Acetyl-CoA metabolism in cancer

Nature reviews. Cancer, Год журнала: 2023, Номер 23(3), С. 156 - 172

Опубликована: Янв. 19, 2023

Few metabolites can claim a more central and versatile role in cell metabolism than acetyl coenzyme A (acetyl-CoA). Acetyl-CoA is produced during nutrient catabolism to fuel the tricarboxylic acid cycle essential building block for fatty isoprenoid biosynthesis. It also functions as signalling metabolite substrate lysine acetylation reactions, enabling modulation of protein response acetyl-CoA availability. Recent years have seen exciting advances our understanding normal physiology cancer, buoyed by new mouse models, vivo stable-isotope tracing approaches improved methods measuring acetyl-CoA, including specific subcellular compartments. Efforts target metabolic enzymes are advancing, with one therapeutic agent targeting synthesis receiving approval from US Food Drug Administration. In this Review, we give an overview regulation cancer relevance major pathways which participates. We further discuss recent tissues tumours potential these therapeutically. conclude commentary on emerging nodes that may impact biology.

Язык: Английский

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GDF15 promotes weight loss by enhancing energy expenditure in muscle

Nature, Год журнала: 2023, Номер 619(7968), С. 143 - 150

Опубликована: Июнь 28, 2023

Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with type 2 diabetes1. Despite its effectiveness, most individuals, usually not maintained partly due to physiological adaptations suppress energy expenditure, a process known as adaptive thermogenesis, the mechanistic underpinnings of which are unclear2,3. Treatment rodents fed high-fat diet recombinant growth differentiating factor 15 (GDF15) reduces obesity improves glycaemic control through glial-cell-derived neurotrophic family receptor α-like (GFRAL)-dependent suppression food intake4-7. Here we find that, addition suppressing appetite, GDF15 counteracts compensatory reductions eliciting greater (NAFLD) compared caloric alone. This effect maintain expenditure during calorie requires GFRAL-β-adrenergic-dependent signalling axis increases acid oxidation calcium futile cycling skeletal muscle mice. These data indicate therapeutic targeting GDF15-GFRAL pathway may be useful maintaining restriction.

Язык: Английский

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NAFLD and NASH: etiology, targets and emerging therapies

Drug Discovery Today, Год журнала: 2024, Номер 29(3), С. 103910 - 103910

Опубликована: Фев. 1, 2024

Язык: Английский

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Acetylcarnitine shuttling links mitochondrial metabolism to histone acetylation and lipogenesis

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

Опубликована: Май 3, 2023

The metabolite acetyl-CoA is necessary for both lipid synthesis in the cytosol and histone acetylation nucleus. two canonical precursors to nuclear-cytoplasmic compartment are citrate acetate, which processed by ATP-citrate lyase (ACLY) acyl-CoA synthetase short-chain 2 (ACSS2), respectively. It unclear whether other substantial routes nuclear-cytosolic exist. To investigate this, we generated cancer cell lines lacking ACLY ACSS2 [double knockout (DKO) cells]. Using stable isotope tracing, show that glucose fatty acids contribute pools DKO cells acetylcarnitine shuttling can transfer two-carbon units from mitochondria cytosol. Further, absence of ACLY, feed acid a carnitine responsive acetyltransferase (CrAT)-dependent manner. data define as an ACLY- ACSS2-independent precursor support acetylation, synthesis, growth.

Язык: Английский

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Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH)

Science Translational Medicine, Год журнала: 2023, Номер 15(716)

Опубликована: Окт. 4, 2023

Metabolic dysfunction–associated steatohepatitis (MASH) is a severe form of liver disease that poses global health threat because its potential to progress advanced fibrosis, leading cirrhosis and cancer. Recent advances in single-cell methodologies, refined models, genetic epigenetic insights have provided nuanced understanding MASH fibrogenesis, with substantial cellular heterogeneity livers providing potentially targetable cell-cell interactions behavior. Unlike mechanisms underlying fibrosis regression are still inadequately understood, although antifibrotic targets been recently identified. A treatment framework could lead noninvasive assessment targeted therapies preserve hepatocellular function restore the liver’s architectural integrity.

Язык: Английский

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Steatotic Liver Disease: Pathophysiology and Emerging Pharmacotherapies

Pharmacological Reviews, Год журнала: 2024, Номер 76(3), С. 454 - 499

Опубликована: Янв. 30, 2024

Steatotic liver disease (SLD) displays a dynamic and complex phenotype. Consequently, the metabolic dysfunction-associated steatotic (MASLD)/metabolic steatohepatitis (MASH) therapeutic pipeline is expanding rapidly in multiple directions. In parallel, non-invasive tools for diagnosing monitoring responses to interventions are being studied, clinically feasible findings explored as primary outcomes interventional trials. The realization that distinct subgroups exist under umbrella of SLD should guide more precise personalized treatment recommendations facilitate advancements pharmacotherapeutics. This review summarizes recent updates pathophysiology-based nomenclature outlines both effective pharmacotherapeutics those MASLD/MASH, detailing their mode action current status phase 2 3 clinical Of extensive arsenal MASLD/MASH pipeline, several have been rejected, whereas other, mainly monotherapy options, shown only marginal benefits now tested part combination therapies, yet others still development monotherapies. Although successful drug candidate (or combinations) remains elusive, such approaches will ideally target MASH fibrosis while improving cardiometabolic risk factors. Due urgent need novel strategies potential availability safety tolerability data, repurposing existing approved drugs an appealing option. Finally, it essential highlight and, by extension, MASLD be recognized approached systemic affecting organs, with vigorous implementation interdisciplinary coordinated plans. Significance Statement SLD, including, among others, MASH, considered most prevalent chronic condition than one-fourth global population. aims provide information regarding pathophysiology, diagnosis, management line guidelines Collectively, hoped provided furthers understanding state direct implications stimulates additional research initiatives.

Язык: Английский

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Bempedoic Acid: for Whom and When

Current Atherosclerosis Reports, Год журнала: 2022, Номер 24(10), С. 791 - 801

Опубликована: Июль 28, 2022

Abstract Purpose of Review The aim creating an orally active non-statin cholesterol-lowering drug was achieved with bempedoic acid, a small linear molecule providing both significant low-density lipoprotein cholesterol (LDL-C) reduction and anti-inflammatory effect by decreasing high-sensitivity C-reactive protein. Bempedoic acid antagonizes ATP citrate-lyase, cytosolic enzyme upstream HMGCoA reductase which is the rate-limiting step biosynthesis. pro-drug converted to its metabolite very-long-chain acyl-CoA synthetase 1 present mostly in liver absent skeletal muscles. This limits risk myalgia myopathy. remit this review give clinical insights on safety efficacy understand for whom it should be prescribed. Recent Findings single daily dose (180 mg) reduces LDL-C mean 24.5% when given alone, 18% top major statin 38–40% fixed-dose combination ezetimibe. does not lead new-onset diabetes, moderately improves glycaemic profile. Summary extensive knowledge mechanism, metabolism side effects has led improved understanding potential benefits agent offers possible alternative cardiologists practitioners somewhat worn out today occurrence muscular statins.

Язык: Английский

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The aldolase inhibitor aldometanib mimics glucose starvation to activate lysosomal AMPK

Nature Metabolism, Год журнала: 2022, Номер 4(10), С. 1369 - 1401

Опубликована: Окт. 10, 2022

The activity of 5'-adenosine monophosphate-activated protein kinase (AMPK) is inversely correlated with the cellular availability glucose. When glucose levels are low, glycolytic enzyme aldolase not bound to fructose-1,6-bisphosphate (FBP) and, instead, signals activate lysosomal AMPK. Here, we show that blocking FBP binding small molecule aldometanib selectively activates pool AMPK and has beneficial metabolic effects in rodents. We identify a screen for inhibitors it prevents from v-ATPase-associated AMPK, thereby mimicking state starvation. In male mice, elicits an insulin-independent glucose-lowering effect, without causing hypoglycaemia. Aldometanib also alleviates fatty liver nonalcoholic steatohepatitis obese Moreover, extends lifespan healthspan both Caenorhabditis elegans mice. Taken together, mimics adopts activation pathway associated starvation exert physiological roles, might have potential as therapeutic disorders humans.

Язык: Английский

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Branched-Chain Amino Acids and Insulin Resistance, from Protein Supply to Diet-Induced Obesity

Nutrients, Год журнала: 2022, Номер 15(1), С. 68 - 68

Опубликована: Дек. 23, 2022

For more than a decade, there has been wide debate about the branched-chain amino acids (BCAA) leucine, valine, and isoleucine, with, on one hand, supporters of their anabolic effects and, other those who suspect them promoting insulin resistance. Indeed, role leucine in postprandial activation protein synthesis clearly established, even though supplementation studies aimed at taking advantage this property are rather disappointing. Furthermore, is ample evidence an association between elevation plasma concentrations resistance or risk developing type 2 diabetes, although many confounding factors, starting with level animal consumption. After summary metabolism properties, we analyze review factors likely to increase BCAAs, including insulin-resistance. analysis restriction search direct BCAAs resistance, discuss indirect through some metabolites: keto acids, C3 C5 acylcarnitines, hydroxyisobutyrate. Overall, given importance these it very that small alterations sensitivity responsible for reduction catabolism long before onset impaired glucose tolerance.

Язык: Английский

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Mechanism of action and therapeutic use of bempedoic acid in atherosclerosis and metabolic syndrome

Frontiers in Cardiovascular Medicine, Год журнала: 2022, Номер 9

Опубликована: Окт. 28, 2022

Bempedoic acid is a new cholesterol-lowering drug, which has recently received US FDA and EMA approval. This drug targets lipid glucose metabolism as well inflammation via downregulation of ATP-citrate lyase upregulation AMP-activated protein kinase (AMPK). The primary effect the reduction cholesterol synthesis in liver its administration generally not associated to unwanted muscle effects. Suppression hepatic fatty leads decreased triglycerides and, possibly, improved non-alcoholic disease. may decrease gluconeogenesis leading insulin sensitivity, metabolism, metabolic syndrome. anti-inflammatory action bempedoic mainly achieved activation AMPK pathway immune cells, plasma levels C-reactive protein. Effects on atherosclerotic cardiovascular disease, type 2 diabetes chronic disease have been assessed randomized clinical trials but require further confirmation. Safety phase III indicate that well-tolerated combination with statins, ezetimibe, or proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors achieve low-density lipoprotein targets. aim this narrative review explore underlying mechanisms potential targets, present existing evidence from trials, describe practical management patients.

Язык: Английский

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