bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2024–08–04
eightteen papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. Phosphorylation of PFKL regulates metabolic reprogramming in macrophages following pattern recognition receptor activation.
  2. Opa1 processing is dispensable in mouse development but is protective in mitochondrial cardiomyopathy.
  3. Etomoxir-carnitine, a novel pharmaco-metabolite of etomoxir, inhibits phospholipases A2 and mitochondrial respiration.
  4. ASCT2 is a major contributor to serine uptake in cancer cells.
  5. Lipid droplet-associated hydrolase mobilizes stores of liver X receptor sterol ligands and protects against atherosclerosis.
  6. The Warburg Effect Revisited through Blood and Electron Flow.
  7. Development of a functional beige fat cell line uncovers independent subclasses of cells expressing UCP1 and the futile creatine cycle.
  8. CPT1A-IL-10-mediated macrophage metabolic and phenotypic alterations ameliorate acute lung injury.
  9. Harnessing intestinal tryptophan catabolism to relieve atherosclerosis in mice.
  10. A three-way organelle junction controls PI(4)P metabolism and mitochondrial division.
  11. Stable isotope-resolved metabolomics analyses of metabolic phenotypes reveal variable glutamine metabolism in different patient-derived models of non-small cell lung cancer from a single patient.
  12. ABCA1 deficiency causes tissue-specific dysregulation of the SREBP2 pathway in mice.
  13. Mitochondria to plasma membrane redox signaling is essential for fatty acid β-oxidation-driven insulin secretion.
  14. Cilia-enriched oxysterol 7β,27-DHC is required for polycystin ion channel activation.
  15. Mitochondrial bioenergetics and cardiolipin remodeling abnormalities in mitochondrial trifunctional protein deficiency.
  16. A microbial metabolite inhibits the HIF-2α-ceramide pathway to mediate the beneficial effects of time-restricted feeding on MASH.
  17. Hepatic stearoyl-CoA desaturase-1 deficiency induces fibrosis and hepatocellular carcinoma-related gene activation under a high carbohydrate low fat diet.
  18. Cancer stem cells release interleukin-33 within large oncosomes to promote immunosuppressive differentiation of macrophage precursors.
  1. Nat Commun. 2024 Jul 31. 15(1): 6438
    Phosphorylation of PFKL regulates metabolic reprogramming in macrophages following pattern recognition receptor activation.
    Meiyue Wang, Heinrich Flaswinkel, Abhinav Joshi, Matteo Napoli, Sergi Masgrau-Alsina, Julia M Kamper, Antonia Henne, Alexander Heinz, Marleen Berouti, Niklas A Schmacke, Karsten Hiller, Elisabeth Kremmer, Benedikt Wefers, Wolfgang Wurst, Markus Sperandio, Jürgen Ruland, Thomas Fröhlich, Veit Hornung.
      Innate immune responses are linked to key metabolic pathways, yet the proximal signaling events that connect these systems remain poorly understood. Here we show that phosphofructokinase 1, liver type (PFKL), a rate-limiting enzyme of glycolysis, is phosphorylated at Ser775 in macrophages following several innate stimuli. This phosphorylation increases the catalytic activity of PFKL, as shown by biochemical assays and glycolysis monitoring in cells expressing phosphorylation-defective PFKL variants. Using a genetic mouse model in which PFKL Ser775 phosphorylation cannot take place, we observe that upon activation, glycolysis in macrophages is lower than in the same cell population of wild-type animals. Consistent with their higher glycolytic activity, wild-type cells have higher levels of HIF1α and IL-1β than PfklS775A/S775A after LPS treatment. In an in vivo inflammation model, PfklS775A/S775A mice show reduced levels of MCP-1 and IL-1β. Our study thus identifies a molecular link between innate immune activation and early induction of glycolysis.
    DOI:  https://doi.org/10.1038/s41467-024-50104-7
  2. Sci Adv. 2024 Aug 02. 10(31): eadp0443
    Opa1 processing is dispensable in mouse development but is protective in mitochondrial cardiomyopathy.
    Sofia Ahola, Lilli A Pazurek, Fiona Mayer, Philipp Lampe, Steffen Hermans, Lore Becker, Oana V Amarie, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabe de Angelis, Dietmar Riedel, Hendrik Nolte, Thomas Langer.
      Mitochondrial fusion and fission accompany adaptive responses to stress and altered metabolic demands. Inner membrane fusion and cristae morphogenesis depends on optic atrophy 1 (Opa1), which is expressed in different isoforms and is cleaved from a membrane-bound, long to a soluble, short form. Here, we have analyzed the physiological role of Opa1 isoforms and Opa1 processing by generating mouse lines expressing only one cleavable Opa1 isoform or a non-cleavable variant thereof. Our results show that expression of a single cleavable or non-cleavable Opa1 isoform preserves embryonic development and the health of adult mice. Opa1 processing is dispensable under metabolic and thermal stress but prolongs life span and protects against mitochondrial cardiomyopathy in OXPHOS-deficient Cox10-/- mice. Mechanistically, loss of Opa1 processing disturbs the balance between mitochondrial biogenesis and mitophagy, suppressing cardiac hypertrophic growth in Cox10-/- hearts. Our results highlight the critical regulatory role of Opa1 processing, mitochondrial dynamics, and metabolism for cardiac hypertrophy.
    DOI:  https://doi.org/10.1126/sciadv.adp0443
  3. J Lipid Res. 2024 Jul 31. pii: S0022-2275(24)00116-0. [Epub ahead of print] 100611
    Etomoxir-carnitine, a novel pharmaco-metabolite of etomoxir, inhibits phospholipases A2 and mitochondrial respiration.
    Sung Ho Moon, Xinping Liu, Christopher M Jenkins, Beverly Gibson Dilthey, Gary J Patti, Richard W Gross.
      Mitochondrial fatty acid oxidation serves as an essential process for cellular survival, differentiation, proliferation, and energy metabolism. Numerous studies have utilized etomoxir (ETO) for the irreversible inhibition of carnitine palmitoylcarnitine transferase 1 (CPT1) which catalyzes the rate-limiting step for mitochondrial long-chain fatty acid β-oxidation to examine the bioenergetic roles of mitochondrial fatty acid metabolism in many tissues in multiple diverse disease states. Herein, we demonstrate that intact mitochondria robustly metabolize etomoxir to etomoxir-carnitine (ETO-carnitine) prior to nearly complete etomoxir-mediated inhibition of CPT1. The novel pharmaco-metabolite, ETO-carnitine, was conclusively identified by accurate mass, fragmentation patterns, and isotopic fine structure. On the basis of these data, ETO-carnitine was successfully differentiated from isobaric structures (e.g., 3-hydroxy-C18:0 carnitine and 3-hydroxy-C18:1 carnitine). Mechanistically, generation of ETO-carnitine from mitochondria required exogenous Mg2+, ATP or ADP, CoASH, and L-carnitine indicating that thioesterification by long-chain acyl-CoA synthetase to form ETO-CoA precedes its conversion to ETO-carnitine by CPT1. CPT1-dependent generation of ETO-carnitine was substantiated by an orthogonal approach using ST1326 (a CPT1 inhibitor) which effectively inhibits mitochondrial ETO-carnitine production. Surprisingly, purified ETO-carnitine potently inhibited calcium-independent PLA2γ and PLA2β as well as mitochondrial respiration independent of CPT1. Robust production and release of ETO-carnitine from HepG2 cells incubated in the presence of ETO was also demonstrated. Collectively, this study identifies the chemical mechanism for the biosynthesis of a novel pharmaco-metabolite of etomoxir, ETO-carnitine, that is generated by CPT1 in mitochondria and likely impacts multiple downstream (non-CPT1 related) enzymes and processes in multiple subcellular compartments.
    Keywords:  Lipidomics; Lipids/Chemistry; Lipolysis and fatty acid metabolism; carnitine palmitoyltransferase (CPT); etomoxir; etomoxir-carnitine; mitochondria; off-target effects; pharmaco-metabolite; phospholipases A(2)
    DOI:  https://doi.org/10.1016/j.jlr.2024.100611
  4. Cell Rep. 2024 Jul 26. pii: S2211-1247(24)00881-7. [Epub ahead of print]43(8): 114552
    ASCT2 is a major contributor to serine uptake in cancer cells.
    Kelly O Conger, Christopher Chidley, Mete Emir Ozgurses, Huiping Zhao, Yumi Kim, Svetlana E Semina, Philippa Burns, Vipin Rawat, Lina Lietuvninkas, Ryan Sheldon, Issam Ben-Sahra, Jonna Frasor, Peter K Sorger, Gina M DeNicola, Jonathan L Coloff.
      The non-essential amino acid serine is a critical nutrient for cancer cells due to its diverse biosynthetic functions. While some tumors can synthesize serine de novo, others are auxotrophic and therefore reliant on serine uptake. Importantly, despite several transporters being known to be capable of transporting serine, the transporters that mediate serine uptake in cancer cells are not known. Here, we characterize the amino acid transporter ASCT2 (SLC1A5) as a major contributor to serine uptake in cancer cells. ASCT2 is well known as a glutamine transporter in cancer, and our work demonstrates that serine and glutamine compete for uptake through ASCT2. We further show that ASCT2-mediated serine uptake is essential for purine nucleotide biosynthesis and that estrogen receptor α (ERα) promotes serine uptake by directly activating SLC1A5 transcription. Collectively, our work defines an additional important role for ASCT2 as a serine transporter in cancer and evaluates ASCT2 as a potential therapeutic target.
    Keywords:  ASCT2; CP: Cancer; ERα; SLC1A5; amino acid uptake; breast cancer; cancer metabolism; diet; purine biosynthesis; serine starvation; serine transporter
    DOI:  https://doi.org/10.1016/j.celrep.2024.114552
  5. Nat Commun. 2024 Aug 02. 15(1): 6540
    Lipid droplet-associated hydrolase mobilizes stores of liver X receptor sterol ligands and protects against atherosclerosis.
    Young-Hwa Goo, Janeesh Plakkal Ayyappan, Francis D Cheeran, Sushant Bangru, Pradip K Saha, Paula Baar, Sabine Schulz, Todd A Lydic, Bernhard Spengler, Andreas H Wagner, Auinash Kalsotra, Vijay K Yechoor, Antoni Paul.
      Foam cells in atheroma are engorged with lipid droplets (LDs) that contain esters of regulatory lipids whose metabolism remains poorly understood. LD-associated hydrolase (LDAH) has a lipase structure and high affinity for LDs of foam cells. Using knockout and transgenic mice of both sexes, here we show that LDAH inhibits atherosclerosis development and promotes stable lesion architectures. Broad and targeted lipidomic analyzes of primary macrophages and comparative lipid profiling of atheroma identified a broad impact of LDAH on esterified sterols, including natural liver X receptor (LXR) sterol ligands. Transcriptomic analyzes coupled with rescue experiments show that LDAH modulates the expression of prototypical LXR targets and leads macrophages to a less inflammatory phenotype with a profibrotic gene signature. These studies underscore the role of LDs as reservoirs and metabolic hubs of bioactive lipids, and suggest that LDAH favorably modulates macrophage activation and protects against atherosclerosis via lipolytic mobilization of regulatory sterols.
    DOI:  https://doi.org/10.1038/s41467-024-50949-y
  6. Cancer Res. 2024 Jul 02. 84(13): 2046-2048
    The Warburg Effect Revisited through Blood and Electron Flow.
    Yahui Wang, Chi V Dang.
      The Warburg effect describes the propensity of many cancers to consume glucose avidly and convert it to lactate in the presence of oxygen. The benefit of the Warburg effect on cancer cells remains enigmatic, particularly because extracellular disposal of incompletely oxidized lactate is wasteful. However, lactate is not discarded from the body, but rather recycled as pyruvate for metabolism through the tricarboxylic acid cycle in oxidative tissues and cells. Hence, tissue and interorgan metabolism play important roles in tumor metabolism. The production of tumor lactate to be recycled elsewhere parallels the Cori cycle, in which lactate produced by muscle activity is shuttled to the liver, where it is converted to pyruvate and subsequently stored as glucose moieties in glycogen. This perspective will consider this organismal contextwhile discussing how glucose is used in tumors. We highlight several key articles published decades ago in Cancer Research that are foundational to our current understanding of cancer biology and metabolism.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-0474
  7. Cell Metab. 2024 Jul 24. pii: S1550-4131(24)00273-0. [Epub ahead of print]
    Development of a functional beige fat cell line uncovers independent subclasses of cells expressing UCP1 and the futile creatine cycle.
    Ariana Vargas-Castillo, Yizhi Sun, Amanda L Smythers, Louisa Grauvogel, Phillip A Dumesic, Margo P Emont, Linus T Tsai, Evan D Rosen, Nathan W Zammit, Sydney M Shaffer, Martha Ordonez, Edward T Chouchani, Steven P Gygi, Tongtong Wang, Anand K Sharma, Miroslav Balaz, Christian Wolfrum, Bruce M Spiegelman.
      Although uncoupling protein 1 (UCP1) is established as a major contributor to adipose thermogenesis, recent data have illustrated an important role for alternative pathways, particularly the futile creatine cycle (FCC). How these pathways co-exist in cells and tissues has not been explored. Beige cell adipogenesis occurs in vivo but has been difficult to model in vitro; here, we describe the development of a murine beige cell line that executes a robust respiratory response, including uncoupled respiration and the FCC. The key FCC enzyme, tissue-nonspecific alkaline phosphatase (TNAP), is localized almost exclusively to mitochondria in these cells. Surprisingly, single-cell cloning from this cell line shows that cells with the highest levels of UCP1 express little TNAP, and cells with the highest expression of TNAP express little UCP1. Immunofluorescence analysis of subcutaneous fat from cold-exposed mice confirms that the highest levels of these critical thermogenic components are expressed in distinct fat cell populations.
    Keywords:  Alpl gene; SV40 large T antigen; TNAP; UCP1; aP2-Prdm16 transgenic mice; functional beige cell line; futile creatine cycle; immortalized beige adipocytes; thermogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.002
  8. Clin Transl Med. 2024 Aug;14(8): e1785
    CPT1A-IL-10-mediated macrophage metabolic and phenotypic alterations ameliorate acute lung injury.
    Muyun Wang, Di Wu, Ximing Liao, Haiyang Hu, Jing Gao, Linlin Meng, Feilong Wang, Wujian Xu, Shaoyong Gao, Jing Hua, Yuanyuan Wang, Qiang Li, Kun Wang, Wei Gao.
       BACKGROUND: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common acute respiratory failure due to diffuse pulmonary inflammation and oedema. Elaborate regulation of macrophage activation is essential for managing this inflammatory process and maintaining tissue homeostasis. In the past decades, metabolic reprogramming of macrophages has emerged as a predominant role in modulating their biology and function. Here, we observed reduced expression of carnitine palmitoyltransferase 1A (CPT1A), a key rate-limiting enzyme of fatty acid oxidation (FAO), in macrophages of lipopolysaccharide (LPS)-induced ALI mouse model. We assume that CPT1A and its regulated FAO is involved in the regulation of macrophage polarization, which could be positive regulated by interleukin-10 (IL-10).
    METHODS: After nasal inhalation rIL-10 and/or LPS, wild type (WT), IL-10-/-, Cre-CPT1Afl/fl and Cre+CPT1Afl/fl mice were sacrificed to harvest bronchoalveolar lavage fluid, blood serum and lungs to examine cell infiltration, cytokine production, lung injury severity and IHC. Bone marrow-derived macrophages (BMDMs) were extracted from mice and stimulated by exogenous rIL-10 and/or LPS. The qRT-PCR, Seahorse XFe96 and FAO metabolite related kits were used to test the glycolysis and FAO level in BMDMs. Immunoblotting assay, confocal microscopy and fluorescence microplate were used to test macrophage polarization as well as mitochondrial structure and function damage.
    RESULTS: In in vivo experiments, we found that mice lacking CPT1A or IL-10 produced an aggravate inflammatory response to LPS stimulation. However, the addition of rIL-10 could alleviate the pulmonary inflammation in mice effectively. IHC results showed that IL-10 expression in lung macrophage decreased dramatically in Cre+CPT1Afl/fl mice. The in vitro experiments showed Cre+CPT1Afl/fl and IL-10-/- BMDMs became more "glycolytic", but less "FAO" when subjected to external attacks. However, the supplementation of rIL-10 into macrophages showed reverse effect. CPT1A and IL-10 can drive the polarization of BMDM from M1 phenotype to M2 phenotype, and CPT1A-IL-10 axis is also involved in the process of maintaining mitochondrial homeostasis.
    CONCLUSIONS: CPT1A modulated metabolic reprogramming and polarisation of macrophage under LPS stimulation. The protective effects of CPT1A may be partly attributed to the induction of IL-10/IL-10 receptor expression.
    Keywords:  acute lung injury; carnitine palmitoyltransferase 1A; fatty acid oxidation; interleukin‐10; macrophage
    DOI:  https://doi.org/10.1002/ctm2.1785
  9. Nat Commun. 2024 Jul 29. 15(1): 6390
    Harnessing intestinal tryptophan catabolism to relieve atherosclerosis in mice.
    Mouna Chajadine, Ludivine Laurans, Tobias Radecke, Nirmala Mouttoulingam, Rida Al-Rifai, Emilie Bacquer, Clara Delaroque, Héloïse Rytter, Marius Bredon, Camille Knosp, José Vilar, Coralie Fontaine, Nadine Suffee, Marie Vandestienne, Bruno Esposito, Julien Dairou, Jean Marie Launay, Jacques Callebert, Alain Tedgui, Hafid Ait-Oufella, Harry Sokol, Benoit Chassaing, Soraya Taleb.
      Tryptophan (Trp) is an essential amino acid, whose metabolism is a key gatekeeper of intestinal homeostasis. Yet, its systemic effects, particularly on atherosclerosis, remain unknown. Here we show that high-fat diet (HFD) increases the activity of intestinal indoleamine 2, 3-dioxygenase 1 (IDO), which shifts Trp metabolism from the production of microbiota-derived indole metabolites towards kynurenine production. Under HFD, the specific deletion of IDO in intestinal epithelial cells leads to intestinal inflammation, impaired intestinal barrier, augmented lesional T lymphocytes and atherosclerosis. This is associated with an increase in serotonin production and a decrease in indole metabolites, thus hijacking Trp for the serotonin pathway. Inhibition of intestinal serotonin production or supplementation with indole derivatives alleviates plaque inflammation and atherosclerosis. In summary, we uncover a pivotal role of intestinal IDO in the fine-tuning of Trp metabolism with systemic effects on atherosclerosis, paving the way for new therapeutic strategies to relieve gut-associated inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41467-024-50807-x
  10. J Cell Biol. 2024 Sep 02. pii: e202407125. [Epub ahead of print]223(9):
    A three-way organelle junction controls PI(4)P metabolism and mitochondrial division.
    York Posor, Volker Haucke.
      Membrane contact sites (MCS) facilitate communication between organelles. Casler et al. (https://doi.org/10.1083/jcb.202308144) show that tripartite MCS between mitochondria, the endoplasmic reticulum (ER), and the plasma membrane (PM) regulate mitochondrial division and the distribution of phosphatidylinositol 4-phosphate [PI(4)P] on the PM.
    DOI:  https://doi.org/10.1083/jcb.202407125
  11. Metabolomics. 2024 Jul 27. 20(4): 87
    Stable isotope-resolved metabolomics analyses of metabolic phenotypes reveal variable glutamine metabolism in different patient-derived models of non-small cell lung cancer from a single patient.
    Connor J Kinslow, Michael Bousamra Ll, Yihua Cai, Jun Yan, Pawel K Lorkiewicz, Ahmad Al-Attar, Jinlian Tan, Richard M Higashi, Andrew N Lane, Teresa W-M Fan.
       INTRODUCTION: Stable isotope tracers have been increasingly used in preclinical cancer model systems, including cell culture and mouse xenografts, to probe the altered metabolism of a variety of cancers, such as accelerated glycolysis and glutaminolysis and generation of oncometabolites. Comparatively little has been reported on the fidelity of the different preclinical model systems in recapitulating the aberrant metabolism of tumors.
    OBJECTIVES: We have been developing several different experimental model systems for systems biochemistry analyses of non-small cell lung cancer (NSCLC1) using patient-derived tissues to evaluate appropriate models for metabolic and phenotypic analyses.
    METHODS: To address the issue of fidelity, we have carried out a detailed Stable Isotope-Resolved Metabolomics study of freshly resected tissue slices, mouse patient derived xenografts (PDXs), and cells derived from a single patient using both 13C6-glucose and 13C5,15N2-glutamine tracers.
    RESULTS: Although we found similar glucose metabolism in the three models, glutamine utilization was markedly higher in the isolated cell culture and in cell culture-derived xenografts compared with the primary cancer tissue or direct tissue xenografts (PDX).
    CONCLUSIONS: This suggests that caution is needed in interpreting cancer biochemistry using patient-derived cancer cells in vitro or in xenografts, even at very early passage, and that direct analysis of patient derived tissue slices provides the optimal model for ex vivo metabolomics. Further research is needed to determine the generality of these observations.
    Keywords:  Cancer metabolism; Non-small cell lung cancer; Patient-derived xenografts; Preclinical models; Primary cell culture; Stable isotope-resolved metabolomics
    DOI:  https://doi.org/10.1007/s11306-024-02126-x
  12. Biochim Biophys Acta Mol Cell Biol Lipids. 2024 Jul 30. pii: S1388-1981(24)00096-9. [Epub ahead of print] 159546
    ABCA1 deficiency causes tissue-specific dysregulation of the SREBP2 pathway in mice.
    Yoshio Yamauchi, Sumiko Abe-Dohmae, Noriyuki Iwamoto, Ryuichiro Sato, Shinji Yokoyama.
      ABCA1 plays an essential role in the formation of high-density lipoprotein (HDL), and its mutations cause Tangier disease (TD), a familial HDL deficiency. In addition to the disappearance of HDL, TD patients exhibit cholesterol deposition in peripheral tissues through a mechanism poorly understood, which may contribute to the development of premature atherosclerosis. We and others previously showed that ABCA1 deficiency causes hyperactivation of the SREBP2 pathway in vitro. Here we show that in Abca1 knockout mice, ABCA1 deficiency leads to tissue-specific dysregulation of SREBP2 activity in a nutritional status-dependent manner, which may underlie the pathophysiology of TD.
    Keywords:  ABCA1; HDL; SREBP2; Tangier disease
    DOI:  https://doi.org/10.1016/j.bbalip.2024.159546
  13. Redox Biol. 2024 Jul 23. pii: S2213-2317(24)00261-1. [Epub ahead of print]75 103283
    Mitochondria to plasma membrane redox signaling is essential for fatty acid β-oxidation-driven insulin secretion.
    Martin Jabůrek, Eduardo Klöppel, Pavla Průchová, Oleksandra Mozheitova, Jan Tauber, Hana Engstová, Petr Ježek.
      We asked whether acute redox signaling from mitochondria exists concomitantly to fatty acid- (FA-) stimulated insulin secretion (FASIS) at low glucose by pancreatic β-cells. We show that FA β-oxidation produces superoxide/H2O2, providing: i) mitochondria-to-plasma-membrane redox signaling, closing KATP-channels synergically with elevated ATP (substituting NADPH-oxidase-4-mediated H2O2-signaling upon glucose-stimulated insulin secretion); ii) activation of redox-sensitive phospholipase iPLA2γ/PNPLA8, cleaving mitochondrial FAs, enabling metabotropic GPR40 receptors to amplify insulin secretion (IS). At fasting glucose, palmitic acid stimulated IS in wt mice; palmitic, stearic, lauric, oleic, linoleic, and hexanoic acids also in perifused pancreatic islets (PIs), with suppressed 1st phases in iPLA2γ/PNPLA8-knockout mice/PIs. Extracellular/cytosolic H2O2-monitoring indicated knockout-independent redox signals, blocked by mitochondrial antioxidant SkQ1, etomoxir, CPT1 silencing, and catalase overexpression, all inhibiting FASIS, keeping ATP-sensitive K+-channels open, and diminishing cytosolic [Ca2+]-oscillations. FASIS in mice was a postprandially delayed physiological event. Redox signals of FA β-oxidation are thus documented, reaching the plasma membrane, essentially co-stimulating IS.
    Keywords:  Fatty acid-stimulated insulin secretion; GPR40; Mitochondrial fatty acids; Pancreatic β-cells; Redox signaling; Redox-activated phospholipase iPLA2γ
    DOI:  https://doi.org/10.1016/j.redox.2024.103283
  14. Nat Commun. 2024 Jul 31. 15(1): 6468
    Cilia-enriched oxysterol 7β,27-DHC is required for polycystin ion channel activation.
    Kodaji Ha, Nadine Mundt-Machado, Paola Bisignano, Aide Pinedo, David R Raleigh, Gabriel Loeb, Jeremy F Reiter, Erhu Cao, Markus Delling.
      Polycystin-1 (PC-1) and PC-2 form a heteromeric ion channel complex that is abundantly expressed in primary cilia of renal epithelial cells. This complex functions as a non-selective cation channel, and mutations within the polycystin complex cause autosomal dominant polycystic kidney disease (ADPKD). The spatial and temporal regulation of the polycystin complex within the ciliary membrane remains poorly understood. Using both whole-cell and ciliary patch-clamp recordings, we identify a cilia-enriched oxysterol, 7β,27-dihydroxycholesterol (DHC), that serves as a necessary activator of the polycystin complex. We further identify an oxysterol-binding pocket within PC-2 and showed that mutations within this binding pocket disrupt 7β,27-DHC-dependent polycystin activation. Pharmacologic and genetic inhibition of oxysterol synthesis reduces channel activity in primary cilia. In summary, our findings reveal a regulator of the polycystin complex. This oxysterol-binding pocket in PC-2 may provide a specific target for potential ADPKD therapeutics.
    DOI:  https://doi.org/10.1038/s41467-024-50318-9
  15. JCI Insight. 2024 Aug 01. pii: e176887. [Epub ahead of print]
    Mitochondrial bioenergetics and cardiolipin remodeling abnormalities in mitochondrial trifunctional protein deficiency.
    Eduardo Vieira Neto, Meicheng Wang, Austin J Szuminsky, Lethicia Ferraro, Erik Koppes, Yudong Wang, Clinton Van't Land, Al-Walid Mohsen, Geancarlo Zanatta, Areeg H El-Gharbawy, Tamil S Anthonymuthu, Yulia Y Tyurina, Vladimir A Tyurin, Valerian Kagan, Hülya Bayir, Jerry Vockley.
      Mitochondrial trifunctional protein (TFP) deficiency is an inherited metabolic disorder leading to a block in long-chain fatty acid β-oxidation. Mutations in either HADHA and HADHB, which encode the TFPα and β subunits, respectively, usually result in combined TFP deficiency. A single common mutation, HADHA c.1528G>C (p.E510Q), leads to isolated 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. TFP also catalyzes a step in the remodeling of cardiolipin (CL), a phospholipid critical to mitochondrial membrane stability and function. We explored the effect of mutations in TFP subunits on CL and other phospholipid content and composition and the consequences of these changes on mitochondrial bioenergetics in patient-derived fibroblasts. Abnormalities in these parameters varied extensively among different fibroblasts, and some cells were able to maintain basal oxygen consumption rates similar to controls. Although CL reduction was universally identified, a simultaneous increase in monolysocardiolipins was discrepant among cells. A similar profile was seen in liver mitochondria isolates from a TFP-deficient mouse model. Response to new potential drugs targeting cardiolipin metabolism might be dependent on patient genotype.
    Keywords:  Fatty acid oxidation; Genetics; Intermediary metabolism; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1172/jci.insight.176887
  16. Cell Metab. 2024 Jul 23. pii: S1550-4131(24)00275-4. [Epub ahead of print]
    A microbial metabolite inhibits the HIF-2α-ceramide pathway to mediate the beneficial effects of time-restricted feeding on MASH.
    Yi Zhang, Xuemei Wang, Jun Lin, Jia Liu, Kai Wang, Qixing Nie, Chuan Ye, Lulu Sun, Yanpeng Ma, Ruize Qu, Yuejian Mao, Xuguang Zhang, Hua Lu, Pengyan Xia, Dongyu Zhao, Guang Wang, Zhipeng Zhang, Wei Fu, Changtao Jiang, Yanli Pang.
      Time-restricted feeding (TRF) is a potent dietary intervention for improving metabolic diseases, including metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis (MASLD/MASH). However, the mechanism of this efficacy has remained elusive. Here, we show that TRF improves MASLD, which is associated with a significant enrichment of Ruminococcus torques (R. torques). Mechanistically, R. torques suppresses the intestinal HIF-2α-ceramide pathway via the production of 2-hydroxy-4-methylpentanoic acid (HMP). We identify rtMor as a 4-methyl-2-oxopentanoate reductase that synthesizes HMP in R. torques. Finally, we show that either the colonization of R. torques or oral HMP supplementation can ameliorate inflammation and fibrosis in a MASH mouse model. These findings identify R. torques and HMP as potential TRF mimetics for the treatment of metabolic disorders.
    Keywords:  MASLD/MASH; bacterial metabolites; gut microbiota; time-restricted feeding
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.004
  17. Biochim Biophys Acta Mol Cell Biol Lipids. 2024 Jul 25. pii: S1388-1981(24)00088-X. [Epub ahead of print]1869(7): 159538
    Hepatic stearoyl-CoA desaturase-1 deficiency induces fibrosis and hepatocellular carcinoma-related gene activation under a high carbohydrate low fat diet.
    Jayne-Norah Ntambi, Mugagga Kalyesubula, Dylan Cootway, Sarah A Lewis, Yar Xin Phang, Zhaojin Liu, Lucas M O'Neill, Lucas Lefers, Hailey Huff, Jacqueline Rose Miller, Veronica Pegkou Christofi, Ethan Anderson, Ahmed Aljohani, Francis Mutebi, Mainak Dutta, Andrew Patterson, James M Ntambi.
      Stearoyl-CoA desaturase-1 (SCD1) is a pivotal enzyme in lipogenesis, which catalyzes the synthesis of monounsaturated fatty acids (MUFA) from saturated fatty acids, whose ablation downregulates lipid synthesis, preventing steatosis and obesity. Yet deletion of SCD1 promotes hepatic inflammation and endoplasmic reticulum stress, raising the question of whether hepatic SCD1 deficiency promotes further liver damage, including fibrosis. To delineate whether SCD1 deficiency predisposes the liver to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), we employed in vivo SCD1 deficient global and liver-specific mouse models fed a high carbohydrate low-fat diet and in vitro established AML12 mouse cells. The absence of liver SCD1 remarkably increased the saturation of liver lipid species, as indicated by lipidomic analysis, and led to hepatic fibrosis. Consistently, SCD1 deficiency promoted hepatic gene expression related to fibrosis, cirrhosis, and HCC. Deletion of SCD1 increased the circulating levels of Osteopontin, known to be increased in fibrosis, and alpha-fetoprotein, often used as an early marker and a prognostic marker for patients with HCC. De novo lipogenesis or dietary supplementation of oleate, an SCD1-generated MUFA, restored the gene expression related to fibrosis, cirrhosis, and HCC. Although SCD1 deficient mice are protected against obesity and fatty liver, our results show that MUFA deprivation results in liver injury, including fibrosis, thus providing novel insights between MUFA insufficiency and pathways leading to fibrosis, cirrhosis, and HCC under lean non-steatotic conditions.
    Keywords:  Fibrosis; Lipotoxicity; Oleic acid; Saturated fatty acids; Stearoyl-CoA desaturase
    DOI:  https://doi.org/10.1016/j.bbalip.2024.159538
  18. Immunity. 2024 Jul 25. pii: S1074-7613(24)00353-4. [Epub ahead of print]
    Cancer stem cells release interleukin-33 within large oncosomes to promote immunosuppressive differentiation of macrophage precursors.
    Hannah L Erickson, Sachiko Taniguchi, Anish Raman, Justin J Leitenberger, Sanjay V Malhotra, Naoki Oshimori.
      In squamous cell carcinoma (SCC), macrophages responding to interleukin (IL)-33 create a TGF-β-rich stromal niche that maintains cancer stem cells (CSCs), which evade chemotherapy-induced apoptosis in part via activation of the NRF2 antioxidant program. Here, we examined how IL-33 derived from CSCs facilitates the development of an immunosuppressive microenvironment. CSCs with high NRF2 activity redistributed nuclear IL-33 to the cytoplasm and released IL-33 as cargo of large oncosomes (LOs). Mechanistically, NRF2 increased the expression of the lipid scramblase ATG9B, which exposed an "eat me" signal on the LO surface, leading to annexin A1 (ANXA1) loading. These LOs promoted the differentiation of AXNA1 receptor+ myeloid precursors into immunosuppressive macrophages. Blocking ATG9B's scramblase activity or depleting ANXA1 decreased niche macrophages and hindered tumor progression. Thus, IL-33 is released from live CSCs via LOs to promote the differentiation of alternatively activated macrophage, with potential relevance to other settings of inflammation and tissue repair.
    Keywords:  ATG9b; FPR2; IL-33; annexin A1; cancer stem cell niche; cancer stem cells; large oncosomes; macrophages; squamous cell carcinoma; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.immuni.2024.07.004
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