Lithocholic acid activates mTOR signaling inducing endoplasmic reticulum stress in placenta during intrahepatic cholestasis of pregnancy

Sheng, Chao; Lin, Xi Zhang; Wang, Haizhen; Fu, Lu‐Di; Liang, Shao-Zhen; Su, Zhiwen; Weiliang, Huang; Jia, Chunhong; Wang, Ying; Wu, Fan; Gao, Yunfei

doi:10.1016/j.lfs.2018.12.050

Cited by 22 publications

(13 citation statements)

References 36 publications

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“…Li et al 30 found that LCA levels were significantly elevated in patients with ICP and negatively correlated with the LCA detoxifying enzyme sulfotransferase 2A1, suggesting that the accumulation and abnormal metabolism of LCA might be an important cause of development in ICP. Chao et al 31 revealed that the effector protein levels in the mTOR signaling pathway were elevated in the placenta of pregnant women with ICP, and pretreatment of LCA to human placental trophoblast cell lines could further activate this pathway, suggesting that LCA might contribute to the onset and development of ICP by activating mTOR signaling. In addition, the possibility of CA and LCA as risk predictors for ICP in pregnant women with high levels of TBA was explored in the present study, and it was found that the combined evaluation had the best efficacy.…”

Section: Discussionmentioning

confidence: 99%

Predictive Value of Serum Cholic Acid and Lithocholic Acid for the Diagnosis in an Intrahepatic Cholestasis of Pregnancy Population with High Levels of Total Bile Acids and the Correlation with Placental Hypoxia-Inducible Factor-1α

Cheng¹,

Zeng²,

Wang³

et al. 2022

IJWH

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Objective This study aimed to investigate the ability of serum cholic acid (CA) and lithocholic acid (LCA) in the diagnosis and perinatal prognosis assessment of intrahepatic cholestasis of pregnancy (ICP), and the relationship between both indicators and hypoxia-inducible factor-1α (HIF-1α). Methods Between March 2020 and March 2021, pregnant women with high levels of total bile acid (TBA) in the late pregnancy with TBA ≥10 μmol/L and TBA <10 μmol/L (control group) were included for the retrospective study. Those with TBA ≥10 μmol/L were divided into the ICP group and the asymptomatic hypercholanaemia of pregnancy (AHP) group based on ICP symptoms. The comparison of the bile acid profiles, the receiver operating characteristic (ROC) curve analysis, and Pearson correlation analysis were conducted successively. Results Nine types of bile acids were significantly higher in ICP and AHP than in the control group, while CA and LCA serum levels in the AHP group were significantly lower than those in the ICP group ( P < 0.05). The ROC curve analysis showed that LCA, CA, and LCA+CA were all diagnostic indicators for ICP, and LCA+CA displayed the greatest diagnostic value (area under the curve (AUC), 0.923). Subgroup analysis using the LCA+CA cut-off point (3.28 μmol/L) as the subgroup indicator proved that the incidence of adverse perinatal outcomes and the placental HIF-1α positivity were significantly higher in the high LCA+CA group than in the low LCA+CA group ( P < 0.05). Pearson correlation analysis revealed significant positive correlations of HIF-1α expression levels to LCA, CA and LCA+CA (r = 0.473, 0.537, 0.619, respectively. P < 0.05 in all). Conclusion This study confirmed that CA and LCA have a predictive diagnostic value for ICP in pregnant women, and the combined evaluation is associated with adverse perinatal outcomes, and LCA+CA positively correlates to placental HIF-1α expression levels.

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Section: Discussionmentioning

confidence: 99%

Predictive Value of Serum Cholic Acid and Lithocholic Acid for the Diagnosis in an Intrahepatic Cholestasis of Pregnancy Population with High Levels of Total Bile Acids and the Correlation with Placental Hypoxia-Inducible Factor-1α

Cheng¹,

Zeng²,

Wang³

et al. 2022

IJWH

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“…In this study, we found 143 differentially expressed lncRNAs using a CapitalBio Technology Human lncRNA Array v4 and identified three lncRNAs using qPCR. Bioinformatics technology revealed that target mRNA is mainly enriched in some processes such as cell cycle, fatty acid metabolism, apoptotic signaling, and oxidative stress [26][27][28][29]. According to the software prediction, the transcription factor of lncRNA ENST00000505175.1 is Oct-1 which participates in regulating a variety of physiological and pathological processes [30].…”

Section: Discussionmentioning

confidence: 99%

Diagnostic and Prognostic Value of Long Noncoding RNAs as Potential Novel Biomarkers in Intrahepatic Cholestasis of Pregnancy

Zou

Zhao

Wang

et al. 2021

BioMed Research International

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Long noncoding RNAs (lncRNAs) are a class of important regulators participating in various pathological processes. Until now, the role of lncRNAs in the occurrence and development of intrahepatic cholestasis of pregnancy (ICP) has rarely been investigated. The data from microarray screening revealed 58 upregulated and 85 downregulated lncRNAs and 47 upregulated and 71 downregulated mRNAs in ICP patients compared to healthy controls. Bioinformatics analysis revealed biological processes focused on lipid metabolism, apoptosis, cell cycle, cell differentiation, and oxidative stress. Furthermore, the expressions of three lncRNAs (ENST00000505175.1, ASO3480, and ENST00000449605.1) chosen for verification were significantly decreased and showed the diagnostic and prognostic value for ICP based on ROC analysis. This is the first study to report the specific role of lncRNAs in ICP, which may be helpful for the diagnosis and prognosis of ICP clinically.

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“…Immunohistochemical analysis was completed as described previously 42 . In brief, after deparaffinization, antigen retrieval and background blocking, sections were incubated with anti‐PCNA at 4°C overnight.…”

Section: Methodsmentioning

confidence: 99%

“…Immunohistochemical analysis was completed as described previously. 42 In brief, after deparaffinization, antigen retrieval and background blocking, sections were incubated with anti-PCNA at 4 C overnight. The next morning, the sections were washed with PBS and then incubated with a HRP conjugated secondary antibody at room temperature for 1 h. Immunoreactivity was then observed by staining with 3,3 0 -diaminobenzidine (DAB; Vector Laboratories, Burlingame, CA).…”

Section: Immunohistochemistrymentioning

confidence: 99%

The inhibition of enterocyte proliferation by lithocholic acid exacerbates necrotizing enterocolitis through downregulating the Wnt/β‐catenin signalling pathway

et al. 2022

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Objectives: Necrotizing enterocolitis (NEC) is a catastrophic gastrointestinal emergency in preterm infants, whose exact aetiology remains unknown. The role of lithocholic acid (LCA), a key component of secondary bile acids (BAs), in NEC is unclear.Methods: Clinical data were collected to analyse the changes of BAs in NEC patients.In vitro studies, the cell proliferation and cell death were assessed. In vivo experiments, the newborn rats were administered with low or high dose of LCA and further induced NEC.Results: Clinically, compared with control group, total BAs in the NEC patients were significantly higher when NEC occurred. In vitro, LCA treatment significantly inhibited the cell proliferation through arresting cell cycle at G1/S phase without inducing apoptosis or necroptosis. Mechanistically, the Wnt/β-catenin pathway was involved. In vivo, LCA inhibited intestinal cell proliferation leading to disruption of intestinal barrier, and thereby increased the severity of NEC. Specifically, LCA supplementation caused higher levels of FITC-labelled dextran in serum, reduced PCNA expression and inhibited the activity of Wnt/β-catenin pathway in enterocytes. The LC-MS/MS test found that LCA was significantly higher in intestinal tissue of NEC group, and more obviously in the NEC-L and NEC-H group compared with the DM group. Conclusion: LCA exacerbates NEC by inhibiting intestinal cell proliferation throughdownregulating the Wnt/β-catenin pathway. | INTRODUCTIONNecrotizing enterocolitis (NEC) is a catastrophic disease that predominantly occurs in preterm infants. Approximately 7% of infants with a birth weight between 500 and 1500 g develop NEC, with an overall mortality rate of 10%-50%. 1,2 According to our previous retrospective analysis from 2008 to 2017 in Guangdong province, the incidence of NEC in very preterm infants was 10.1%. 3 This disease can be mild to severe with clinical symptoms including abdominal distension, pneumatosis intestinalis, bowel Zhoushan Feng, Chunhong Jia and Xiaojun Li contributed to this work equally.

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Lithocholic acid activates mTOR signaling inducing endoplasmic reticulum stress in placenta during intrahepatic cholestasis of pregnancy

Cited by 22 publications

References 36 publications

Predictive Value of Serum Cholic Acid and Lithocholic Acid for the Diagnosis in an Intrahepatic Cholestasis of Pregnancy Population with High Levels of Total Bile Acids and the Correlation with Placental Hypoxia-Inducible Factor-1α

Predictive Value of Serum Cholic Acid and Lithocholic Acid for the Diagnosis in an Intrahepatic Cholestasis of Pregnancy Population with High Levels of Total Bile Acids and the Correlation with Placental Hypoxia-Inducible Factor-1α

Diagnostic and Prognostic Value of Long Noncoding RNAs as Potential Novel Biomarkers in Intrahepatic Cholestasis of Pregnancy

The inhibition of enterocyte proliferation by lithocholic acid exacerbates necrotizing enterocolitis through downregulating the Wnt/β‐catenin signalling pathway

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