CYP51-mediated cholesterol biosynthesis is required for the proliferation of CD4+ T cells in Sjogren’s syndrome

Yin, Jian; Fu, Jiayao; Shao, Yanxiong; Xu, Jiabao; Li, Hui; Chen, Changyu; Zhao, Yijie; Zheng, Zhanglong; Yu, Chuangqi; Zheng, Lingyan; Wang, Baoli

doi:10.1007/s10238-022-00939-5

Cited by 6 publications

(5 citation statements)

References 90 publications

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“…We predicted that the activation of CYP3A11 and CYP3A25 by bicyclol might be beneficial in NAFLD/NASH treatment. Moreover, CYP51 is a super family of cytochrome P450 enzymes that plays an important role in sterol and cholesterol biosynthesis (Yin et al, 2022). As illustrated in Figure 6C, Figure 9B, the HFD feeding downregulated both mRNA and protein expression levels of CYP51, which were attenuated by bicyclol.…”

Section: Discussionmentioning

confidence: 95%

Bicyclol attenuates high fat diet-induced non-alcoholic fatty liver disease/non-alcoholic steatohepatitis through modulating multiple pathways in mice

Jia

et al. 2023

Front. Pharmacol.

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Introduction: The pathological progression of non-alcoholic fatty liver disease (NAFLD) is driven by multiple factors, and non-alcoholic steatohepatitis (NASH) represents its progressive form. In our previous studies, we found that bicyclol had beneficial effects on NAFLD/ NASH. Here we aim to investigate the underlying molecular mechanisms of the bicyclol effect on NAFLD/NASH induced by high-fat diet (HFD) feeding.Methods: A mice model of NAFLD/NASH induced by HFD-feeding for 8 weeks was used. As a pretreatment, bicyclol (200 mg/kg) was given to mice by oral gavage twice daily. Hematoxylin and eosin (H&E) stains were processed to evaluate hepatic steatosis, and hepatic fibrous hyperplasia was assessed by Masson staining. Biochemistry analyses were used to measure serum aminotransferase, serum lipids, and lipids in liver tissues. Proteomics and bioinformatics analyses were performed to identify the signaling pathways and target proteins. Data are available via Proteome X change with identifier PXD040233. The real-time RT-PCR and Western blot analyses were performed to verify the proteomics data.Results: Bicyclol had a markedly protective effect against NAFLD/NASH by suppressing the increase of serum aminotransferase, hepatic lipid accumulation and alleviating histopathological changes in liver tissues. Proteomics analyses showed that bicyclol remarkably restored major pathways related to immunological responses and metabolic processes altered by HFD feeding. Consistent with our previous results, bicyclol significantly inhibited inflammation and oxidative stress pathway related indexes (SAA1, GSTM1 and GSTA1). Furthermore, the beneficial effects of bicyclol were closely associated with the signaling pathways of bile acid metabolism (NPC1, SLCOLA4 and UGT1A1), cytochrome P450-mediated metabolism (CYP2C54, CYP3A11 and CYP3A25), biological processes such as metal ion metabolism (Ceruloplasmin and Metallothionein-1), angiogenesis (ALDH1A1) and immunological responses (IFI204 and IFIT3).Discussion: These findings suggested that bicyclol is a potential preventive agent for NAFLD/NASH by targeting multiple mechanisms in future clinical investigations.

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Section: Discussionmentioning

confidence: 95%

Bicyclol attenuates high fat diet-induced non-alcoholic fatty liver disease/non-alcoholic steatohepatitis through modulating multiple pathways in mice

Jia

et al. 2023

Front. Pharmacol.

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“…Based on our previously published sequencing data (Yin et al, 2022c), we found that the expression of key genes involved in de novo cholesterol synthesis was significantly increased after the activation of murine CD4 + T cells (Figure 4A). To confirm whether the inhibition of HUWE1/Huwe1 affects the cholesterol synthesis pathway, we detected the expression of several relevant genes.…”

Section: Huwe1-deficient Cd4 + T Cells Exhibited Elevated Levels Of C...mentioning

confidence: 64%

“…However, no significant correlation was observed between HUWE1 expression and clinical characteristics, such as age and sex ( Figure 1F ). Using splenic CD4 + T cells from mice, we examined the expression of ubiquitin ligase genes in activated cells by gene sequencing ( Yin et al, 2022c ). As shown in Figure 1G , Huwe1 was highly expressed in activated murine CD4 + T cells.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, interference with cholesterol synthesis in T cells has been shown to impede both the proliferation and activation of these cells in response to TCR signals ( Kidani et al, 2013 ), ( Kidani et al, 2013 ). Our previous study has shown that blocking de novo cholesterol synthesis by targeting cytochrome P450, family 51 ( Cyp51 ) inhibits the activation and proliferation of both CD4 + and CD8 + T cells ( Yin et al, 2022c ). Meanwhile, pharmacological inhibition of cholesterol synthesis alleviated symptoms and reduced CD4 + T cell infiltration in salivary glands of SS-like mice.…”

Section: Discussionmentioning

confidence: 99%

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HECT, UBA and WWE domain containing 1 represses cholesterol efflux during CD4+ T cell activation in Sjögren’s syndrome

Yin

Chen

et al. 2023

Front. Pharmacol.

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Introduction: Sjögren’s syndrome (SS) is a chronic autoimmune disorder characterized by exocrine gland dysfunction, leading to loss of salivary function. Histological analysis of salivary glands from SS patients reveals a high infiltration of immune cells, particularly activated CD4+ T cells. Thus, interventions targeting abnormal activation of CD4+ T cells may provide promising therapeutic strategies for SS. Here, we demonstrate that Hect, uba, and wwe domain containing 1 (HUWE1), a member of the eukaryotic Hect E3 ubiquitin ligase family, plays a critical role in CD4+ T-cell activation and SS pathophysiology.Methods: In the context of HUWE1 inhibition, we investigated the impact of the HUWE1 inhibitor BI8626 and sh-Huwe1 on CD4+ T cells in mice, focusing on the assessment of activation levels, proliferation capacity, and cholesterol abundance. Furthermore, we examined the therapeutic potential of BI8626 in NOD/ShiLtj mice and evaluated its efficacy as a treatment strategy.Results: Inhibition of HUWE1 reduces ABCA1 ubiquitination and promotes cholesterol efflux, decreasing intracellular cholesterol and reducing the expression of phosphorylated ZAP-70, CD25, and other activation markers, culminating in the suppressed proliferation of CD4+ T cells. Moreover, pharmacological inhibition of HUWE1 significantly reduces CD4+ T-cell infiltration in the submandibular glands and improves salivary flow rate in NOD/ShiLtj mice.Conclusion: These findings suggest that HUWE1 may regulate CD4+ T-cell activation and SS development by modulating ABCA1-mediated cholesterol efflux and presents a promising target for SS treatment.

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“…5 A and B . Further leveraging previously acquired sequencing data [ 59 ], we depicted the expression profiles of m6A-regulated genes in resting and activated CD4 + T cells through comprehensive heatmap analyses ( Fig. 5 C–E).…”

Section: Resultsmentioning

confidence: 99%

Integrated analysis of m6A regulator-mediated RNA methylation modification patterns and immune characteristics in Sjögren's syndrome

Yin,

Fu,

et al. 2024

Heliyon

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CYP51-mediated cholesterol biosynthesis is required for the proliferation of CD4+ T cells in Sjogren’s syndrome

Cited by 6 publications

References 90 publications

Bicyclol attenuates high fat diet-induced non-alcoholic fatty liver disease/non-alcoholic steatohepatitis through modulating multiple pathways in mice

Bicyclol attenuates high fat diet-induced non-alcoholic fatty liver disease/non-alcoholic steatohepatitis through modulating multiple pathways in mice

HECT, UBA and WWE domain containing 1 represses cholesterol efflux during CD4+ T cell activation in Sjögren’s syndrome

Integrated analysis of m6A regulator-mediated RNA methylation modification patterns and immune characteristics in Sjögren's syndrome

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