Metabolic regulation of the hallmarks of stem cell biology

Cell stem cell, Год журнала: 2024, Номер 31(2), С. 161 - 180

Опубликована: Фев. 1, 2024

Язык: Английский

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BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis

Cell, Год журнала: 2024, Номер 187(10), С. 2359 - 2374.e18

Опубликована: Апрель 22, 2024

Brown adipose tissue (BAT) is best known for thermogenesis. Rodent studies demonstrated that enhanced BAT thermogenesis tightly associated with increased energy expenditure, reduced body weight, and improved glucose homeostasis. However, human protective against type 2 diabetes, independent of weight. The mechanism underlying this dissociation remains unclear. Here, we report impaired mitochondrial catabolism branched-chain amino acids (BCAAs) in BAT, by deleting BCAA carriers (MBCs), caused systemic insulin resistance without affecting expenditure adipocytes catabolized the mitochondria as nitrogen donors biosynthesis non-essential glutathione. Impaired BCAA-nitrogen flux resulted oxidative stress, decreased hepatic signaling, circulating BCAA-derived metabolites. A high-fat diet attenuated metabolite synthesis whereas cold-activated synthesis. This work uncovers a metabolite-mediated pathway through which controls metabolic health beyond

Язык: Английский

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Emerging targets in lipid metabolism for cancer therapy

Trends in Pharmacological Sciences, Год журнала: 2024, Номер 45(6), С. 537 - 551

Опубликована: Май 17, 2024

Cancer cells perturb lipid metabolic pathways for a variety of pro-tumorigenic functions, and deregulated cellular metabolism is hallmark cancer cells. Although alterations in have been appreciated over 20 years, there are no FDA-approved treatments that target lipid-related pathways. Recent advances pertaining to cell fatty acid synthesis (FAS), desaturation, uptake, microenvironmental dietary lipids, tumor-infiltrating immune illuminated promising clinical applications targeting metabolism. This review highlights emerging targets tumor may soon impact treatment.

Язык: Английский

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Snapshots of acyl carrier protein shuttling in human fatty acid synthase

Nature, Год журнала: 2025, Номер unknown

Опубликована: Фев. 20, 2025

The mammalian fatty acid synthase (FASN) enzyme is a dynamic multienzyme that belongs to the megasynthase family. In mammals, single gene encodes six catalytically active domains and flexibly tethered acyl carrier protein (ACP) domain shuttles intermediates between sites for biosynthesis1. FASN an essential in development through role acids have membrane formation, energy storage, cell signalling modifications. Thus, promising target treatment of large variety diseases including cancer, metabolic dysfunction-associated liver disease, viral parasite infections2,3. multi-faceted mechanism nature protein, particular ACP, made it challenging understand at molecular level. Here we report cryo-electron microscopy structures human multitude conformational states with NADPH NADP+ plus acetoacetyl-CoA present, ACP stalled dehydratase (DH) enoyl-reductase (ER) domains. We show activity vitro de novo lipogenesis cells inhibited by mutations ACP-DH ACP-ER interfaces. Together, these studies provide new insights into shuttling mechanism, implications developing improved FASN-targeted therapeutics.

Язык: Английский

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Integrative Metabolism in MASLD and MASH: Pathophysiology and Emerging Mechanisms

Journal of Hepatology, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

The liver acts as a central metabolic hub, integrating signals from the gastrointestinal tract and adipose tissue to regulate carbohydrate, lipid, amino acid metabolism. Gut-derived metabolites, such acetate ethanol non-esterified fatty acids white (WAT), influence hepatic processes, which rely on mitochondrial function maintain systemic energy balance. Metabolic dysregulation obesity, insulin resistance, type 2 diabetes disrupt these pathways, leading dysfunction-associated steatotic disease (MASLD) steatohepatitis (MASH). This review explores fluxes within gut-adipose tissue-liver axis, focusing pivotal role of de novo lipogenesis (DNL), dietary substrates like glucose fructose, changes in during MASLD progression. It highlights contributions resistance impaired dynamics lipid accumulation. Further understanding how interplay between substrate flux gastro-intestinal integrates with intersects structural functional alterations mitochondria will be important identify novel therapeutic targets advance treatment MASH.

Язык: Английский

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Inter-organelle cross-talk supports acetyl-coenzyme A homeostasis and lipogenesis under metabolic stress

Science Advances, Год журнала: 2023, Номер 9(18)

Опубликована: Май 3, 2023

Proliferating cells rely on acetyl-CoA to support membrane biogenesis and acetylation. Several organelle-specific pathways are available for provision of as nutrient availability fluctuates, so understanding how maintain homeostasis under such stresses is critically important. To this end, we applied

Язык: Английский

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Mitochondrial fatty acid oxidation regulates monocytic type I interferon signaling via histone acetylation

Science Advances, Год журнала: 2025, Номер 11(4)

Опубликована: Янв. 22, 2025

Although lipid-derived acetyl–coenzyme A (CoA) is a major carbon source for histone acetylation, the contribution of fatty acid β-oxidation (FAO) to this process remains poorly characterized. To investigate this, we generated mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1, distal FAO enzyme) knockout macrophages. 13 C-carbon tracing confirmed reduced FA-derived incorporation into H3, and RNA sequencing identified diminished interferon-stimulated gene expression in absence ACAT1. Chromatin accessibility at Stat1 locus was ACAT1 −/− cells. immunoprecipitation analysis demonstrated acetyl-H3 binding promoter/enhancer regions, increasing acetylation rescued expression. Interferon-β release blunted recovered by reconstitution. Furthermore, ACAT1-dependent required an intact acetylcarnitine shuttle. Last, obese subjects’ monocytes exhibited increased levels. Thus, our study identifies intriguing link between FAO-mediated epigenetic control type I interferon signaling uncovers potential mechanistic nexus obesity signaling.

Язык: Английский

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A genetically encoded fluorescent biosensor for visualization of acetyl-CoA in live cells

Cell chemical biology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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Acetyl-CoA metabolism as a therapeutic target for cancer

Biomedicine & Pharmacotherapy, Год журнала: 2023, Номер 168, С. 115741 - 115741

Опубликована: Окт. 19, 2023

Acetyl-coenzyme A (acetyl-CoA), an essential metabolite, not only takes part in numerous intracellular metabolic processes, powers the tricarboxylic acid cycle, serves as a key hub for biosynthesis of fatty acids and isoprenoids, but also signaling substrate acetylation reactions post-translational modification proteins, which is crucial epigenetic inheritance cells. Acetyl-CoA links lipid metabolism with histone to create more intricate regulatory system that affects growth, aggressiveness, drug resistance malignancies such glioblastoma, breast cancer, hepatocellular carcinoma. These fascinating advances knowledge acetyl-CoA during carcinogenesis normal physiology have raised interest regarding its modulation malignancies. In this review, we provide overview regulation cancer relevance main pathways participates. We summarize role reprogramming stress cells, well medical application inhibitors targeting dysregulation therapeutic intervention cancers.

Язык: Английский

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Bendamustine lymphodepletion before axicabtagene ciloleucel is safe and associates with reduced inflammatory cytokines

Blood Advances, Год журнала: 2023, Номер 8(3), С. 653 - 666

Опубликована: Дек. 19, 2023

Lymphodepletion (LD) is an integral component of chimeric antigen receptor T-cell (CART) immunotherapies. In this study, we compared the safety and efficacy bendamustine (Benda) to standard fludarabine/cyclophosphamide (Flu/Cy) LD before CD19-directed, CD28-costimulated CART axicabtagene ciloleucel (axi-cel) for patients with large B-cell lymphoma (LBCL) follicular (FL). We analyzed 59 diagnosed LBCL (n = 48) FL 11) consecutively treated axi-cel at University Pennsylvania. also serum samples cytokine levels metabolomic changes after LD. Flu/Cy Benda demonstrated similar efficacy, complete remission rates 51.4% 50.0% (P .981), respectively, progression-free overall survivals. Any-grade cytokine-release syndrome occurred in 91.9% receiving vs 72.7% .048); any-grade neurotoxicity 45.9% 18.2% .031). addition, was associated a higher incidence grade ≥3 neutropenia (100% 54.5%; P < .001), infections (78.4% 27.3%; neutropenic fever 13.6%; .001). These results were confirmed both those FL. Mechanistically, had greater increase inflammatory cytokines reduced metabolites critical redox balance biosynthesis. This study suggests that may be safe alternative CD28-based CD19-directed immunotherapy toxicities. increased anabolic metabolites.

Язык: Английский

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