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The EMBO Journal Jul 2023Lipid droplets (LDs) form inter-organelle contacts with the endoplasmic reticulum (ER) that promote their biogenesis, while LD contacts with mitochondria enhance...
Lipid droplets (LDs) form inter-organelle contacts with the endoplasmic reticulum (ER) that promote their biogenesis, while LD contacts with mitochondria enhance β-oxidation of contained fatty acids. Viruses have been shown to take advantage of lipid droplets to promote viral production, but it remains unclear whether they also modulate the interactions between LDs and other organelles. Here, we showed that coronavirus ORF6 protein targets LDs and is localized to the mitochondria-LD and ER-LD contact sites, where it regulates LD biogenesis and lipolysis. At the molecular level, we find that ORF6 inserts into the LD lipid monolayer via its two amphipathic helices. ORF6 further interacts with ER membrane proteins BAP31 and USE1 to mediate ER-LDs contact formation. Additionally, ORF6 interacts with the SAM complex in the mitochondrial outer membrane to link mitochondria to LDs. In doing so, ORF6 promotes cellular lipolysis and LD biogenesis to reprogram host cell lipid flux and facilitate viral production.
Topics: Coronavirus; Endoplasmic Reticulum; Lipid Droplets; Lipolysis; Fatty Acids
PubMed: 37218505
DOI: 10.15252/embj.2022112542 -
Trends in Molecular Medicine Jun 2023Lysosomal acid lipase (LAL) is the sole enzyme known to degrade neutral lipids in the lysosome. Mutations in the LAL-encoding LIPA gene lead to rare lysosomal lipid... (Review)
Review
Lysosomal acid lipase (LAL) is the sole enzyme known to degrade neutral lipids in the lysosome. Mutations in the LAL-encoding LIPA gene lead to rare lysosomal lipid storage disorders with complete or partial absence of LAL activity. This review discusses the consequences of defective LAL-mediated lipid hydrolysis on cellular lipid homeostasis, epidemiology, and clinical presentation. Early detection of LAL deficiency (LAL-D) is essential for disease management and survival. LAL-D must be considered in patients with dyslipidemia and elevated aminotransferase concentrations of unknown etiology. Enzyme replacement therapy, sometimes in combination with hematopoietic stem cell transplantation (HSCT), is currently the only therapy for LAL-D. New technologies based on mRNA and viral vector gene transfer are recent efforts to provide other effective therapeutic strategies.
Topics: Humans; Wolman Disease; Sterol Esterase; Hematopoietic Stem Cell Transplantation; Lipids
PubMed: 37028992
DOI: 10.1016/j.molmed.2023.03.001 -
Tidsskrift For Den Norske Laegeforening... Dec 2023This clinical review will give doctors who work with children and neonates an introduction to the diagnosis and treatment of congenital hyperinsulinism, the most common...
This clinical review will give doctors who work with children and neonates an introduction to the diagnosis and treatment of congenital hyperinsulinism, the most common cause of persistent neonatal hypoglycaemia. The condition is a rare monogenic disorder characterised by elevated insulin secretion and is a result of mutations in genes that regulate insulin secretion from pancreatic beta cells. The anabolic effect of insulin induces systemic glucose uptake and inhibits gluconeogenesis, glycogenolysis, ketogenesis and lipolysis. Low levels of glucose and ketone bodies in the blood are harmful to the central nervous system and can lead to brain damage or death. Early diagnosis and treatment of congenital hyperinsulinism are therefore crucial for a good prognosis.
Topics: Child; Infant, Newborn; Humans; Congenital Hyperinsulinism; Ketone Bodies; Insulin
PubMed: 38088279
DOI: 10.4045/tidsskr.23.0425 -
Genes & Diseases Sep 2023Lactate is an end product of glycolysis. Owing to the lactate shuttle concept introduced in the early 1980s, increasing researchers indicate lactate as a critical energy... (Review)
Review
Lactate is an end product of glycolysis. Owing to the lactate shuttle concept introduced in the early 1980s, increasing researchers indicate lactate as a critical energy source for mitochondrial respiration and as a precursor of gluconeogenesis. Lactate also acts as a multifunctional signaling molecule through receptors expressed in various cells, resulting in diverse biological consequences including decreased lipolysis, immune regulation, and anti-inflammation wound healing, and enhanced exercise performance in association with the gut microbiome. Furthermore, increasing evidence reveals that lactate contributes to epigenetic gene regulation by lactylating lysine residues of histones, which accounts for its key role in immune modulation and maintenance of homeostasis. Here, we summarize the function and mechanism of lactate and lactylation in tumor metabolism and microenvironment.
PubMed: 37492749
DOI: 10.1016/j.gendis.2022.10.006 -
International Journal of Molecular... Jul 2023Macrophage polarization is influenced by lipids, which also exert significant control over macrophage functions. Lipids and their metabolites are players in intricate... (Review)
Review
Macrophage polarization is influenced by lipids, which also exert significant control over macrophage functions. Lipids and their metabolites are players in intricate signaling pathways that modulate macrophages' responses to pathogens, phagocytosis, ferroptosis, and inflammation. This review focuses on lipid metabolism and macrophage functions and addresses potential molecular targets for the treatment of macrophage-related diseases. While lipogenesis is crucial for lipid accumulation and phagocytosis in M1 macrophages, M2 macrophages likely rely on fatty acid β-oxidation to utilize fatty acids as their primary energy source. Cholesterol metabolism, regulated by factors such as SREBPs, PPARs, and LXRs, is associated with the cholesterol efflux capacity and the formation of foam cells (M2-like macrophages). Foam cells, which are targets for atherosclerosis, are associated with an increase in inflammatory cytokines. Lipolysis and fatty acid uptake markers, such as CD36, also contribute to the production of cytokines. Enhancing the immune system through the inhibition of lipid-metabolism-related factors can potentially serve as a targeted approach against tumor cells. Cyclooxygenase inhibitors, which block the conversion of arachidonic acid into various inflammatory mediators, influence macrophage polarization and have generated attention in cancer research.
Topics: Lipid Metabolism; Cell Polarity; Inflammation; Neoplasms; Macrophages; Cholesterol; Fatty Acids; Ferroptosis; Humans
PubMed: 37569407
DOI: 10.3390/ijms241512032 -
Cell Metabolism Aug 2023Obesity, in which the functional importance of small nucleolar RNAs (snoRNAs) remains elusive, correlates with risk for many cancer types. Here, we identify that the...
Obesity, in which the functional importance of small nucleolar RNAs (snoRNAs) remains elusive, correlates with risk for many cancer types. Here, we identify that the serum copies of adipocyte-expressed SNORD46 correlate with body mass index (BMI), and serum SNORD46 antagonizes interleukin-15 (IL-15) signaling. Mechanically, SNORD46 binds IL-15 via G11, and G11A (a mutation that significantly enhances binding affinity) knockin drives obesity in mice. Functionally, SNORD46 blocks IL-15-induced, FER kinase-dependent phosphorylation of platelet glycoprotein 4 (CD36) and monoglyceride lipase (MGLL) in adipocytes, leading to inhibited lipolysis and browning. In natural killer (NK) cells, SNORD46 suppresses the IL-15-dependent autophagy, leading to reduced viability of obese NK. SNORD46 power inhibitors exhibit anti-obesity effects, concurring with improved viability of obese NK and anti-tumor immunity of CAR-NK cell therapy. Hence, our findings demonstrate the functional importance of snoRNAs in obesity and the utility of snoRNA power inhibitors for antagonizing obesity-associated immune resistance.
Topics: Animals; Mice; Lipolysis; RNA, Small Nucleolar; Interleukin-15; Rejuvenation; Adipocytes; Obesity; Killer Cells, Natural
PubMed: 37329887
DOI: 10.1016/j.cmet.2023.05.009 -
Nature Communications Aug 2023Cancer-associated cachexia is a multi-organ weight loss syndrome, especially with a wasting disorder of adipose tissue and skeletal muscle. Small extracellular vesicles...
Cancer-associated cachexia is a multi-organ weight loss syndrome, especially with a wasting disorder of adipose tissue and skeletal muscle. Small extracellular vesicles (sEVs) serve as emerging messengers to connect primary tumour and metabolic organs to exert systemic regulation. However, whether and how tumour-derived sEVs regulate white adipose tissue (WAT) browning and fat loss is poorly defined. Here, we report breast cancer cell-secreted exosomal miR-204-5p induces hypoxia-inducible factor 1A (HIF1A) in WAT by targeting von Hippel-Lindau (VHL) gene. Elevated HIF1A protein induces the leptin signalling pathway and thereby enhances lipolysis in WAT. Additionally, exogenous VHL expression blocks the effect of exosomal miR-204-5p on WAT browning. Reduced plasma phosphatidyl ethanolamine level is detected in mice lack of cancer-derived miR-204-5p secretion in vivo. Collectively, our study reveals circulating miR-204-5p induces hypoxia-mediated leptin signalling pathway to promote lipolysis and WAT browning, shedding light on both preventive screenings and early intervention for cancer-associated cachexia.
Topics: Animals; Mice; Adipose Tissue, White; Cachexia; Hypoxia; Leptin; MicroRNAs; Neoplasms
PubMed: 37620316
DOI: 10.1038/s41467-023-40571-9