/02/2023] [Accepted: 03/09/2023] [Indexed: 04/25/2023]
Abstract
The hepatitis C virus (HCV) causes chronic hepatitis by establishing a persistent infection. Patients with chronic hepatitis frequently develop hepatic cirrhosis, which can lead to liver cancer-the progressive liver damage results from the host's immune response to the unresolved infection. The HCV replication process, including the entry, replication, assembly, and release stages, while the virus circulates in the bloodstream, it is intricately linked to the host's lipid metabolism, including the dynamic of the cytosolic lipid droplets (cLDs). This review article depicts how this interaction regulates viral cell tropism and aids immune evasion by coining viral particle characteristics. cLDs are intracellular organelles that store most of the cytoplasmic components of neutral lipids and are assumed to play an increasingly important role in the pathophysiology of lipid metabolism and host-virus interactions. cLDs are involved in the replication of several clinically significant viruses, where viruses alter the lipidomic profiles of host cells to improve viral life cycles. cLDs are involved in almost every phase of the HCV life cycle. Indeed, pharmacological modulators of cholesterol synthesis and intracellular trafficking, lipoprotein maturation, and lipid signaling molecules inhibit the assembly of HCV virions. Likewise, small-molecule inhibitors of cLD-regulating proteins inhibit HCV replication. Thus, addressing the molecular architecture of HCV replication will aid in elucidating its pathogenesis and devising preventive interventions that impede persistent infection and prevent disease progression. This is possible via repurposing the available therapeutic agents that alter cLDs metabolism. This review highlights the role of cLD in HCV replication.
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Affiliation(s)
- Abdullah A. Awadh
- Department of Basic Medical Sciences, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Jeddah 21423, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah 21423, Saudi Arabia
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28
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Schelbert S, Schindeldecker M, Drebber U, Witzel HR, Weinmann A, Dries V, Schirmacher P, Roth W, Straub BK. Lipid Droplet-Associated Proteins Perilipin 1 and 2: Molecular Markers of Steatosis and Microvesicular Steatotic Foci in Chronic Hepatitis C. Int J Mol Sci 2022; 23:ijms232415456. [PMID: 36555099 PMCID: PMC9778710 DOI: 10.3390/ijms232415456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 11/29/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022] Open
Abstract
Chronic infection with hepatitis C (HCV) is a major risk factor in the development of cirrhosis and hepatocellular carcinoma. Lipid metabolism plays a major role in the replication and deposition of HCV at lipid droplets (LDs). We have demonstrated the importance of LD-associated proteins of the perilipin family in steatotic liver diseases. Using a large collection of 231 human liver biopsies with HCV, perilipins 1 and 2 have been localized to LDs of hepatocytes that correlate with the degree of steatosis and specific HCV genotypes, but not significantly with the HCV viral load. Perilipin 1- and 2-positive microvesicular steatotic foci were observed in 36% of HCV liver biopsies, and also in chronic hepatitis B, autoimmune hepatitis and mildly steatotic or normal livers, but less or none were observed in normal livers of younger patients. Microvesicular steatotic foci did not frequently overlap with glycogenotic/clear cell foci as determined by PAS stain in serial sections. Steatotic foci were detected in all liver zones with slight architectural disarrays, as demonstrated by immunohistochemical glutamine synthetase staining of zone three, but without elevated Ki67-proliferation rates. In conclusion, microvesicular steatotic foci are frequently found in chronic viral hepatitis, but the clinical significance of these foci is so far not clear.
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Affiliation(s)
- Selina Schelbert
- Institute of Pathology, University Medical Center Mainz, 55131 Mainz, Germany
- Institute of Pathology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany
| | | | - Uta Drebber
- Institute of Pathology, University Clinic Cologne, 50931 Cologne, Germany
| | - Hagen Roland Witzel
- Institute of Pathology, University Medical Center Mainz, 55131 Mainz, Germany
| | - Arndt Weinmann
- Department of Internal Medicine, University Medical Center, 55131 Mainz, Germany
| | - Volker Dries
- Institute of Pathology, University Clinic Cologne, 50931 Cologne, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Medical Center Heidelberg, 69120 Heidelberg, Germany
| | - Wilfried Roth
- Institute of Pathology, University Medical Center Mainz, 55131 Mainz, Germany
| | - Beate Katharina Straub
- Institute of Pathology, University Medical Center Mainz, 55131 Mainz, Germany
- Correspondence: ; Tel.: +49-6131-17-7307
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29
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Farías MA, Diethelm-Varela B, Navarro AJ, Kalergis AM, González PA. Interplay between Lipid Metabolism, Lipid Droplets, and DNA Virus Infections. Cells 2022; 11:2224. [PMID: 35883666 PMCID: PMC9324743 DOI: 10.3390/cells11142224] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 07/05/2022] [Accepted: 07/09/2022] [Indexed: 12/10/2022] Open
Abstract
Lipid droplets (LDs) are cellular organelles rich in neutral lipids such as triglycerides and cholesterol esters that are coated by a phospholipid monolayer and associated proteins. LDs are known to play important roles in the storage and availability of lipids in the cell and to serve as a source of energy reserve for the cell. However, these structures have also been related to oxidative stress, reticular stress responses, and reduced antigen presentation to T cells. Importantly, LDs are also known to modulate viral infection by participating in virus replication and assembly. Here, we review and discuss the interplay between neutral lipid metabolism and LDs in the replication cycle of different DNA viruses, identifying potentially new molecular targets for the treatment of viral infections.
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Affiliation(s)
- Mónica A. Farías
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile; (M.A.F.); (B.D.-V.); (A.J.N.); (A.M.K.)
| | - Benjamín Diethelm-Varela
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile; (M.A.F.); (B.D.-V.); (A.J.N.); (A.M.K.)
| | - Areli J. Navarro
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile; (M.A.F.); (B.D.-V.); (A.J.N.); (A.M.K.)
| | - Alexis M. Kalergis
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile; (M.A.F.); (B.D.-V.); (A.J.N.); (A.M.K.)
- Departamento de Endocrinología, Facultad de Medicina, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile
| | - Pablo A. González
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile; (M.A.F.); (B.D.-V.); (A.J.N.); (A.M.K.)
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30
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Leitner N, Hlavaty J, Heider S, Ertl R, Gabriel C, Walter I. Lipid droplet dynamics in healthy and pyometra-affected canine endometrium. BMC Vet Res 2022; 18:221. [PMID: 35689217 PMCID: PMC9188128 DOI: 10.1186/s12917-022-03321-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 05/20/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Accumulation of lipid droplets (LDs) was recently observed in pyometra-affected uteri. As data about their nature and function are missing we intended to compare the localization, quality and quantity of LDs in canine healthy and pyometra-affected tissues and in an in vitro model. METHODS AND RESULTS We characterized LDs in healthy and pyometra uterine tissue samples as well as in canine endometrial epithelial cells (CEECs) in vitro by means of histochemistry, immunohistochemistry, transmission electron microscopy, western blot, and RT-qPCR. Oil Red O (ORO) staining and quantification as well as p-phenylenediamine staining showed a higher number of LDs in epithelial cells of pyometra samples. Immunohistochemistry revealed that the amount of LDs coated by perilipin2 (PLIN2) protein was also higher in pyometra samples. Transmission electron microscopy showed an increase of LD size in surface and glandular epithelial cells of pyometra samples. In cell culture experiments with CEECs, supplementation with oleic acid alone or in combination with cholesterol lead to an increased LD accumulation. The expression of PLIN2 at protein and mRNA level was also higher upon oleic acid supplementation. Most LDs were double positive for ORO and PLIN2. However, ORO positive LDs lacking PLIN2 coating or LDs positive for PLIN2 but containing a lipid class not detectable by ORO staining were identified. CONCLUSIONS We found differences in the healthy and pyometra-affected endometrium with respect to LDs size. Moreover, several kinds of LDs seem to be present in the canine endometrium. In vitro studies with CEECs could show their responsiveness to external lipids. Since epithelial cells reacted only to oleic acid stimulation, we assume that the cyclic lipid accumulation in the canine endometrium is based mainly on triglycerides and might serve as energy provision for the developing early embryo. Further studies are necessary to verify the complex role of lipids in the healthy and pyometra-affected canine endometrium.
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Affiliation(s)
- Natascha Leitner
- Institute of Morphology, Working Group Histology, University of Veterinary Medicine, Veterinaerplatz 1, A-1210, Vienna, Austria
| | - Juraj Hlavaty
- Institute of Morphology, Working Group Histology, University of Veterinary Medicine, Veterinaerplatz 1, A-1210, Vienna, Austria
| | - Susanne Heider
- Institute of Morphology, Working Group Histology, University of Veterinary Medicine, Veterinaerplatz 1, A-1210, Vienna, Austria
| | - Reinhard Ertl
- VetCORE Facility for Research, University of Veterinary Medicine, Veterinaerplatz 1, A-1210, Vienna, Austria
| | - Cordula Gabriel
- Institute of Morphology, Working Group Histology, University of Veterinary Medicine, Veterinaerplatz 1, A-1210, Vienna, Austria
| | - Ingrid Walter
- Institute of Morphology, Working Group Histology, University of Veterinary Medicine, Veterinaerplatz 1, A-1210, Vienna, Austria. .,VetCORE Facility for Research, University of Veterinary Medicine, Veterinaerplatz 1, A-1210, Vienna, Austria.
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Xu H, Wang X, Tao R, Bi J, He X, Zhu F, Liu K, Xu Y, Li J. Optimal Stage for Cryotop Vitrification of Porcine Embryos. Cell Reprogram 2022; 24:132-141. [PMID: 35699425 DOI: 10.1089/cell.2022.0001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Different development stages of porcine embryos have different tolerance to low temperature. Therefore, we took the porcine embryos after parthenogenetic activation (PA) as the model, to explore the optimal development stage for vitrification during morula (D4), early blastocyst (D5), and expanded blastocyst (D6) after PA (D0). Embryos were observed with microscope and analyzed by different staining after cryo-recovery for 24 hours. The quality of embryos was damaged after vitrification, including embryonic nuclei, DNA, cytoskeleton, and organelles. The re-expansion rate at 24 hours of D5 embryos was significantly higher than those of D4 and D6 embryos (D5 vs. D4 vs. D6, 27.620 ± 0.041 vs. 7.809 ± 0.027 vs. 13.970 ± 0.032, p < 0.05). Therefore, D5 embryos were selected as research objects to explore the effect of vitrification on lipid in vitrified embryos. The results showed that the expression levels of perilipin PLIN3 messenger RNA (mRNA) and triacylglycerol synthesis-related genes AGPAT1 and DGAT mRNA are significantly reduced (p < 0.05). Vitrification affected lipid synthesis, which might have an irreversible impact on embryonic development. In conclusion, our data demonstrated that the optimal stage of vitrification was D5 for early blastocysts.
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Affiliation(s)
- Hongxia Xu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Xuguang Wang
- College of Animal Science, Xinjiang Agricultural University, Ulumuqi, Xinjiang, China
| | - Ruixin Tao
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Jiaying Bi
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Xu He
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Fuquan Zhu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Ke Liu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Yinxue Xu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Juan Li
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, China
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Barrett JS, Whytock KL, Strauss JA, Wagenmakers AJM, Shepherd SO. High intramuscular triglyceride turnover rates and the link to insulin sensitivity: influence of obesity, type 2 diabetes and physical activity. Appl Physiol Nutr Metab 2022; 47:343-356. [PMID: 35061523 DOI: 10.1139/apnm-2021-0631] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Large intramuscular triglyceride (IMTG) stores in sedentary, obese individuals have been linked to insulin resistance, yet well-trained athletes exhibit high IMTG levels whilst maintaining insulin sensitivity. Contrary to previous assumptions, it is now known that IMTG content per se does not result in insulin resistance. Rather, insulin resistance is caused, at least in part, by the presence of high concentrations of harmful lipid metabolites, such as diacylglycerols and ceramides in muscle. Several mechanistic differences between obese sedentary individuals and their highly trained counterparts have been identified, which determine the differential capacity for IMTG synthesis and breakdown in these populations. In this review, we first describe the most up-to-date mechanisms by which a low IMTG turnover rate (both breakdown and synthesis) leads to the accumulation of lipid metabolites and results in skeletal muscle insulin resistance. We then explore current and potential exercise and nutritional strategies that target IMTG turnover in sedentary obese individuals, to improve insulin sensitivity. Overall, improving IMTG turnover should be an important component of successful interventions that aim to prevent the development of insulin resistance in the ever-expanding sedentary, overweight and obese populations. Novelty: A description of the most up-to-date mechanisms regulating turnover of the IMTG pool. An exploration of current and potential exercise/nutritional strategies to target and enhance IMTG turnover in obese individuals. Overall, highlights the importance of improving IMTG turnover to prevent the development of insulin resistance.
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Affiliation(s)
- J S Barrett
- Research Institute for Sport & Exercise Sciences, Liverpool John Moores University, Liverpool, UK
| | - K L Whytock
- Translational Research Institute, AdventHealth, Orlando, FL 32804, USA
| | - J A Strauss
- Research Institute for Sport & Exercise Sciences, Liverpool John Moores University, Liverpool, UK
| | - A J M Wagenmakers
- Research Institute for Sport & Exercise Sciences, Liverpool John Moores University, Liverpool, UK
| | - S O Shepherd
- Research Institute for Sport & Exercise Sciences, Liverpool John Moores University, Liverpool, UK
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Pino-de la Fuente F, Bórquez JC, Díaz-Castro F, Espinosa A, Chiong M, Troncoso R. Exercise regulation of hepatic lipid droplet metabolism. Life Sci 2022; 298:120522. [PMID: 35367244 DOI: 10.1016/j.lfs.2022.120522] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 03/16/2022] [Accepted: 03/27/2022] [Indexed: 01/02/2023]
Abstract
Lipid droplets (LD) are not just lipid stores. They are now recognized as highly dynamic organelles, having a life cycle that includes biogenesis, growth, steady-state, transport, and catabolism. Importantly, LD exhibit different features in terms of size, number, lipid composition, proteins, and interaction with other organelles, and all these features exert an impact on cellular homeostasis. The imbalance of LD function causes non-alcoholic fatty liver disease (NAFLD). Studies show that exercise attenuates NAFLD by decreasing LD content; however, reports show metabolic benefits without changes in LD amount (intrahepatic triglyceride levels) in NAFLD. Due to the multiple effects of exercise in LD features, we think that these metabolic benefits occur through changes in LD features in NAFLD, rather than only the reduction in content. Exercise increases energy mobilization and utilization from storages such as LD, and is one of the non-pharmacological treatments against NAFLD. Therefore, exercise modification of LD could be a target for NAFLD treatment. Here, we review the most up-to-date literature on this topic, and focus on recent findings showing that LD features could play an important role in the severity of NAFLD.
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Affiliation(s)
- Francisco Pino-de la Fuente
- Laboratorio de Investigación en Nutrición y Actividad Física (LABINAF), Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile; Departamento de Tecnología Médica, Facultad de Medicina, Universidad de Chile, Chile; Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
| | - Juan Carlos Bórquez
- Laboratorio de Investigación en Nutrición y Actividad Física (LABINAF), Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile
| | - Francisco Díaz-Castro
- Laboratorio de Investigación en Nutrición y Actividad Física (LABINAF), Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile
| | - Alejandra Espinosa
- Departamento de Tecnología Médica, Facultad de Medicina, Universidad de Chile, Chile
| | - Mario Chiong
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
| | - Rodrigo Troncoso
- Laboratorio de Investigación en Nutrición y Actividad Física (LABINAF), Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile; Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
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Buser DP, Bader G, Spiess M. Retrograde transport of CDMPR depends on several machineries as analyzed by sulfatable nanobodies. Life Sci Alliance 2022; 5:5/7/e202101269. [PMID: 35314489 PMCID: PMC8961009 DOI: 10.26508/lsa.202101269] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 03/08/2022] [Accepted: 03/09/2022] [Indexed: 11/24/2022] Open
Abstract
Nanobody toolkit enables the quantitative analysis of endosome-to-TGN transport of the mannose-6-phosphate receptor in cells depleted of retrograde transport machineries Retrograde protein transport from the cell surface and endosomes to the TGN is essential for membrane homeostasis in general and for the recycling of mannose-6-phosphate receptors (MPRs) for sorting of lysosomal hydrolases in particular. We used a nanobody-based sulfation tool to more directly determine transport kinetics from the plasma membrane to the TGN for the cation-dependent MPR (CDMPR) with and without rapid or gradual inactivation of candidate machinery proteins. Although knockdown of retromer (Vps26), epsinR, or Rab9a reduced CDMPR arrival to the TGN, no effect was observed upon silencing of TIP47. Strikingly, when retrograde transport was analyzed by rapamycin-induced rapid depletion (knocksideways) or long-term depletion by knockdown of the clathrin adaptor AP-1 or of the GGA machinery, distinct phenotypes in sulfation kinetics were observed, suggesting a potential role of GGA adaptors in retrograde and anterograde transport. Our study illustrates the usefulness of derivatized, sulfation-competent nanobodies, reveals novel insights into CDMPR trafficking biology, and further outlines that the selection of machinery inactivation is critical for phenotype analysis.
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Affiliation(s)
| | - Gaétan Bader
- Biozentrum, University of Basel, Basel, Switzerland
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Abstract
Lipid droplets (LDs) are ubiquitous organelles that store and supply lipids for energy metabolism, membrane synthesis and production of lipid-derived signaling molecules. While compositional differences in the phospholipid monolayer or neutral lipid core of LDs impact their metabolism and function, the proteome of LDs has emerged as a major influencer in all aspects of LD biology. The perilipins (PLINs) are the most studied and abundant proteins residing on the LD surface. This Cell Science at a Glance and the accompanying poster summarize our current knowledge of the common and unique features of the mammalian PLIN family of proteins, the mechanisms through which they affect cell metabolism and signaling, and their links to disease.
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Affiliation(s)
- Charles P. Najt
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA
| | - Mahima Devarajan
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA
| | - Douglas G. Mashek
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA
- Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, University of Minnesota, Minneapolis, MN 55455, USA
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Lipid droplets associated perilipins protein insights into finding a therapeutic target approach to cure non-alcoholic fatty liver disease (NAFLD). FUTURE JOURNAL OF PHARMACEUTICAL SCIENCES 2022. [DOI: 10.1186/s43094-021-00395-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Abstract
Background
Non-alcoholic fatty liver disease (NAFLD) is now the most common form of chronic liver disease in the world, and it’s linked to a slew of other risk factors including diabetes, obesity, dysbiosis and inflammatory bowel disease. More than 30 years ago, a patient was diagnosed with fatty liver with excessive fat accumulation in hepatocytes, a disorder known as hepatosteatosis. There will be no promising therapeutic medicines available from 1980 to 2021 which can reverse the fatty liver to normal liver state. In this review, we highlighted on lipid droplet associated protein which play a major role in accumulation of fat in liver cells and how these cellular pathway could be a promising therapeutic approach to treat the fatty liver disease.
Main body
Over the last few decades, Western countries follow a high-fat diet and change their lifestyle pattern due to certain metabolic disorders prevalence rate is very high all over the world. NAFLD is a major health issue and burden globally nowadays. Researchers are trying to find out the potential therapeutic target to combat the disease. The exact pathophysiology of the disease is still unclear. In the present decades. There is no Food and Drug Administration approved drugs are available to reverse the chronic condition of the disease. Based on literature survey, lipid droplets and their associated protein like perilipins play an eminent role in body fat regulation. In this review, we explain all types of perilipins such as perilipin1-5 (PLIN1-5) and their role in the pathogenesis of fatty liver which will be helpful to find the novel pharmacological target to treat the fatty liver.
Conclusion
In this review, majorly focussed on how fat is get deposited into hepatocytes follow the cellular signalling involved during lipid droplet biogenesis and leads to NAFLD. However, up to date still there mechanism of action is unclear. In this review, we hypothesized that lipid droplets associated proteins like perilipins could be better pharmacological target to reverse the chronic stage of fatty liver disease and how these lipid droplets associated proteins hide a clue to maintain the normal lipid homeostasis in the human body.
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Zhang W, Xu L, Zhu L, Liu Y, Yang S, Zhao M. Lipid Droplets, the Central Hub Integrating Cell Metabolism and the Immune System. Front Physiol 2021; 12:746749. [PMID: 34925055 PMCID: PMC8678573 DOI: 10.3389/fphys.2021.746749] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 11/08/2021] [Indexed: 12/16/2022] Open
Abstract
Lipid droplets (LDs) are commonly found in various biological cells and are organelles related to cell metabolism. LDs, the number and size of which are heterogeneous across cell type, are primarily composed of polar lipids and proteins on the surface with neutral lipids in the core. Neutral lipids stored in LDs can be degraded by lipolysis and lipophagocytosis, which are regulated by various proteins. The process of LD formation can be summarized in four steps. In addition to energy production, LDs play an extremely pivotal role in a variety of physiological and pathological processes, such as endoplasmic reticulum stress, lipid toxicity, storage of fat-soluble vitamins, regulation of oxidative stress, and reprogramming of cell metabolism. Interestingly, LDs, the hub of integration between metabolism and the immune system, are involved in antitumor immunity, anti-infective immunity (viruses, bacteria, parasites, etc.) and some metabolic immune diseases. Herein, we summarize the role of LDs in several major immune cells as elucidated in recent years, including T cells, dendritic cells, macrophages, mast cells, and neutrophils. Additionally, we analyze the role of the interaction between LDs and immune cells in two typical metabolic immune diseases: atherosclerosis and Mycobacterium tuberculosis infection.
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Affiliation(s)
- Wei Zhang
- Department of Pediatrics, Third Xiangya Hospital, Central South University, Changsha, China
- Xiangya Hospital, Central South University, Changsha, China
| | - Linyong Xu
- School of Life Sciences, Central South University, Changsha, China
| | - Ling Zhu
- School of Life Sciences, Central South University, Changsha, China
| | - Yifan Liu
- Department of Pediatrics, Third Xiangya Hospital, Central South University, Changsha, China
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Siwei Yang
- Department of Pediatrics, Third Xiangya Hospital, Central South University, Changsha, China
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Mingyi Zhao
- Department of Pediatrics, Third Xiangya Hospital, Central South University, Changsha, China
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Garcia-Macia M, Santos-Ledo A, Leslie J, Paish HL, Collins AL, Scott RS, Watson A, Burgoyne RA, White S, French J, Hammond J, Borthwick LA, Mann J, Bolaños JP, Korolchuk VI, Oakley F, Mann DA. A Mammalian Target of Rapamycin-Perilipin 3 (mTORC1-Plin3) Pathway is essential to Activate Lipophagy and Protects Against Hepatosteatosis. Hepatology 2021; 74:3441-3459. [PMID: 34233024 DOI: 10.1002/hep.32048] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 05/28/2021] [Accepted: 06/13/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS NAFLD is the most common hepatic pathology in western countries and no treatment is currently available. NAFLD is characterized by the aberrant hepatocellular accumulation of fatty acids in the form of lipid droplets (LDs). Recently, it was shown that liver LD degradation occurs through a process termed lipophagy, a form of autophagy. However, the molecular mechanisms governing liver lipophagy are elusive. Here, we aimed to ascertain the key molecular players that regulate hepatic lipophagy and their importance in NAFLD. APPROACH AND RESULTS We analyzed the formation and degradation of LD in vitro (fibroblasts and primary mouse hepatocytes), in vivo and ex vivo (mouse and human liver slices) and focused on the role of the autophagy master regulator mammalian target of rapamycin complex (mTORC) 1 and the LD coating protein perilipin (Plin) 3 in these processes. We show that the autophagy machinery is recruited to the LD on hepatic overload of oleic acid in all experimental settings. This led to activation of lipophagy, a process that was abolished by Plin3 knockdown using RNA interference. Furthermore, Plin3 directly interacted with the autophagy proteins focal adhesion interaction protein 200 KDa and autophagy-related 16L, suggesting that Plin3 functions as a docking protein or is involved in autophagosome formation to activate lipophagy. Finally, we show that mTORC1 phosphorylated Plin3 to promote LD degradation. CONCLUSIONS These results reveal that mTORC1 regulates liver lipophagy through a mechanism dependent on Plin3 phosphorylation. We propose that stimulating this pathway can enhance lipophagy in hepatocytes to help protect the liver from lipid-mediated toxicity, thus offering a therapeutic strategy in NAFLD.
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Affiliation(s)
- Marina Garcia-Macia
- Newcastle Fibrosis Research Group, Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- Institute of Biomedical Research of Salamanca, University Hospital of Salamanca, Salamanca, Spain
- Institute of Functional Biology and Genomics, University of Salamanca, CSIC, Salamanca, Spain
- Centro de Investigación Biomédica en Red sobre Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
| | | | - Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Hannah L Paish
- Newcastle Fibrosis Research Group, Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Amy L Collins
- Newcastle Fibrosis Research Group, Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Rebecca S Scott
- Newcastle Fibrosis Research Group, Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- FibroFind Ltd, William Leech Building, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Abigail Watson
- FibroFind Ltd, William Leech Building, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Rachel A Burgoyne
- Newcastle Fibrosis Research Group, Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Steve White
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Jeremy French
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - John Hammond
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Lee A Borthwick
- Newcastle Fibrosis Research Group, Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Jelena Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Juan P Bolaños
- Institute of Biomedical Research of Salamanca, University Hospital of Salamanca, Salamanca, Spain
- Institute of Functional Biology and Genomics, University of Salamanca, CSIC, Salamanca, Spain
- Centro de Investigación Biomédica en Red sobre Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
| | - Viktor I Korolchuk
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Fiona Oakley
- Newcastle Fibrosis Research Group, Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Derek A Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
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Hello from the other side: Membrane contact of lipid droplets with other organelles and subsequent functional implications. Prog Lipid Res 2021; 85:101141. [PMID: 34793861 DOI: 10.1016/j.plipres.2021.101141] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/10/2021] [Accepted: 11/10/2021] [Indexed: 02/06/2023]
Abstract
Lipid droplets (LDs) are ubiquitous organelles that play crucial roles in response to physiological and environmental cues. The identification of several neutral lipid synthesizing and regulatory protein complexes have propelled significant advance on the mechanisms of LD biogenesis in the endoplasmic reticulum (ER). Increasing evidence suggests that distinct proteins and regulatory factors, which localize to membrane contact sites (MCS), are involved not only in interorganellar lipid exchange and transport, but also function in other important cellular processes, including autophagy, mitochondrial dynamics and inheritance, ion signaling and inter-regulation of these MCS. More and more tethers and molecular determinants are associated to MCS and to a diversity of cellular and pathophysiological processes, demonstrating the dynamics and importance of these junctions in health and disease. The conjugation of lipids with proteins in supramolecular complexes is known to be paramount for many biological processes, namely membrane biosynthesis, cell homeostasis, regulation of organelle division and biogenesis, and cell growth. Ultimately, this physical organization allows the contact sites to function as crucial metabolic hubs that control the occurrence of chemical reactions. This leads to biochemical and metabolite compartmentalization for the purposes of energetic efficiency and cellular homeostasis. In this review, we will focus on the structural and functional aspects of LD-organelle interactions and how they ensure signaling exchange and metabolites transfer between organelles.
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High fat / high cholesterol diet does not provoke atherosclerosis in the ω3-and ω6-polyunsaturated fatty acid synthesis-inactivated Δ6-fatty acid desaturase-deficient mouse. Mol Metab 2021; 54:101335. [PMID: 34530175 PMCID: PMC8479258 DOI: 10.1016/j.molmet.2021.101335] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/30/2021] [Accepted: 08/31/2021] [Indexed: 11/29/2022] Open
Abstract
Objective An increased ω6/ω3-polyunsaturated fatty acid ratio in the current Western diet is regarded as a critical epigenetic nutritional factor in the pathogenesis of several human lifestyle diseases, metabolic syndrome, cardiovascular disease, the central nervous system and the female and male reproductive systems. The impact of nutrient ω3-and ω6-PUFAs in the pathogenesis of dyslipoproteinemia and atherosclerosis has been a topic of intense efforts for several decades. Cellular homeostasis of the ω3-and ω6- PUFA pool is maintained by the synthesis of ω3-and ω6-PUFAs from essential fatty acids (EFA) (linoleic and α-linolenic acid) and their dietary supply. In this study, we used the auxotrophic Δ6-fatty acid desaturase- (FADS2) deficient mouse (fads2−/−), an unbiased model congenial for stringent feeding experiments, to investigate the molecular basis of the proposed protective role of dietary ω3-and ω6-PUFAs (Western diet) in the pathogenesis of multifactorial dyslipoproteinemia and atherosclerosis. We focused on the metabolic axis—liver endoplasmic reticulum (ER), serum lipoprotein system (Lp) and aorta vessel wall. Furthermore, we addressed the impact of the inactivated fads2-locus with inactivated PUFA synthesis on the development and progression of extended atherosclerosis in two different mouse mutants with disrupted cholesterol homeostasis, using the apoe−/− and ldlr−/− mutants and the fads2−/− x apoe−/− and fads2−/− x ldlr−/− double mutants. Methods Cohorts of +/+ and fads2−/− mice underwent two long-term dietary regimens: a) a PUFA-free standard chow diet containing only EFAs, essential for viability, and b) a high fat/high cholesterol (HFHC) diet, a mimicry of the human atherogenic “Western” diet. c) To study the molecular impact of PUFA synthesis deficiency on the development and progression of atherosclerosis in the hypercholesterolemic apoe−/− and ldlr−/− mouse models fed PUFA-free regular and sustained HFHC diets, we generated the fads2−/− x apoe−/− and the fads2−/− x ldlr−/− double knockout mutants. We assessed essential molecular, biochemical and cell biological links between the diet-induced modified lipidomes of the membrane systems of the endoplasmic reticulum/Golgi complex, the site of lipid synthesis, the PL monolayer and neutral lipid core of LD and serum-Lp profiles and cellular reactions in the aortic wall. Results ω3-and ω6-PUFA synthesis deficiency in the fads2−/− mouse causes a) hypocholesterolemia and hypotriglyceridemia, b) dyslipoproteinemia with a shift of high-density lipoprotein (HDL) to very low-density lipoprotein (VLDL)-enriched Lp-pattern and c) altered liver lipid droplet structures. d) Long-term HFHC diet does not trigger atherosclerotic plaque formation in the aortic arc, the thoracic and abdominal aorta of PUFA-deficient fads2−/− mice. Inactivation of the fads2−/− locus, abolishing systemic PUFA synthesis in the fads2−/− x apoe−/− and fads2−/− x ldlr−/− double knockout mouse lines. Conclusions Deficiency of ω3-and ω6-PUFA in the fads2−/− mutant perturbs liver lipid metabolism, causes hypocholesterolemia and hypotriglyceridemia and renders the fads2−/− mutant resistant to sustained atherogenic HFHC diet. Neither PUFA-free regular nor long-term HFHC-diet impacts the apoe- and LDL-receptor deficiency–provoked hypercholesterolemia and atherosclerotic plaque formation, size and distribution in the aorta. Our study strongly suggests that the absence of PUFAs as highly vulnerable chemical targets of autoxidation attenuates inflammatory responses and the formation of atherosclerotic lesions. The cumulative data and insight into the molecular basis of the pleiotropic functions of PUFAs challenge a differentiated view of PUFAs as culprits or benefactors during a lifespan, pivotal for legitimate dietary recommendations.
ω3-and ω6-PUFA synthesis deficiency in the auxotrophic fads2−/− mouse. Perturbs liver membrane lipidomes and lipid metabolism Remodels the lipid droplet- and serum lipoprotein-systems Prevents PUFA-derived peroxidation products, protein modification, and inflammation Protects from high fat/high cholesterol (“Western diet”) that promotes atherosclerosis
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Brandenburg J, Marwitz S, Tazoll SC, Waldow F, Kalsdorf B, Vierbuchen T, Scholzen T, Gross A, Goldenbaum S, Hölscher A, Hein M, Linnemann L, Reimann M, Kispert A, Leitges M, Rupp J, Lange C, Niemann S, Behrends J, Goldmann T, Heine H, Schaible UE, Hölscher C, Schwudke D, Reiling N. WNT6/ACC2-induced storage of triacylglycerols in macrophages is exploited by Mycobacterium tuberculosis. J Clin Invest 2021; 131:e141833. [PMID: 34255743 DOI: 10.1172/jci141833] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 07/06/2021] [Indexed: 11/17/2022] Open
Abstract
In view of emerging drug-resistant tuberculosis (TB), host-directed adjunct therapies are urgently needed to improve treatment outcomes with currently available anti-TB therapies. One approach is to interfere with the formation of lipid-laden "foamy" macrophages in the host, as they provide a nutrient-rich host cell environment for Mycobacterium tuberculosis (Mtb). Here, we provide evidence that Wnt family member 6 (WNT6), a ligand of the evolutionarily conserved Wingless/Integrase 1 (WNT) signaling pathway, promotes foam cell formation by regulating key lipid metabolic genes including acetyl-CoA carboxylase 2 (ACC2) during pulmonary TB. Using genetic and pharmacological approaches, we demonstrated that lack of functional WNT6 or ACC2 significantly reduced intracellular triacylglycerol (TAG) levels and Mtb survival in macrophages. Moreover, treatment of Mtb-infected mice with a combination of a pharmacological ACC2 inhibitor and the anti-TB drug isoniazid (INH) reduced lung TAG and cytokine levels, as well as lung weights, compared with treatment with INH alone. This combination also reduced Mtb bacterial numbers and the size of mononuclear cell infiltrates in livers of infected mice. In summary, our findings demonstrate that Mtb exploits WNT6/ACC2-induced storage of TAGs in macrophages to facilitate its intracellular survival, a finding that opens new perspectives for host-directed adjunctive treatment of pulmonary TB.
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Affiliation(s)
- Julius Brandenburg
- Microbial Interface Biology, Research Center Borstel, Leibniz Lung Center, Borstel, Germany.,German Center for Infection Research (DZIF), Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
| | - Sebastian Marwitz
- Pathology, Research Center Borstel, Borstel, Germany.,Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany
| | - Simone C Tazoll
- Microbial Interface Biology, Research Center Borstel, Leibniz Lung Center, Borstel, Germany
| | - Franziska Waldow
- German Center for Infection Research (DZIF), Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany.,Bioanalytical Chemistry
| | - Barbara Kalsdorf
- German Center for Infection Research (DZIF), Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany.,Clinical Infectious Diseases
| | | | | | - Annette Gross
- Microbial Interface Biology, Research Center Borstel, Leibniz Lung Center, Borstel, Germany
| | - Svenja Goldenbaum
- Microbial Interface Biology, Research Center Borstel, Leibniz Lung Center, Borstel, Germany
| | | | | | - Lara Linnemann
- Cellular Microbiology, Research Center Borstel, Borstel, Germany
| | | | - Andreas Kispert
- Institute for Molecular Biology, Hannover Medical School, Hannover, Germany
| | - Michael Leitges
- Division of BioMedical Sciences/Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada
| | - Jan Rupp
- German Center for Infection Research (DZIF), Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany.,Department of Infectious Diseases and Microbiology and
| | - Christoph Lange
- German Center for Infection Research (DZIF), Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany.,Clinical Infectious Diseases.,Respiratory Medicine & International Health, University of Lübeck, Lübeck, Germany.,Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA
| | - Stefan Niemann
- German Center for Infection Research (DZIF), Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany.,Molecular and Experimental Mycobacteriology, Research Center Borstel, Borstel, Germany
| | | | - Torsten Goldmann
- Pathology, Research Center Borstel, Borstel, Germany.,Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany
| | | | - Ulrich E Schaible
- German Center for Infection Research (DZIF), Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany.,Cellular Microbiology, Research Center Borstel, Borstel, Germany
| | - Christoph Hölscher
- German Center for Infection Research (DZIF), Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany.,Infection Immunology, and
| | - Dominik Schwudke
- German Center for Infection Research (DZIF), Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany.,Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany.,Bioanalytical Chemistry
| | - Norbert Reiling
- Microbial Interface Biology, Research Center Borstel, Leibniz Lung Center, Borstel, Germany.,German Center for Infection Research (DZIF), Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
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42
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Wilson MH, Ekker SC, Farber SA. Imaging cytoplasmic lipid droplets in vivo with fluorescent perilipin 2 and perilipin 3 knock-in zebrafish. eLife 2021; 10:e66393. [PMID: 34387191 PMCID: PMC8460263 DOI: 10.7554/elife.66393] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 08/10/2021] [Indexed: 12/26/2022] Open
Abstract
Cytoplasmic lipid droplets are highly dynamic storage organelles that are critical for cellular lipid homeostasis. While the molecular details of lipid droplet dynamics are a very active area of investigation, this work has been primarily performed in cultured cells. Taking advantage of the powerful transgenic and in vivo imaging opportunities available in zebrafish, we built a suite of tools to study lipid droplets in real time from the subcellular to the whole organism level. Fluorescently tagging the lipid droplet-associated proteins, perilipin 2 and perilipin 3, in the endogenous loci permits visualization of lipid droplets in the intestine, liver, and adipose tissue. Using these tools, we found that perilipin 3 is rapidly loaded on intestinal lipid droplets following a high-fat meal and later replaced by perilipin 2. These powerful new tools will facilitate studies on the role of lipid droplets in different tissues, under different genetic and physiological manipulations, and in a variety of human disease models.
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Affiliation(s)
- Meredith H Wilson
- Carnegie Institution for Science Department of EmbryologyBaltimoreUnited States
| | - Stephen C Ekker
- Department of Biochemistry and Molecular Biology, Mayo ClinicRochesterUnited States
| | - Steven A Farber
- Carnegie Institution for Science Department of EmbryologyBaltimoreUnited States
- Johns Hopkins University Department of BiologyBaltimoreUnited States
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43
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Cottier S, Schneiter R. Lipid droplets form a network interconnected by the endoplasmic reticulum through which their proteins equilibrate. J Cell Sci 2021; 135:271208. [PMID: 34373922 DOI: 10.1242/jcs.258819] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 07/03/2021] [Indexed: 01/13/2023] Open
Abstract
Lipid droplets (LDs) are globular intracellular structures dedicated to the storage of neutral lipids. They are closely associated with the endoplasmic reticulum (ER) and are delineated by a monolayer of phospholipids that is continuous with the cytoplasmic leaflet of the ER membrane. LDs contain a specific set of proteins, but how these proteins are targeted to the LD surface is not fully understood. Here, we devised a yeast mating-based microscopic readout to monitor the transfer of LD proteins upon zygote formation. The results of this analysis indicate that ER fusion between mating partners is required for transfer of LD proteins and that this transfer is continuous, bidirectional and affects most LDs simultaneously. These observations suggest that LDs do not fuse upon mating of yeast cells, but that they form a network that is interconnected through the ER membrane. Consistent with this, ER-localized LD proteins rapidly move onto LDs of a mating partner and this protein transfer is affected by seipin, a protein important for proper LD biogenesis and the functional connection of LDs with the ER membrane.
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Affiliation(s)
- Stéphanie Cottier
- Department of Biology, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland
| | - Roger Schneiter
- Department of Biology, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland
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44
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Hussain SS, Tran TM, Ware TB, Luse MA, Prevost CT, Ferguson AN, Kashatus JA, Hsu KL, Kashatus DF. RalA and PLD1 promote lipid droplet growth in response to nutrient withdrawal. Cell Rep 2021; 36:109451. [PMID: 34320341 PMCID: PMC8344381 DOI: 10.1016/j.celrep.2021.109451] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 06/04/2021] [Accepted: 07/02/2021] [Indexed: 01/22/2023] Open
Abstract
Lipid droplets (LDs) are dynamic organelles that undergo dynamic changes in response to changing cellular conditions. During nutrient depletion, LD numbers increase to protect cells against toxic fatty acids generated through autophagy and provide fuel for beta-oxidation. However, the precise mechanisms through which these changes are regulated have remained unclear. Here, we show that the small GTPase RalA acts downstream of autophagy to directly facilitate LD growth during nutrient depletion. Mechanistically, RalA performs this function through phospholipase D1 (PLD1), an enzyme that converts phosphatidylcholine (PC) to phosphatidic acid (PA) and that is recruited to lysosomes during nutrient stress in a RalA-dependent fashion. RalA inhibition prevents recruitment of the LD-associated protein perilipin 3, which is required for LD growth. Our data support a model in which RalA recruits PLD1 to lysosomes during nutrient deprivation to promote the localized production of PA and the recruitment of perilipin 3 to expanding LDs.
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Affiliation(s)
- Syed S Hussain
- Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Tuyet-Minh Tran
- Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Timothy B Ware
- Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA
| | - Melissa A Luse
- Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Christopher T Prevost
- Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Ashley N Ferguson
- Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Jennifer A Kashatus
- Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Ku-Lung Hsu
- Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA; University of Virginia Cancer Center, University of Virginia Health System, Charlottesville, VA 22903, USA
| | - David F Kashatus
- Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA; University of Virginia Cancer Center, University of Virginia Health System, Charlottesville, VA 22903, USA.
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45
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Tavares LA, Januário YC, daSilva LLP. HIV-1 Hijacking of Host ATPases and GTPases That Control Protein Trafficking. Front Cell Dev Biol 2021; 9:622610. [PMID: 34307340 PMCID: PMC8295591 DOI: 10.3389/fcell.2021.622610] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 06/07/2021] [Indexed: 12/22/2022] Open
Abstract
The human immunodeficiency virus (HIV-1) modifies the host cell environment to ensure efficient and sustained viral replication. Key to these processes is the capacity of the virus to hijack ATPases, GTPases and the associated proteins that control intracellular protein trafficking. The functions of these energy-harnessing enzymes can be seized by HIV-1 to allow the intracellular transport of viral components within the host cell or to change the subcellular distribution of antiviral factors, leading to immune evasion. Here, we summarize how energy-related proteins deviate from their normal functions in host protein trafficking to aid the virus in different phases of its replicative cycle. Recent discoveries regarding the interplay among HIV-1 and host ATPases and GTPases may shed light on potential targets for pharmacological intervention.
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Affiliation(s)
- Lucas A Tavares
- Department of Cell and Molecular Biology, Center for Virology Research, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Yunan C Januário
- Department of Cell and Molecular Biology, Center for Virology Research, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Luis L P daSilva
- Department of Cell and Molecular Biology, Center for Virology Research, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
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46
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Zhao Y, Albrecht E, Li Z, Schregel J, Sciascia QL, Metges CC, Maak S. Distinct Roles of Perilipins in the Intramuscular Deposition of Lipids in Glutamine-Supplemented, Low-, and Normal-Birth-Weight Piglets. Front Vet Sci 2021; 8:633898. [PMID: 34235195 PMCID: PMC8257002 DOI: 10.3389/fvets.2021.633898] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 05/10/2021] [Indexed: 11/13/2022] Open
Abstract
Piglets with low birth weight (LBW) usually have reduced muscle mass and increased lipid deposition compared with their normal-birth-weight (NBW) littermates. Supplementation of piglets with amino acids during the first days of life may improve muscle growth and simultaneously alter the intramuscular lipid deposition. The aim of the current study was to investigate the influence of glutamine (Gln) supplementation during the early suckling period on lipid deposition in the longissimus muscle (MLD) and the role of different perilipin (PLIN) family members in this process. Four groups were generated consisting of 72 male LBW piglets and 72 NBW littermates. Piglets were supplemented with either 1 g Gln/kg body weight or an isonitrogenous amount of alanine (Ala) between days post natum (dpn) 1 and 12. Twelve piglets per group were slaughtered at 5, 12, and 26 dpn, and muscle tissue was collected. Perilipins were localized by immunohistochemistry in muscle sections. The mRNA and protein abundances of PLIN family members and related lipases were quantified by quantitative RT-PCR (qPCR) and western blots, respectively. While PLIN1 was localized around lipid droplets in mature and developing adipocytes, PLIN2 was localized at intramyocellular lipid droplets, PLIN3 and 4 at cell membranes of muscle fibers and adipocytes, and PLIN5 in the cytoplasm of undefined cells. The western blot results indicated higher protein abundances of PLIN2, 3, 4, and 5 in LBW piglets (p < 0.05) at 5 dpn compared with their NBW littermates independent of supplementation, while not directly reflecting the mRNA expression levels. The mRNA abundance of PLIN2 was lower while PLIN4 was higher in piglets at 26 dpn in comparison with piglets at 5 dpn (p < 0.01). Relative mRNA expression of LPL and CGI-58 was lowest in piglets at 5 dpn (p < 0.001). However, ATGL mRNA was not influenced by birth weight or supplementation, but the Spearman correlation coefficient analysis revealed close correlations with PLIN2, 4, and 5 mRNA at 5 and 26 dpn (r > 0.5, p < 0.001). The results indicated the importance of birth weight and age for intramuscular lipid deposition and different roles of PLIN family members in this process, but no clear modulating effect of Gln supplementation.
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Affiliation(s)
- Yaolu Zhao
- Institute of Muscle Biology and Growth, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Elke Albrecht
- Institute of Muscle Biology and Growth, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Zeyang Li
- Institute of Nutritional Physiology "Oskar Kellner", Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Johannes Schregel
- Institute of Nutritional Physiology "Oskar Kellner", Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Quentin L Sciascia
- Institute of Nutritional Physiology "Oskar Kellner", Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Cornelia C Metges
- Institute of Nutritional Physiology "Oskar Kellner", Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Steffen Maak
- Institute of Muscle Biology and Growth, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
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47
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Tu Y, Seaman MNJ. Navigating the Controversies of Retromer-Mediated Endosomal Protein Sorting. Front Cell Dev Biol 2021; 9:658741. [PMID: 34222232 PMCID: PMC8247582 DOI: 10.3389/fcell.2021.658741] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 05/14/2021] [Indexed: 01/01/2023] Open
Abstract
The retromer complex was first identified more than 20 years ago through studies conducted in the yeast Saccharomyces cerevisiae. Data obtained using many different model systems have revealed that retromer is a key component of the endosomal protein sorting machinery being necessary for recognition of membrane “cargo” proteins and formation of tubular carriers that function as transport intermediates. Naturally, over the course of time and with literally hundreds of papers published on retromer, there have arisen disparities, conflicting observations and some controversies as to how retromer functions in endosomal protein sorting – the most note-worthy being associated with the two activities that define a vesicle coat: cargo selection and vesicle/tubule formation. In this review, we will attempt to chart a course through some of the more fundamental controversies to arrive at a clearer understanding of retromer.
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Affiliation(s)
- Yingfeng Tu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Matthew N J Seaman
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
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48
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Khaddaj R, Mari M, Cottier S, Reggiori F, Schneiter R. The surface of lipid droplets constitutes a barrier for endoplasmic reticulum-resident integral membrane proteins. J Cell Sci 2021; 135:268334. [PMID: 34028531 DOI: 10.1242/jcs.256206] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 04/14/2021] [Indexed: 12/12/2022] Open
Abstract
Lipid droplets (LDs) are globular subcellular structures that store neutral lipids. LDs are closely associated with the endoplasmic reticulum (ER) and are limited by a phospholipid monolayer harboring a specific set of proteins. Most of these proteins associate with LDs through either an amphipathic helix or a membrane-embedded hairpin motif. Here, we address the question of whether integral membrane proteins can localize to the surface of LDs. To test this, we fused perilipin 3 (PLIN3), a mammalian LD-targeted protein, to ER-resident proteins. The resulting fusion proteins localized to the periphery of LDs in both yeast and mammalian cells. This peripheral LD localization of the fusion proteins, however, was due to a redistribution of the ER around LDs, as revealed by bimolecular fluorescence complementation between ER- and LD-localized partners. A LD-tethering function of PLIN3-containing membrane proteins was confirmed by fusing PLIN3 to the cytoplasmic domain of an outer mitochondrial membrane protein, OM14. Expression of OM14-PLIN3 induced a close apposition between LDs and mitochondria. These data indicate that the ER-LD junction constitutes a barrier for ER-resident integral membrane proteins.
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Affiliation(s)
- Rasha Khaddaj
- Department of Biology, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland
| | - Muriel Mari
- Department of Biomedical Sciences of Cells and Systems, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands
| | - Stéphanie Cottier
- Department of Biology, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland
| | - Fulvio Reggiori
- Department of Biomedical Sciences of Cells and Systems, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands
| | - Roger Schneiter
- Department of Biology, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland
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49
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Boucher DM, Vijithakumar V, Ouimet M. Lipid Droplets as Regulators of Metabolism and Immunity. IMMUNOMETABOLISM 2021; 3. [DOI: 10.20900/immunometab20210021] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 05/28/2021] [Indexed: 01/03/2025]
Abstract
Abstract
A hallmark of sterile and nonsterile inflammation is the increased accumulation of cytoplasmic lipid droplets (LDs) in non-adipose cells. LDs are ubiquitous organelles specialized in neutral lipid storage and hydrolysis. Originating in the ER, LDs are comprised of a core of neutral lipids (cholesterol esters, triglycerides) surrounded by a phospholipid monolayer and several LD-associated proteins. The perilipin (PLIN1-5) family are the most abundant structural proteins present on the surface of LDs. While PLIN1 is primarily expressed in adipocytes, PLIN2 and PLIN3 are ubiquitously expressed. LDs also acquire a host of enzymes and proteins that regulate LD metabolism. Amongst these are neutral lipases and selective lipophagy factors that promote hydrolysis of LD-associated neutral lipid. In addition, LDs physically associate with other organelles such as mitochondria through inter-organelle membrane contact sites that facilitate lipid transport. Beyond serving as a source of energy storage, LDs participate in inflammatory and infectious diseases, regulating both innate and adaptive host immune responses. Here, we review recent studies on the role of LDs in the regulation of immunometabolism.
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Affiliation(s)
- Dominique M. Boucher
- University of Ottawa Heart Institute, 40 Ruskin St, Ottawa, ON, K1Y 4W7, Canada
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
| | - Viyashini Vijithakumar
- University of Ottawa Heart Institute, 40 Ruskin St, Ottawa, ON, K1Y 4W7, Canada
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
| | - Mireille Ouimet
- University of Ottawa Heart Institute, 40 Ruskin St, Ottawa, ON, K1Y 4W7, Canada
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
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50
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Giménez-Andrés M, Emeršič T, Antoine-Bally S, D'Ambrosio JM, Antonny B, Derganc J, Čopič A. Exceptional stability of a perilipin on lipid droplets depends on its polar residues, suggesting multimeric assembly. eLife 2021; 10:61401. [PMID: 33856341 PMCID: PMC8064757 DOI: 10.7554/elife.61401] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 04/14/2021] [Indexed: 12/23/2022] Open
Abstract
Numerous proteins target lipid droplets (LDs) through amphipathic helices (AHs). It is generally assumed that AHs insert bulky hydrophobic residues in packing defects at the LD surface. However, this model does not explain the targeting of perilipins, the most abundant and specific amphipathic proteins of LDs, which are weakly hydrophobic. A striking example is Plin4, whose gigantic and repetitive AH lacks bulky hydrophobic residues. Using a range of complementary approaches, we show that Plin4 forms a remarkably immobile and stable protein layer at the surface of cellular or in vitro generated oil droplets, and decreases LD size. Plin4 AH stability on LDs is exquisitely sensitive to the nature and distribution of its polar residues. These results suggest that Plin4 forms stable arrangements of adjacent AHs via polar/electrostatic interactions, reminiscent of the organization of apolipoproteins in lipoprotein particles, thus pointing to a general mechanism of AH stabilization via lateral interactions.
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Affiliation(s)
- Manuel Giménez-Andrés
- Institut Jacques Monod, CNRS, Université de Paris, Paris, France.,Université Paris-Saclay, Saint-Aubin, France
| | - Tadej Emeršič
- Institute of Biophysics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | | | - Juan Martin D'Ambrosio
- Institut Jacques Monod, CNRS, Université de Paris, Paris, France.,CRBM, University of Montpellier and CNRS, Montpellier, France
| | - Bruno Antonny
- Université Côte d'Azur, CNRS, IPMC, Valbonne, France
| | - Jure Derganc
- Institute of Biophysics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.,Chair of Microprocess Engineering and Technology - COMPETE, University of Ljubljana, Ljubljana, Slovenia
| | - Alenka Čopič
- Institut Jacques Monod, CNRS, Université de Paris, Paris, France.,CRBM, University of Montpellier and CNRS, Montpellier, France
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