The cooperative interplay among inflammation, necroptosis and YAP pathway contributes to the folate deficiency-induced liver cells enlargement

Chi, Wen‐Rong; Hsiao, Tsun-Hsien; Lee, Gang Hui; Su, I-Hsiu; Chen, Bing‐Hung; Tang, Min; Fu, Tzu-Fun

doi:10.1007/s00018-022-04425-9

Cited by 4 publications

(5 citation statements)

References 54 publications

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“…42 Recent evidence also indicates that the Hippo signaling pathway serves as an important regulator in the occurrence and development of inflammation. [43][44][45] Overall, these findings suggest that MST1/2 activates the TAZ-dependent non-canonical Hippo signaling pathway through NDR1/2 to regulate Th17 cell differentiation in AS. Considering the expression of key molecules (Figure 5), the Hippo signaling pathway may play a significant role in AS; however, further studies are needed to confirm these findings and fully understand the mechanisms underlying the role of the Hippo signaling pathway in AS.…”

Section: Discussionmentioning

confidence: 68%

“…Moreover, the loss of NDR1/2 phenocopied the deletion of MST1 in thymocytes, 41 indicating that NDR1 plays a significant role in regulating T cell homeostasis 42 . Recent evidence also indicates that the Hippo signaling pathway serves as an important regulator in the occurrence and development of inflammation 43–45 . Overall, these findings suggest that MST1/2 activates the TAZ‐dependent non‐canonical Hippo signaling pathway through NDR1/2 to regulate Th17 cell differentiation in AS.…”

Section: Discussionmentioning

confidence: 94%

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Molecules in the hippo pathway that regulate Th17 differentiation reveal the severity of ankylosing spondylitis

Xu,

Liu,

Liu

et al. 2024

Int J of Rheum Dis

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AimAnkylosing spondylitis (AS) is a chronic, progressive, and inflammatory autoimmune disease of unknown origin that affects the axial skeleton and sacroiliac joints, resulting in pain and loss of function. AS is characterized by the overdifferentiation of T helper 17 (Th17) cells, which contribute to the development of the disease. The Hippo signaling pathway is an important regulator of Th17 differentiation, but its role in patients with AS is unclear. We aimed to investigate the role of key molecules of the Hippo signaling pathway in inflammatory Th17 differentiation in patients with AS and to examine their correlation with disease stages.MethodsWe examined the activity of the Hippo pathway in patients with AS and the regulation of Th17 differentiation during AS‐mediated inflammation. Blood samples were collected from 60 patients with AS at various stages and 30 healthy controls. Peripheral blood mononuclear cells (PBMCs) were isolated from peripheral blood by density gradient centrifugation. The Serum Interleukin‐17 (IL‐17) levels in patients with AS and healthy controls were quantified by ELISA. The key molecules of Hippo pathway were assessed by real‐time PCR for their mRNA expression, and protein levels were determined by Western blot analysis.ResultsElevated serum interleukin‐17 (IL‐17) levels were observed in patients with AS compared with healthy controls. The protein and mRNA levels of retinoic acid receptor‐related orphan receptor γt (RORγt), transcriptional coactivator with a PDZ‐binding motif (TAZ), and key upstream transcription factors in the Hippo signaling pathway were measured. The expression of RORγt and TAZ was increased in the blood of patients with AS, whereas the expression of other Hippo pathway proteins, such as MST1/2 and NDR1/2, was significantly decreased. Increased levels of IL‐17 and TAZ were significantly associated with disease activity. In addition, MST1, MST2, and NDR1 levels were negatively correlated with TAZ, RORγt, and IL‐17 levels.ConclusionOur findings suggest that the Hippo pathway plays a significant role in the regulation of Th17 differentiation and disease activity in patients with AS. The upregulation of TAZ and downregulation of key Hippo pathway proteins, such as MST1/2 and NDR1/2, may contribute to AS pathogenesis. These proteins may serve as biomarkers and may lead to the development of novel therapeutic strategies for AS.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 94%

Molecules in the hippo pathway that regulate Th17 differentiation reveal the severity of ankylosing spondylitis

Xu,

Liu,

Liu

et al. 2024

Int J of Rheum Dis

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“…The redistribution of mitochondria observed in FD Huh7 cells signifies a cellular response to the stress conditions caused by FD and the ultimate lipid accumulation, which may convey an adaptive response critical for cell survival and homeostasis. We have reported previously that disturbing folate-mediated OCM homeostasis impeded F-actin polymerization both in hepatocytes and in developing embryos [ 19 , 35 ]. F-actin is crucial to mitochondria distribution and dynamics through its involvement in the anchoring, positioning and transport of mitochondria [ 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

“…It should be noted that the staining efficacy of JC-1 is influenced by the surface-to-volume (S/V) ratios of the cell [ 38 ]. We have previously reported that FD induces hepatic cell size enlargement [ 19 ]. It is likely that the elevated JC-1 aggregates/monomers are a result of the increased surface-to-volume (S/V) ratios of FD cells.…”

Section: Discussionmentioning

confidence: 99%

“…Contrary to our initial hypothesis, the observed hepatomegaly in these FD fish was not attributed to nucleotide depletion or lipid accumulation. Instead, it emerged as a consequence of the collaborative interplay among inflammation, necroptosis, and the YAP signaling pathway [ 19 ]. In the present study, we delved into the potential mechanism underlying FD-induced hepatic lipid accumulation and discovered that impaired autophagy, due to down-regulated cathepsin L, played a crucial role in this phenomenon.…”

Section: Introductionmentioning

confidence: 99%

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Disturbed intracellular folate homeostasis impairs autophagic flux and increases hepatocytic lipid accumulation

Chi,

Lee,

Tang

et al. 2024

BMC Biol

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Background Metabolic associated fatty liver disease (MAFLD), a prevalent liver disorder affecting one-third of the global population, encompasses a spectrum ranging from fatty liver to severe hepatic steatosis. Both genetic and lifestyle factors, particularly diet and nutrition, contribute to its etiology. Folate deficiency, a frequently encountered type of malnutrition, has been associated with the pathogenesis of MAFLD and shown to impact lipid deposition. However, the underlying mechanisms of this relationship remain incompletely understood. We investigated the impact of disturbed folate-mediated one-carbon metabolism (OCM) on hepatic lipid metabolism both in vitro using human hepatoma cells and in vivo using transgenic fluorescent zebrafish displaying extent-, stage-, and duration-controllable folate deficiency upon induction. Results Disturbed folate-mediated one-carbon metabolism, either by inducing folate deficiency or adding anti-folate drug, compromises autophagy and causes lipid accumulation in liver cells. Disturbed folate status down-regulates cathepsin L, a key enzyme involved in autophagy, through inhibiting mTOR signaling. Interfered mitochondrial biology, including mitochondria relocation and increased fusion-fission dynamics, also occurs in folate-deficient hepatocytes. Folate supplementation effectively mitigated the impaired autophagy and lipid accumulation caused by the inhibition of cathepsin L activity, even when the inhibition was not directly related to folate deficiency. Conclusions Disruption of folate-mediated OCM diminishes cathepsin L expression and impedes autophagy via mTOR signaling, leading to lipid accumulation within hepatocytes. These findings underscore the crucial role of folate in modulating autophagic processes and regulating lipid metabolism in the liver.

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Mechanical stiffness across skin layers in human: a pilot study

Chi,

Huang,

Lee

et al. 2024

Tissue Barriers

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The cooperative interplay among inflammation, necroptosis and YAP pathway contributes to the folate deficiency-induced liver cells enlargement

Cited by 4 publications

References 54 publications

Molecules in the hippo pathway that regulate Th17 differentiation reveal the severity of ankylosing spondylitis

Molecules in the hippo pathway that regulate Th17 differentiation reveal the severity of ankylosing spondylitis

Disturbed intracellular folate homeostasis impairs autophagic flux and increases hepatocytic lipid accumulation

Mechanical stiffness across skin layers in human: a pilot study

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