Adiponectin and related C1q/TNF-related proteins bind selectively to anionic phospholipids and sphingolipids

ABSTRACTAdiponectin (also known as Acrp30) is a well-known adipokine associated with protection from cardiovascular disease, insulin resistance, and inflammation. Though multiple studies have investigated the mechanism of action of adiponectin and its relationship with tissue ceramide levels, several aspects of adiponectin biology remain unexplained, including its high circulating levels, tendency to oligomerize, and marked structural similarity to the opsonin C1q. Given the connection between adiponectin and ceramide metabolism, and the lipid-binding properties of C1q, we hypothesized that adiponectin may function as a lipid binding protein. Indeed, we found that recombinant adiponectin bound to various anionic phospholipids and sphingolipids, including phosphatidylserine, ceramide-1-phosphate, and sulfatide. The globular head-domain of adiponectin was necessary and sufficient for lipid binding. Adiponectin oligomerization was also observed to be critical for efficient lipid binding. In addition to lipids in liposomes, adiponectin bound LDL in an oligomerization-dependent manner. Other C1qTNF-related protein (CTRP) family members Cbln1, CTRP1, CTRP5, and CTRP13 also bound similar target lipids in liposomes. These findings suggest that adiponectin and other CTRP family members may not only function as classical hormones, but also as lipid binding opsonins or carrier proteins.

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Adiponectin and related C1q/TNF-related proteins bind selectively to anionic phospholipids and sphingolipids

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1922270117 ◽

2020 ◽

Vol 117 (29) ◽

pp. 17381-17388 ◽

Cited By ~ 1

Author(s):

Jessica J. Ye ◽

Xin Bian ◽

Jaechul Lim ◽

Ruslan Medzhitov

Keyword(s):

Family Members ◽

Lipid Binding ◽

Low Density Lipoproteins ◽

Low Density ◽

Liquid Chromatography Mass Spectrometry ◽

Shotgun Lipidomics ◽

Anionic Phospholipids ◽

Related Proteins ◽

Ceramide 1 ◽

Representative Family

Adiponectin (Acrp30) is an adipokine associated with protection from cardiovascular disease, insulin resistance, and inflammation. Although its effects are conventionally attributed to binding Adipor1/2 and T-cadherin, its abundance in circulation, role in ceramide metabolism, and homology to C1q suggest an overlooked role as a lipid-binding protein, possibly generalizable to other C1q/TNF-related proteins (CTRPs) and C1q family members. To investigate this, adiponectin, representative family members, and variants were expressed in Expi293 cells and tested for binding to lipids in liposomes using density centrifugation. Binding to physiological lipids were also analyzed using gradient ultracentrifugation, liquid chromatography-mass spectrometry, and shotgun lipidomics. Interestingly, adiponectin selectively bound several anionic phospholipids and sphingolipids, including phosphatidylserine, ceramide-1-phosphate, glucosylceramide, and sulfatide, via the C1q domain in an oligomerization-dependent fashion. Binding to lipids was observed in liposomes, low-density lipoproteins, cell membranes, and plasma. Other CTRPs and C1q family members (Cbln1, CTRP1, CTRP5, and CTRP13) also bound similar lipids. These findings suggest that adiponectin and CTRPs function not only as hormones, but also as lipid opsonins, as may other C1q family proteins.

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Lipid-regulated sterol transfer between closely apposed membranes by oxysterol-binding protein homologues

The Journal of Cell Biology ◽

10.1083/jcb.200905007 ◽

2009 ◽

Vol 187 (6) ◽

pp. 889-903 ◽

Cited By ~ 150

Author(s):

Timothy A. Schulz ◽

Mal-Gi Choi ◽

Sumana Raychaudhuri ◽

Jason A. Mears ◽

Rodolfo Ghirlando ◽

...

Keyword(s):

Binding Protein ◽

Binding Pocket ◽

Lipid Binding ◽

Dependent Manner ◽

Oxysterol Binding Protein ◽

The Core ◽

Contact Sites ◽

Core Lipid ◽

Related Proteins ◽

Distal Site

Sterols are transferred between cellular membranes by vesicular and poorly understood nonvesicular pathways. Oxysterol-binding protein–related proteins (ORPs) have been implicated in sterol sensing and nonvesicular transport. In this study, we show that yeast ORPs use a novel mechanism that allows regulated sterol transfer between closely apposed membranes, such as organelle contact sites. We find that the core lipid-binding domain found in all ORPs can simultaneously bind two membranes. Using Osh4p/Kes1p as a representative ORP, we show that ORPs have at least two membrane-binding surfaces; one near the mouth of the sterol-binding pocket and a distal site that can bind a second membrane. The distal site is required for the protein to function in cells and, remarkably, regulates the rate at which Osh4p extracts and delivers sterols in a phosphoinositide-dependent manner. Together, these findings suggest a new model of how ORPs could sense and regulate the lipid composition of adjacent membranes.

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Differential Regulation of the Kar3p Kinesin-related Protein by Two Associated Proteins, Cik1p and Vik1p

The Journal of Cell Biology ◽

10.1083/jcb.144.6.1219 ◽

1999 ◽

Vol 144 (6) ◽

pp. 1219-1233 ◽

Cited By ~ 69

Author(s):

Brendan D. Manning ◽

Jennifer G. Barrett ◽

Julie A. Wallace ◽

Howard Granok ◽

Michael Snyder

Keyword(s):

Spindle Pole Body ◽

Structural Similarity ◽

Spindle Pole ◽

Body Region ◽

Growth Defect ◽

Temperature Sensitive ◽

Dependent Manner ◽

Related Protein ◽

Phenotypic Analysis ◽

Related Proteins

The mechanisms by which kinesin-related proteins interact with other proteins to carry out specific cellular processes is poorly understood. The kinesin-related protein, Kar3p, has been implicated in many microtubule functions in yeast. Some of these functions require interaction with the Cik1 protein (Page, B.D., L.L. Satterwhite, M.D. Rose, and M. Snyder. 1994. J. Cell Biol. 124:507–519). We have identified a Saccharomyces cerevisiae gene, named VIK1, encoding a protein with sequence and structural similarity to Cik1p. The Vik1 protein is detected in vegetatively growing cells but not in mating pheromone-treated cells. Vik1p physically associates with Kar3p in a complex separate from that of the Kar3p-Cik1p complex. Vik1p localizes to the spindle-pole body region in a Kar3p-dependent manner. Reciprocally, concentration of Kar3p at the spindle poles during vegetative growth requires the presence of Vik1p, but not Cik1p. Phenotypic analysis suggests that Cik1p and Vik1p are involved in different Kar3p functions. Disruption of VIK1 causes increased resistance to the microtubule depolymerizing drug benomyl and partially suppresses growth defects of cik1Δ mutants. The vik1Δ and kar3Δ mutations, but not cik1Δ, partially suppresses the temperature-sensitive growth defect of strains lacking the function of two other yeast kinesin-related proteins, Cin8p and Kip1p. Our results indicate that Kar3p forms functionally distinct complexes with Cik1p and Vik1p to participate in different microtubule-mediated events within the same cell.

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Faculty Opinions recommendation of Structure of the split PH domain and distinct lipid-binding properties of the PH-PDZ supramodule of alpha-syntrophin.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1030902.360593 ◽

2006 ◽

Author(s):

David Cowburn

Keyword(s):

Lipid Binding ◽

Ph Domain ◽

Binding Properties

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Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue

Nature Communications ◽

10.1038/s41467-021-22579-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Anastasia Georgiadi ◽

Valeria Lopez-Salazar ◽

Rabih El- Merahbi ◽

Rhoda Anane Karikari ◽

Xiaochuan Ma ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Dependent Manner ◽

Metabolic Dysfunction ◽

Functional Interaction ◽

White Adipocyte ◽

White Adipocytes ◽

Obesity And Diabetes ◽

Adhesion Gpcr ◽

Circulating Levels

AbstractThe proper functional interaction between different tissues represents a key component in systemic metabolic control. Indeed, disruption of endocrine inter-tissue communication is a hallmark of severe metabolic dysfunction in obesity and diabetes. Here, we show that the FNDC4-GPR116, liver-white adipose tissue endocrine axis controls glucose homeostasis. We found that the liver primarily controlled the circulating levels of soluble FNDC4 (sFNDC4) and lowering of the hepatokine FNDC4 led to prediabetes in mice. Further, we identified the orphan adhesion GPCR GPR116 as a receptor of sFNDC4 in the white adipose tissue. Upon direct and high affinity binding of sFNDC4 to GPR116, sFNDC4 promoted insulin signaling and insulin-mediated glucose uptake in white adipocytes. Indeed, supplementation with FcsFNDC4 in prediabetic mice improved glucose tolerance and inflammatory markers in a white-adipocyte selective and GPR116-dependent manner. Of note, the sFNDC4-GPR116, liver-adipose tissue axis was dampened in (pre) diabetic human patients. Thus our findings will now allow for harnessing this endocrine circuit for alternative therapeutic strategies in obesity-related pre-diabetes.

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Triple-Knockout, Synuclein-Free Mice Display Compromised Lipid Pattern

Molecules ◽

10.3390/molecules26113078 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3078

Author(s):

Irina A. Guschina ◽

Natalia Ninkina ◽

Andrei Roman ◽

Mikhail V. Pokrovskiy ◽

Vladimir L. Buchman

Keyword(s):

Fatty Acids ◽

Lipid Metabolism ◽

Family Members ◽

Ether Lipid ◽

Brain Regions ◽

Membrane Lipid ◽

Lipid Binding ◽

Synaptic Functions ◽

Ethanolamine Plasmalogens ◽

Lipid Pattern

Recent studies have implicated synucleins in several reactions during the biosynthesis of lipids and fatty acids in addition to their recognised role in membrane lipid binding and synaptic functions. These are among aspects of decreased synuclein functions that are still poorly acknowledged especially in regard to pathogenesis in Parkinson’s disease. Here, we aimed to add to existing knowledge of synuclein deficiency (i.e., the lack of all three family members), with respect to changes in fatty acids and lipids in plasma, liver, and two brain regions in triple synuclein-knockout (TKO) mice. We describe changes of long-chain polyunsaturated fatty acids (LCPUFA) and palmitic acid in liver and plasma, reduced triacylglycerol (TAG) accumulation in liver and non-esterified fatty acids in plasma of synuclein free mice. In midbrain, we observed counterbalanced changes in the relative concentrations of phosphatidylcholine (PC) and cerebrosides (CER). We also recorded a notable reduction in ethanolamine plasmalogens in the midbrain of synuclein free mice, which is an important finding since the abnormal ether lipid metabolism usually associated with neurological disorders. In summary, our data demonstrates that synuclein deficiency results in alterations of the PUFA synthesis, storage lipid accumulation in the liver, and the reduction of plasmalogens and CER, those polar lipids which are principal compounds of lipid rafts in many tissues. An ablation of all three synuclein family members causes more profound changes in lipid metabolism than changes previously shown to be associated with γ-synuclein deficiency alone. Possible mechanisms by which synuclein deficiency may govern the reported modifications of lipid metabolism in TKO mice are proposed and discussed.

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The Demethoxy Derivatives of Curcumin Exhibit Greater Differentiation Suppression in 3T3-L1 Adipocytes Than Curcumin: A Mechanistic Study of Adipogenesis and Molecular Docking

Biomolecules ◽

10.3390/biom11071025 ◽

2021 ◽

Vol 11 (7) ◽

pp. 1025

Author(s):

Ahmed Alalaiwe ◽

Jia-You Fang ◽

Hsien-Ju Lee ◽

Chun-Hui Chiu ◽

Ching-Yun Hsu

Keyword(s):

Molecular Docking ◽

Fatty Acid Synthase ◽

Structural Similarity ◽

Mechanistic Study ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Peroxisome Proliferator Activated Receptor ◽

Enhancer Binding Protein ◽

Underlying Mechanisms ◽

Amp Activated Protein Kinase

Curcumin is a known anti-adipogenic agent for alleviating obesity and related disorders. Comprehensive comparisons of the anti-adipogenic activity of curcumin with other curcuminoids is minimal. This study compared adipogenesis inhibition with curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC), and their underlying mechanisms. We differentiated 3T3-L1 cells in the presence of curcuminoids, to determine lipid accumulation and triglyceride (TG) production. The expression of adipogenic transcription factors and lipogenic proteins was analyzed by Western blot. A significant reduction in Oil red O (ORO) staining was observed in the cells treated with curcuminoids at 20 μM. Inhibition was increased in the order of curcumin < DMC < BDMC. A similar trend was observed in the detection of intracellular TG. Curcuminoids suppressed differentiation by downregulating the expression of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), leading to the downregulation of the lipogenic enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). AMP-activated protein kinase α (AMPKα) phosphorylation was also activated by BDMC. Curcuminoids reduced the release of proinflammatory cytokines and leptin in 3T3-L1 cells in a dose-dependent manner, with BDMC showing the greatest potency. BDMC at 20 μM significantly decreased leptin by 72% compared with differentiated controls. Molecular docking computation indicated that curcuminoids, despite having structural similarity, had different interaction positions to PPARγ, C/EBPα, and ACC. The docking profiles suggested a possible interaction of curcuminoids with C/EBPα and ACC, to directly inhibit their expression.

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Genetic Analysis of Factors Affecting Susceptibility of Bacillus subtilis to Daptomycin

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01329-08 ◽

2009 ◽

Vol 53 (4) ◽

pp. 1598-1609 ◽

Cited By ~ 105

Author(s):

Anna-Barbara Hachmann ◽

Esther R. Angert ◽

John D. Helmann

Keyword(s):

Bacillus Subtilis ◽

Cell Envelope ◽

Transcriptional Profiling ◽

Protein A ◽

Multidrug Resistant ◽

Dependent Manner ◽

Membrane Composition ◽

Factors Affecting ◽

Anionic Phospholipids ◽

Cyclic Lipopeptide

ABSTRACT Daptomycin is the first of a new class of cyclic lipopeptide antibiotics used against multidrug-resistant, gram-positive pathogens. The proposed mechanism of action involves disruption of the functional integrity of the bacterial membrane in a Ca2+-dependent manner. We have used transcriptional profiling to demonstrate that treatment of Bacillus subtilis with daptomycin strongly induces the lia operon including the autoregulatory LiaRS two-component system (homologous to Staphylococcus aureus VraSR). The lia operon protects against daptomycin, and deletion of liaH, encoding a phage-shock protein A (PspA)-like protein, leads to threefold increased susceptibility. Since daptomycin interacts with the membrane, we tested mutants with altered membrane composition for effects on susceptibility. Deletion mutations of mprF (lacking lysyl-phosphatidylglycerol) or des (lipid desaturase) increased daptomycin susceptibility, whereas overexpression of MprF decreased susceptibility. Conversely, depletion of the cell for the anionic lipid phosphatidylglycerol led to increased resistance. Fluorescently labeled daptomycin localized to the septa and in a helical pattern around the cell envelope and was delocalized upon the depletion of phosphatidylglycerol. Together, these results indicate that the daptomycin-Ca2+ complex interacts preferentially with regions enriched in anionic phospholipids and leads to membrane stresses that can be ameliorated by PspA family proteins.

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