Beta-hydroxybutyrate dampens adipose progenitors’ profibrotic activation through canonical Tgfβ signaling and non-canonical ZFP36-dependent mechanisms

Lecoutre, Simon; Merabtene, Fatiha; Hachem, Elie-Julien El; Gamblin, Camille; Rouault, Christine; Sokolovska, Nataliya; Soula, Hédi; Lai, Wi S.; Blackshear, Perry J.; Clément, Karine; Dugail, Isabelle

doi:10.1016/j.molmet.2022.101512

Cited by 7 publications

(9 citation statements)

References 49 publications

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“…Thereinto, β-hydroxybutyrate accounts for the majority of ketone bodies in circulation. A previous study showed that β-hydroxybutyrate selectively reduced TGFβ-dependent responses of ECM genes like Fn1 and limits collagen accumulation ( Lecoutre et al, 2022 ). The impaired integrity of ECM components could destroy aortic structure and function ( Andreata et al, 2018 ; Shen et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Tandem mass tag-based quantitative proteomic analysis identification of succinylation related proteins in pathogenesis of thoracic aortic aneurysm and aortic dissection

Zhang,

Wang

et al. 2023

PeerJ

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Background Thoracic aortic aneurysm and dissection (TAAD) are devastating cardiovascular diseases with a high rate of disability and mortality. Lysine succinylation, a newly found post-translational modification, has been reported to play an important role in cardiovascular diseases. However, how succinylation modification influences TAAD remains obscure. Methods Ascending aortic tissues were obtained from patients with thoracic aortic aneurysm (TAA, n = 6), thoracic aortic dissection (TAD) with pre-existing aortic aneurysm (n = 6), and healthy subjects (n = 6). Global lysine succinylation level was analyzed by Western blotting. The differentially expressed proteins (DEPs) were analyzed by tandem mass tag (TMT) labeling and mass spectrometry. Succinylation-related proteins selected from the literature review and AmiGO database were set as a reference inventory for further analysis. Then, the pathological aortic sections were chosen to verify the proteomic results by Western blotting and qRT-PCR. Results The level of global lysine succinylation significantly increased in TAA and TAD patients compared with healthy subjects. Of all proteins identified by proteomic analysis, 197 common DEPs were screened both in TAA and TAD group compared with the control group, of which 93 proteins were significantly upregulated while 104 were downregulated. Among these 197 DEPs, OXCT1 overlapped with the succinylation-related proteins and was selected as the target protein involved in thoracic aortic pathogenesis. OXCT1 was further verified by Western blotting and qRT-PCR, and the results showed that OXCT1 in TAA and TAD patients was significantly lower than that in healthy donors (p < 0.001), which was consistent with the proteomic results. Conclusions OXCT1 represents novel biomarkers for lysine succinylation of TAAD and might be a therapeutic target in the future.

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Section: Discussionmentioning

confidence: 99%

Tandem mass tag-based quantitative proteomic analysis identification of succinylation related proteins in pathogenesis of thoracic aortic aneurysm and aortic dissection

Zhang,

Wang

et al. 2023

PeerJ

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“…19 The immune microenvironment of skin fibrosis is mainly induced by macrophages and T-lymphocytes producing pro-inflammatory and pro-fibrotic cytokines. 16,20 To determine whether the transplantation of BAT affects the infiltration of inflammatory cells in the skin of BLM-induced LoS mice, the sclerotic lesions of different treatment groups were stained with anti-CD4 and anti-F4/80 monoclonal antibodies. Immunofluorescent staining revealed a significant infiltration of F4/80 + macrophages in the sclerosing lesion treated with phosphate-buffered saline.…”

Section: Bat Transplantation Reduced Inflammatory Cell Infiltration I...mentioning

confidence: 99%

“…Brown adipocytes stimulated with β3‐adrenergic agonists could significantly attenuate fibroblast proliferation and fibrosis gene expression, mediated by the rich inducible nitric oxide synthase (iNOS) in exosomes derived from brown adipocytes 13 . In addition, BAT can also secrete a variety of batokines with anti‐fibrotic effects 14–16 . More and more studies have confirmed the effectiveness of enhancing the endocrine activity of batokines by transplanting BAT 17 …”

Section: Introductionmentioning

confidence: 99%

Brown adipose tissue transplantation improves skin fibrosis in localized scleroderma

Zhang,

Liang,

Zhang

et al. 2023

The FASEB Journal

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Adipose tissue transplantation shows great therapeutic potential in reversing localized scleroderma‐associated skin fibrosis. Brown adipose tissue (BAT) can specifically secrete various cytokines against fibrosis, but its therapeutic potential in improving skin fibrosis has not yet been demonstrated. In this study, we have demonstrated the superior therapeutic efficacy of BAT transplantation for sclerotic skin by transplanting two distinct types of adipose tissue. In comparison to the white adipose tissue (WAT) group, mice treated with BAT transplantation exhibited a significant reduction in dermal thickness. BAT transplantation effectively reverses skin sclerosis through mechanisms involving inflammation reduction, promotion of angiogenesis, inhibition of myofibroblast accumulation, and collagen deposition. This therapeutic effect can be attributed to its unique paracrine effects. Furthermore, transcriptome sequencing (RNA‐Seq) revealed upregulation of pathways associated with lipogenesis and fatty acid metabolism in BAT while downregulating pathways are related to transforming growth factor β(TGF‐β), epithelial–mesenchymal transition (EMT), and inflammatory response. These findings suggest that BAT transplantation holds great promise as a novel approach for localized scleroderma treatment.

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“…In addition to this classical regulation of ketogenesis, recent evidence shows non-hepatic sources of ketone bodies impact a variety of organ systems. In adipose tissue, beige PRDM+ adipocytes secrete BHB that is oxidized by adipocyte precursors to preserve adipogenic differentiation and limit fibrotic lineage skewing (Lecoutre et al, 2022; Wang et al, 2019). BHB is produced by small intestine Lgr5+ stem cells and this is important for maintaining their stemness within crypts (Cheng et al, 2019; Stine et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Innate immune cell-intrinsic ketogenesis is dispensable for organismal metabolism and age-related inflammation

Goldberg

Letian

Dlugos

et al. 2022

Preprint

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Aging is accompanied by chronic low-grade inflammation, but the mechanisms that allow this to persist are not well understood. Ketone bodies are alternative fuels produced when glucose is limited and improve indicators of healthspan in aging mouse models. Moreover, the most abundant ketone body, β-hydroxybutyrate (BHB), inhibits the NLRP3 inflammasome in myeloid cells, a key potentiator of age-related inflammation. Given that myeloid cells express ketogenic machinery, we hypothesized this pathway may serve as a metabolic checkpoint of inflammation. To test this hypothesis, we conditionally ablated ketogenesis by disrupting expression of the terminal enzyme required for ketogenesis, 3-Hydroxy-3-Methylglutaryl-CoA Lyase (HMGCL). By deleting HMGCL in the liver, we validated the functional targeting and establish that the liver is the only organ that can produce the life-sustaining quantities of ketone bodies required for survival during fasting or ketogenic diet feeding. Conditional ablation of HMGCL in neutrophils and macrophages had modest effects on body weight and glucose tolerance in agin, but worsened glucose homeostasis in myeloid cell specific Hmgcl deficient mice fed a high-fat diet. Our results suggest that during aging, liver derived circulating ketone bodies might be more important for deactivating NLRP3 inflammasome and controlling organismal metabolism.

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Beta-hydroxybutyrate dampens adipose progenitors’ profibrotic activation through canonical Tgfβ signaling and non-canonical ZFP36-dependent mechanisms

Cited by 7 publications

References 49 publications

Tandem mass tag-based quantitative proteomic analysis identification of succinylation related proteins in pathogenesis of thoracic aortic aneurysm and aortic dissection

Tandem mass tag-based quantitative proteomic analysis identification of succinylation related proteins in pathogenesis of thoracic aortic aneurysm and aortic dissection

Brown adipose tissue transplantation improves skin fibrosis in localized scleroderma

Innate immune cell-intrinsic ketogenesis is dispensable for organismal metabolism and age-related inflammation

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