Itaconic acid underpins hepatocyte lipid metabolism in non-alcoholic fatty liver disease

Weiss, Jonathan M.; Palmieri, Erika M.; Gonzalez-Cotto, Marieli; Bettencourt, Ian A.; Megill, Emily; Snyder, Nathaniel W.; McVicar, Daniel W.

doi:10.21203/rs.3.rs-2109910/v1

Cited by 3 publications

(3 citation statements)

References 47 publications

(55 reference statements)

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“…In general, itaconate is often described as an important component of host innate immunity, having both anti-inflammatory and antimicrobial functions 23,25,[65][66][67] . Recently, its usage for the treatment of inflammation-related heart diseases and non-alcoholic fatty liver disease was suggested 65,68 . Itaconate was shown to increase the permeability of P.…”

Section: Discussionmentioning

confidence: 99%

Dynamic optimization elucidates optimal higher-level pathogenicity strategies of Pseudomonas aeruginosa

Dimitriew,

Schuster

2024

Preprint

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Pseudomonas aeruginosa is a robust pathogen and possesses many virulence components, including the ability to survive inside macrophages. A minimal model is proposed to study the interaction of P. aeruginosa and the human host in terms of nested defence, in which the host and pathogen counter each other in a back-and-forth interaction. In particular, the pathogen attacks the host, macrophages of the host engulf the pathogen and reduce its access to glucose, the pathogen activates the glyoxylate shunt which is started by an enzyme isocitrate lyase (Icl), the host inhibits it by itaconic acid, and the pathogen metabolizes itaconic acid using the enzyme succinyl-CoA:itaconate CoA transferase (Ict). Therefore, the pathogen needs to allocate its limited protein resource between the enzymes Icl and Ict in order to maximize the time integral of a flux through the enzyme Icl. We use both random search and dynamic optimization and analyze three different scenarios of the interaction. We identify the enzyme Ict as a cost-effective means of counter-counter-counter defence and as a possible drug target.

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Section: Discussionmentioning

confidence: 99%

Dynamic optimization elucidates optimal higher-level pathogenicity strategies of Pseudomonas aeruginosa

Dimitriew,

Schuster

2024

Preprint

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“…TCA intermediates, also contribute to pro-inflammatory and anti-inflammatory characteristics [8] . These molecules modulate inflammation and metabolic function in both autocrine and paracrine manners, and some (eg, citrate or itaconate) directly influence FAO [43,50] . Citrate, itaconate, and succinate are highly upregulated upon M1 macrophage activation, as TCA cycle intermediates accumulate due to a break in the cycle [8] .…”

Section: Fatty Acid Oxidation As a Critical Metabolic Pathway In Macr...mentioning

confidence: 99%

Inflammaging and fatty acid oxidation in monocytes and macrophages

Kruglov,

Jang,

Camell

2024

Immunometabolism

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Fatty acid oxidation (FAO), primarily known as β-oxidation, plays a crucial role in breaking down fatty acids within mitochondria and peroxisomes to produce cellular energy and preventing metabolic dysfunction. Myeloid cells, including macrophages, microglia, and monocytes, rely on FAO to perform essential cellular functions and uphold tissue homeostasis. As individuals age, these cells show signs of inflammaging, a condition that includes a chronic onset of low-grade inflammation and a decline in metabolic function. These lead to changes in fatty acid metabolism and a decline in FAO pathways. Recent studies have shed light on metabolic shifts occurring in macrophages and monocytes during aging, correlating with an altered tissue environment and the onset of inflammaging. This review aims to provide insights into the connection of inflammatory pathways and altered FAO in macrophages and monocytes from older organisms. We describe a model in which there is an extended activation of receptor for advanced glycation end products, nuclear factor-κB (NF-κB) and the nod-like receptor family pyrin domain containing 3 inflammasome within macrophages and monocytes. This leads to an increased level of glycolysis, and also promotes pro-inflammatory cytokine production and signaling. As a result, FAO-related enzymes such as 5′ AMP-activated protein kinase and peroxisome proliferator-activated receptor-α are reduced, adding to the escalation of inflammation, accumulation of lipids, and heightened cellular stress. We examine the existing body of literature focused on changes in FAO signaling within macrophages and monocytes and their contribution to the process of inflammaging.

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“…Their immunosuppressive function is also associated with their production of the anti-inflammatory metabolite itaconate [56] . Interestingly, myeloid cell-derived itaconate has recently been shown to enhance FAO in nonmyeloid cells (hepatocytes), amplifying its immunomodulatory signaling in trans [57] . Pharmacologic inhibition of FAO using etomoxir hindered the immunosuppressive function of MDSCs in mouse tumor models and significantly delayed tumor growth in a T cell-dependent manner [58] .…”

Section: Immune Signaling Associated With Fatty Acid Oxidation and Gl...mentioning

confidence: 99%

Immunometabolic control by Klebsiella pneumoniae

Prince

Lung

2023

Immunometabolism

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Klebsiella pneumoniae is a common Gram-negative pathogen associated with community-acquired and healthcare-associated infections. Its ability to acquire genetic elements resulted in its rapid development of resistance to virtually all antimicrobial agents. Once infection is established, K. pneumoniae is able to evade the host immune response and perhaps more importantly, undergo metabolic rewiring to optimize its ability to maintain infection. K. pneumoniae lipopolysaccharide and capsular polysaccharide are central factors in the induction and evasion of immune clearance. Less well understood is the importance of immunometabolism, the intersection between cellular metabolism and immune function, in the host response to K. pneumoniae infection. Bacterial metabolism itself is perceived as a metabolic stress to the host, altering the microenvironment at the site of infection. In this review, we will discuss the metabolic responses induced by K. pneumoniae, particularly in response to stimulation with the metabolically active bacteria versus pathogen-associated molecular patterns alone, and their implications in shaping the nature of the immune response and the infection outcome. A better understanding of the immunometabolic response to K. pneumoniae may help identify new targets for therapeutic intervention in the treatment of multidrug-resistant bacterial infections.

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Itaconic acid underpins hepatocyte lipid metabolism in non-alcoholic fatty liver disease

Cited by 3 publications

References 47 publications

Dynamic optimization elucidates optimal higher-level pathogenicity strategies of Pseudomonas aeruginosa

Dynamic optimization elucidates optimal higher-level pathogenicity strategies of Pseudomonas aeruginosa

Inflammaging and fatty acid oxidation in monocytes and macrophages

Immunometabolic control by Klebsiella pneumoniae

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