Elevated fatty acid β-oxidation by leptin contributes to the proinflammatory characteristics of fibroblast-like synoviocytes from RA patients via LKB1-AMPK pathway

Wei, Jing; Huang, Xinxin; Zhang, Xing; Chen, Guang-Hong; Zhang, Cheng; Zhou, Xinyang; Qi, Juntong; Zhang, Yan; Li, Xia

doi:10.1038/s41419-023-05641-2

Cited by 3 publications

(1 citation statement)

References 43 publications

(48 reference statements)

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“…MiR-126 overexpression decreased PIK3R2 protein, promoted proliferation, and decreased RA-FLS apoptosis, whereas miR-126 inhibition increased apoptosis. Additionally, miR-361-5p promoted FLS proliferation and inhibited apoptosis by targeting ZBTB10 in RA, and its possible mechanism of action involved increasing RA-FLS cells that secrete inflammatory factors ( 62 ).…”

Section: Altered Fls Metabolism and Intracellular Signaling Pathway T...mentioning

confidence: 99%

Metabolic changes in fibroblast-like synoviocytes in rheumatoid arthritis: state of the art review

Hu,

Li,

Zhang

et al. 2024

Front. Immunol.

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Fibroblast-like synoviocytes (FLS) are important components of the synovial membrane. They can contribute to joint damage through crosstalk with inflammatory cells and direct actions on tissue damage pathways in rheumatoid arthritis (RA). Recent evidence suggests that, compared with FLS in normal synovial tissue, FLS in RA synovial tissue exhibits significant differences in metabolism. Recent metabolomic studies have demonstrated that metabolic changes, including those in glucose, lipid, and amino acid metabolism, exist before synovitis onset. These changes may be a result of increased biosynthesis and energy requirements during the early phases of the disease. Activated T cells and some cytokines contribute to the conversion of FLS into cells with metabolic abnormalities and pro-inflammatory phenotypes. This conversion may be one of the potential mechanisms behind altered FLS metabolism. Targeting metabolism can inhibit FLS proliferation, providing relief to patients with RA. In this review, we aimed to summarize the evidence of metabolic changes in FLS in RA, analyze the mechanisms of these metabolic alterations, and assess their effect on RA phenotype. Finally, we aimed to summarize the advances and challenges faced in targeting FLS metabolism as a promising therapeutic strategy for RA in the future.

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Section: Altered Fls Metabolism and Intracellular Signaling Pathway T...mentioning

confidence: 99%

Metabolic changes in fibroblast-like synoviocytes in rheumatoid arthritis: state of the art review

Hu,

Li,

Zhang

et al. 2024

Front. Immunol.

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LKB1 biology: assessing the therapeutic relevancy of LKB1 inhibitors

Trelford,

Shepherd

2024

Cell Commun Signal

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Liver Kinase B1 (LKB1), encoded by Serine-Threonine Kinase 11 (STK11), is a master kinase that regulates cell migration, polarity, proliferation, and metabolism through downstream adenosine monophosphate-activated protein kinase (AMPK) and AMPK-related kinase signalling. Since genetic screens identified STK11 mutations in Peutz-Jeghers Syndrome, STK11 mutants have been implicated in tumourigenesis labelling it as a tumour suppressor. In support of this, several compounds reduce tumour burden through upregulating LKB1 signalling, and LKB1-AMPK agonists are cytotoxic to tumour cells. However, in certain contexts, its role in cancer is paradoxical as LKB1 promotes tumour cell survival by mediating resistance against metabolic and oxidative stressors. LKB1 deficiency has also enhanced the selectivity and cytotoxicity of several cancer therapies. Taken together, there is a need to develop LKB1-specific pharmacological compounds, but prior to developing LKB1 inhibitors, further work is needed to understand LKB1 activity and regulation. However, investigating LKB1 activity is strenuous as cell/tissue type, mutations to the LKB1 signalling pathway, STE-20-related kinase adaptor protein (STRAD) binding, Mouse protein 25-STRAD binding, splicing variants, nucleocytoplasmic shuttling, post-translational modifications, and kinase conformation impact the functional status of LKB1. For these reasons, guidelines to standardize experimental strategies to study LKB1 activity, associate proteins, spliced isoforms, post-translational modifications, and regulation are of upmost importance to the development of LKB1-specific therapies. Therefore, to assess the therapeutic relevancy of LKB1 inhibitors, this review summarizes the importance of LKB1 in cell physiology, highlights contributors to LKB1 activation, and outlines the benefits and risks associated with targeting LKB1.

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LKB1 Regulates Inflammation of Fibroblast-like Synoviocytes from Patients with Rheumatoid Arthritis via AMPK-Dependent SLC7A11-NOX4-ROS Signaling

Lee

Yoo

Kim

et al. 2023

Cells

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Fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) patients have increased reactive oxygen species (ROS) levels and an impaired redox balance compared with FLS from control patients. Liver kinase B1 (LKB1) plays a key role in ROS scavenging and cellular metabolism in various cancers. Here, we aimed to determine the specific mechanism of LKB1 in RA pathogenesis. FLS were obtained from RA patients (n = 10). siRNA-induced LKB1 deficiency in RA FLS increased ROS levels via NADPH oxidase 4 (NOX4) upregulation. RA FLS migration and expression of inflammatory factors, including interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-alpha (TNF-α), and vascular endothelial growth factor (VEGF), were enhanced by LKB1 deficiency. LKB1-deficient RA FLS showed increased sensitivity to oxidative stress damage caused by hydrogen peroxidase exposure. siRNA-induced solute carrier family 7 member 11 (SLC7A11) deficiency in RA FLS enhanced NOX4 and ROS expression and increased cell migration. When LKB1-deficient RA FLS were stimulated with an AMP-activated protein kinase (AMPK) activator, the LKB1-inhibition-induced cell migration significantly decreased through the restoration of SLC7A11/NOX4 expression. LKB1 regulates the AMPK-mediated SLC7A11-NOX4-ROS pathway to control cell migration and inflammation. Our data indicate that LKB1 is a key regulator of redox homeostasis in RA FLS.

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Elevated fatty acid β-oxidation by leptin contributes to the proinflammatory characteristics of fibroblast-like synoviocytes from RA patients via LKB1-AMPK pathway

Cited by 3 publications

References 43 publications

Metabolic changes in fibroblast-like synoviocytes in rheumatoid arthritis: state of the art review

Metabolic changes in fibroblast-like synoviocytes in rheumatoid arthritis: state of the art review

LKB1 biology: assessing the therapeutic relevancy of LKB1 inhibitors

LKB1 Regulates Inflammation of Fibroblast-like Synoviocytes from Patients with Rheumatoid Arthritis via AMPK-Dependent SLC7A11-NOX4-ROS Signaling

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