Glycochenodeoxycholic acid impairs transcription factor E3 -dependent autophagy-lysosome machinery by disrupting reactive oxygen species homeostasis in L02 cells

Lan, Weifeng; Chen, Zhijian; Chen, Yongtai; Tan, Miduo; Chen, Yuan; Chen, Jianwei; Chi, Xiaobin; Chen, Yongbiao

doi:10.1016/j.toxlet.2020.05.017

Cited by 11 publications

(7 citation statements)

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“…The fact that ketotic dairy cows exhibited severe liver injury and impaired lysosomal function confirmed that alterations in lysosomal function contribute to liver injury. In line with these results, recent evidence from mice indicated that liver injury and steatosis were improved by increasing lysosomal biogenesis and activities of lysosomal enzymes (Chao et al, 2018b;Lan et al, 2020;Xu et al, 2021b). Taken together, in the context of ketosis, hepatic lysosomal dysfunction may potentially contribute to liver injury and steatosis, and regulation of lysosomal function can be a therapeutic strategy for ketosis.…”

Section: Discussionsupporting

confidence: 59%

Overactivation of hepatic mechanistic target of rapamycin kinase complex 1 (mTORC1) is associated with low transcriptional activity of transcription factor EB and lysosomal dysfunction in dairy cows with clinical ketosis

Fang

Wang

et al. 2022

Journal of Dairy Science

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Ketosis occurs most frequently in the peripartal period and is associated with liver injury and steatosis. Lysosomes serve as the terminal degradative station and contribute to liver homeostasis through their role in the digestion of dysfunctional organelles and lipid droplets. Transcription factor EB (TFEB) has been identified as a master regulator of lysosomal function. Thus, the objective of the present study was to investigate the status of lysosomal function and TFEB transcriptional activity and potential changes in abundance of upstream effectors of TFEB identified in nonruminants, including mechanistic target of rapamycin kinase complex 1 (mTORC1), protein kinase B (Akt), glycogen synthase kinase β (GSK3β), and extracellular signal-regulated kinase1/2 (ERK1/2), and to explore which factor induces the above changes. Liver and blood samples were collected from healthy cows (n = 10) and ketotic cows (n = 10) that had a similar number of lactations (median = 3, range = 2-4) and days in milk (median = 6 d, range = 3-9 d). Calf hepatocytes were isolated from Holstein calves and treated with 10 ng/ mL growth hormone (GH), 3.0 mM β-hydroxybutyrate (BHB), 1.5 ng/mL interleukin-18 (IL-18), 0.15 ng/mL tumor necrosis factor-α (TNF-α), or 1.2 mM free fatty acid (FFA) for 12 h. Serum levels of FFA and activities of alanine aminotransferase and aspartate aminotransferase were greater in ketotic cows, whereas glucose was lower. Additionally, ketotic dairy cows exhibited higher serum concentrations of GH, IL-18, and TNF-α, and lower serum concentration of insulin. The lower protein abundance of lysosome-associated membrane protein 1 (LAMP1) and mRNA abundance of LAMP1 indicated that hepatic lysosomal mass was lower in ketotic cows. Furthermore, lower protein abundance of cathepsin D (CTSD) and mRNA abundance of CTSD and V0 domain of the vacuolar ATPase along with lower activity of β-N-acetylglucosaminidase indicated impairment in hepatic lysosomal function due to ketosis. The lower nuclear abundance, total protein, and mRNA abundance of TFEB and peroxisome proliferator-activated receptor γ coactivator 1 α along with greater phosphorylated (p)-TFEB in the liver of ketotic cows indicated an impairment of hepatic TFEB transcriptional activity. The protein abundances of phosphorylated mTOR (p-mTOR) and its downstream effectors ribosomal protein S6 kinase B (RPS6KB) and eukaryotic factor 4E-binding protein 1 (EIF4EBP1) were greater, whereas p-Akt, p-GSK3β, and p-ERK1/2 were lower in the liver of ketotic cows. Importantly, elevated phosphorylation of mTOR, RPS6KB, and EIF4EBP1 was observed in calf hepatocytes treated with GH, BHB, IL-18, TNF-α, and FFA. Moreover, BHB, TNF-α, and FFA, not GH and IL-18, reduced TFEB transcriptional activity and impaired lysosomal function in calf hepatocytes. Taken together, these data suggest that BHB, TNF-α, and FFA overactivate the hepatic mTORC1 signaling pathway during ketosis and further impaired TFEB transcriptional activity and lysosomal function, which may contribute to liver injury and s...

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Section: Discussionsupporting

confidence: 59%

Overactivation of hepatic mechanistic target of rapamycin kinase complex 1 (mTORC1) is associated with low transcriptional activity of transcription factor EB and lysosomal dysfunction in dairy cows with clinical ketosis

Fang

Wang

et al. 2022

Journal of Dairy Science

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“…Liquid chromatography/tandem mass spectrometry (LC-MS/MS) analysis of bile acids in mouse liver tissue extracts Mouse liver samples were prepared from WT, Sema7a R145W heterozygous, and homozygous mice and subjected to LC-MS/MS analysis of bile acids (BA), as described previously (Liu et al, 2017;Lan et al, 2020). For analysis of BAs, 60 mg of each mouse liver sample (n = 5 per group) was homogenized in 100 μl Milli-Q water and extracted with 500 μl of methanol.…”

Section: Generation Characterization and Treatment Of Slc10a1 S267f Mutant Micementioning

confidence: 99%

A homozygous R148W mutation in Semaphorin 7A causes progressive familial intrahepatic cholestasis

Pan

Luo

et al. 2021

EMBO Mol Med

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Semaphorin 7A (SEMA7A) is a membrane-bound protein that involves axon growth and other biological processes. SEMA7A mutations are associated with vertebral fracture and Kallmann syndrome. Here, we report a case with a mutation in SEMA7A that displays familial cholestasis. WGS reveals a SEMA7A R148W homozygous mutation in a female child with elevated levels of serum ALT, AST, and total bile acid (TBA) of unknown etiology. This patient also carried a SLC10A1 S267F allele, but Slc10a1 S267F homozygous mice exhibited normal liver function. Similar to the child, Sema7a R145W homozygous mice displayed elevated levels of serum ALT, AST, and TBA. Remarkably, liver histology and LC-MS/MS analyses exhibited hepatocyte hydropic degeneration and increased liver bile acid (BA) levels in Sema7a R145W homozygous mice. Further mechanistic studies demonstrated that Sema7a R145W mutation reduced the expression of canalicular membrane BA transporters, bile salt export pump (Bsep), and multidrug resistance-associated protein-2 (Mrp2), causing intrahepatic cholestasis in mice. Administration with ursodeoxycholic acid and a dietary supplement glutathione improved liver function in the child. Therefore, Sema7a R145W homozygous mutation causes intrahepatic cholestasis by reducing hepatic Bsep and Mrp2 expression.

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“…We found a significant increase in conjugated bile acids (e.g., glycocholic acid, taurochenodesoxycholic acid, and chenodeoxycholic acid glycine conjugate) in patients with chronic DILI-associated cirrhosis. The excessive accumulation of chenodeoxycholic acid glycine conjugate and taurochenodesoxycholic acid promote apoptosis of liver cells and liver failure (39,40). These abnormal accumulations of bile acids may not only be biomarkers for chronic DILI-associated cirrhosis, but also involved in the development of the disease.…”

Section: Discussionmentioning

confidence: 99%

Serum Metabolomic Analysis of Chronic Drug-Induced Liver Injury With or Without Cirrhosis

et al. 2021

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Background: Chronic drug-induced liver injury (DILI) occurs in up to 20% of all DILI patients. It presents a chronic pattern with persistent or relapsed episodes and may even progress to cirrhosis. However, its underlying development mechanism is poorly understood.Aims: To find serum metabolite signatures of chronic DILI with or without cirrhosis, and to elucidate the underlying mechanism.Methods: Untargeted metabolomics coupled with pattern recognition approaches were used to profile and extract metabolite signatures from 83 chronic DILI patients, including 58 non-cirrhosis (NC) cases, 14 compensated cirrhosis (CC) cases, and 11 decompensated cirrhosis (DC) cases.Results: Of the 269 annotated metabolites associated with chronic DILI, metabolic fingerprints associated with cirrhosis (including 30 metabolites) and decompensation (including 25 metabolites), were identified. There was a significantly positive correlation between cirrhosis-associated fingerprint (eigenmetabolite) and the aspartate aminotransferase-to-platelet ratio index (APRI) (r = 0.315, P = 0.003). The efficacy of cirrhosis-associated eigenmetabolite coupled with APRI to identify cirrhosis from non-cirrhosis patients was significantly better than APRI alone [area under the curve (AUC) value 0.914 vs. 0.573]. The decompensation-associated fingerprint (eigenmetabolite) can effectively identify the compensation and decompensation periods (AUC value 0.954). The results of the metabolic fingerprint pathway analysis suggest that the blocked tricarboxylic acid cycle (TCA cycle) and intermediary metabolism, excessive accumulation of bile acids, and perturbed amino acid metabolism are potential mechanisms in the occurrence and development of chronic DILI-associated cirrhosis.Conclusions: The metabolomic fingerprints characterize different stages of chronic DILI progression and deepen the understanding of the metabolic reprogramming mechanism of chronic DILI progression to cirrhosis.

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Glycochenodeoxycholic acid impairs transcription factor E3 -dependent autophagy-lysosome machinery by disrupting reactive oxygen species homeostasis in L02 cells

Cited by 11 publications

References 35 publications

Overactivation of hepatic mechanistic target of rapamycin kinase complex 1 (mTORC1) is associated with low transcriptional activity of transcription factor EB and lysosomal dysfunction in dairy cows with clinical ketosis

Overactivation of hepatic mechanistic target of rapamycin kinase complex 1 (mTORC1) is associated with low transcriptional activity of transcription factor EB and lysosomal dysfunction in dairy cows with clinical ketosis

A homozygous R148W mutation in Semaphorin 7A causes progressive familial intrahepatic cholestasis

Serum Metabolomic Analysis of Chronic Drug-Induced Liver Injury With or Without Cirrhosis

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