ASPP2 Coordinates ERS-Mediated Autophagy and Apoptosis Through mTORC1 Pathway in Hepatocyte Injury Induced by TNF-α

Yao, Jia; Yang, Hui; Wang, Han; Jiao, Yan; Zhang, Ying; Chen, Dexi; Shi, Hang

doi:10.3389/fphar.2022.865389

Cited by 9 publications

(8 citation statements)

References 22 publications

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“…Numerous studies have shown that mTOR plays an important role in lipid metabolism 25,26 . Our previous study found that ASPP2 can mediate the mTOR signaling pathway to regulate autophagy 13 . In this study, we found that ethanol-fed WT mice caused signi cant liver steatosis and liver injury, while deletion of hepatic ASPP2 effectively alleviated lipid accumulation in the liver and suppressed the levels of AST, ALT, TC, and TG.…”

Section: Discussionmentioning

confidence: 99%

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ASPP2 deficiency attenuates lipid accumulation through the PPARγ pathway in alcoholic liver injury

Zhang¹,

Miao

Liu

et al. 2022

Preprint

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Alcoholic liver disease (ALD) is a liver disease caused by long-term heavy alcohol consumption, the initial stage of which is hepatic steatosis. Recent studies have highlighted a possible role for apoptosis-stimulating protein 2 of p53 (ASPP2) in regulating hepatic lipid metabolism. However, the role of ASPP2 in the disease progression of ALD remains unclear. This study aimed to investigate the molecular mechanism of ASPP2 in regulating lipid metabolism in ALD. In the present study, we found that both ASPP2 and peroxisome proliferator-activated receptor (PPARγ) expression were increased in patients with ALD and ethanol-fed mice. To further determine the role of ASPP2 in the development of ALD, we used hepatocyte-specific ASPP2 knockout mice (ASPP2-LKO) to establish an alcoholic liver injury model. We found that deletion of hepatic ASPP2 significantly alleviated hepatic steatosis and injury in a mouse model of ALD. The expression levels of fatty acid oxidation-related genes (AOX, CPT1) and very low-density lipoprotein secretion-related genes (ApoB, MTTP, LFABP) were increased; the expression levels of fatty acid synthesis-related genes (ACC1, FAS) and fatty acid transporter-related genes (CD36) were decreased in ASPP2-LKO mice. Furthermore, we demonstrated that ASPP2 promotes the accumulation of alcohol-induced hepatocyte lipids via HL-7702 cell lines transfected with ASPP2 adenovirus (adv-ASPP2) and ASPP2 short hairpin RNA lentivirus (LV-ASPP2shRNA) under ethanol treatment. Additionally, we found that ASPP2 promoted the expression of PPARγ in vivo and in vitro. Mechanistically, the PPARγ agonist rosiglitazone reversed the protective effect of ASPP2 downregulation on lipid accumulation and liver injury, while the opposite was observed for PPARγ inhibitor T0070907. Collective, ASPP2 exacerbates ethanol-induced hepatic injury and lipid accumulation by upregulating the PPARγ signaling pathway, thus promoting the progression of ALD.

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Section: Discussionmentioning

confidence: 99%

“…A recent study showed that ASPP2 can participate in the regulation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway 13 . Research has shown that mTORC1 plays an important role in lipid metabolism 14 .…”

Section: Introductionmentioning

confidence: 99%

ASPP2 deficiency attenuates lipid accumulation through the PPARγ pathway in alcoholic liver injury

Zhang¹,

Miao

Liu

et al. 2022

Preprint

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“…The data presented in this study indicate that GRb1 may have a protective effect against hepatotoxicity induced by CTD, potentially through its ability to reduce apoptosis, which validated the results of network prediction. Research has reported that apoptosis may be induced due to excess ERS 36 . A growing body of evidence has substantiated that in ERS conditions, the accumulation of unfolded or misfolded proteins occurs within the cellular ER, resulting in apoptosis and ultimately contributing to hepatotoxicity 37 .…”

Section: Discussionmentioning

confidence: 99%

“…Research has reported that apoptosis may be induced due to excess ERS. 36 A growing body of evidence has substantiated that in ERS conditions, the accumulation of unfolded or misfolded proteins occurs within the cellular ER, resulting in apoptosis and ultimately contributing to hepatotoxicity. 37 There is evidence that ERS participates in the occurrence and development of various liver disorders, including fatty liver, ischemia-reperfusion injury, liver fibrosis and DILI.…”

Section: Integrated Network Analysis To Elucidate the Protective Mech...mentioning

confidence: 99%

A novel approach combining network pharmacology and experimental validation to study the protective effect of ginsenoside Rb1 against cantharidin‐induced hepatotoxicity in mice

Xiong,

Lin,

et al. 2024

Basic Clin Pharma Tox

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Cantharidin (CTD) is a widely used anticancer compound, but its clinical use is mainly limited due to hepatotoxicity. Ginsenoside Rb1 (GRb1) shows potential hepatoprotective effects. Nonetheless, the protective effect and underlying mechanism of GRb1 against CTD‐induced hepatotoxicity in mice have not been investigated. This study aims to elucidate the effect and mechanism of GRb1 on CTD‐induced hepatotoxicity using network pharmacology and in vivo experiments. Network pharmacology studies have shown that 263 targets were the main mechanisms by which GRb1 alleviates CTD‐induced hepatotoxicity. KEGG enrichment analysis revealed that 75 hub genes were mainly enriched in TNF, IL‐17 and apoptosis signalling pathways. Molecular docking analysis showed that GRb1 exhibited high affinity with Akt1, Tnf, Il6, Bcl2 and Caspase3. In addition, results from animal studies demonstrated that GRb1 could ameliorate CTD‐induced hepatotoxicity by inhibiting protein expression of Caspase‐3, Caspase‐8, Bcl‐2/Bax, GRP78, ATF6, ATF4, CHOP, IRE1α and PERK. This research revealed the mechanism of GRb1 against CTD‐induced hepatotoxicity by inhibiting apoptosis and endoplasmic reticulum stress (ERS) and it may provide a scientific rationale for the potential use of GRb1 in the treatment of hepatotoxicity induced by CTD.

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“…The enhanced autophagy activity can promote the conversion of long-chain acyl-CoA molecule to acetyl-CoA molecule by increasing fatty acid beta-oxidation, furthermore, leading to the breakdown of long chain fatty acids (50). Overexpression of ASPP2 significantly reduced the activity of autophagy in both HepG2 cells and BALB/c mice, while ASPP2 silencing induced autophagic flux through increasing the conversion of LC3I to LC3II (29,51). Thus, the effect of APSS2 on long-chain fatty acids that we found in the present study is likely due to the activation of autophagy-related lipid metabolic pathways in ASPP2 +/mice.…”

Section: Discussionmentioning

confidence: 99%

Dysregulated hepatic lipid metabolism and gut microbiota associated with early-stage NAFLD in ASPP2-deficiency mice

Xie¹,

Zhang³

et al. 2022

Front. Immunol.

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BackgroundGrowing evidence indicates that lipid metabolism disorders and gut microbiota dysbiosis were related to the progression of non-alcoholic fatty liver disease (NAFLD). Apoptosis-stimulating p53 protein 2 (ASPP2) has been reported to protect against hepatocyte injury by regulating the lipid metabolism, but the mechanisms remain largely unknown. In this study, we investigate the effect of ASPP2 deficiency on NAFLD, lipid metabolism and gut microbiota using ASPP2 globally heterozygous knockout (ASPP2+/-) mice.MethodsASPP2+/- Balb/c mice were fed with methionine and choline deficient diet for 3, 10 and 40 day to induce an early and later-stage of NAFLD, respectively. Fresh fecal samples were collected and followed by 16S rRNA sequencing. HPLC-MRM relative quantification analysis was used to identify changes in hepatic lipid profiles. The expression level of innate immunity-, lipid metabolism- and intestinal permeability-related genes were determined. A spearman’s rank correlation analysis was performed to identify possible correlation between hepatic medium and long-chain fatty acid and gut microbiota in ASPP2-deficiency mice.ResultsCompared with the WT control, ASPP2-deficiency mice developed moderate steatosis at day 10 and severe steatosis at day 40. The levels of hepatic long chain omega-3 fatty acid, eicosapentaenoic (EPA, 20:5 n-3) and docosahexaenoic (DHA, 22:6 n-3), were decreased at day 10 and increased at day 40 in ASPP+/- mice. Fecal microbiota analysis showed significantly increased alpha and beta diversity, as well as the composition of gut microbiota at the phylum, class, order, family, genus, species levels in ASPP2+/- mice. Moreover, ASPP-deficiency mice exhibited impaired intestinal barrier function, reduced expression of genes associated with chemical barrier (REG3B, REG3G, Lysozyme and IAP), and increased expression of innate immune components (TLR4 and TLR2). Furthermore, correlation analysis between gut microbiota and fatty acids revealed that EPA was significantly negatively correlated with Bifidobacterium family.ConclusionOur findings suggested that ASPP2-deficiency promotes the progression of NAFLD, alterations in fatty acid metabolism and gut microbiota dysbiosis. The long chain fatty acid EPA was significantly negatively correlated with Bifidobacterial abundance, which is a specific feature of NAFLD in ASPP2-deficiency mice. Totally, the results provide evidence for a mechanism of ASPP2 on dysregulation of fatty acid metabolism and gut microbiota dysbiosis.

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ASPP2 Coordinates ERS-Mediated Autophagy and Apoptosis Through mTORC1 Pathway in Hepatocyte Injury Induced by TNF-α

Cited by 9 publications

References 22 publications

ASPP2 deficiency attenuates lipid accumulation through the PPARγ pathway in alcoholic liver injury

ASPP2 deficiency attenuates lipid accumulation through the PPARγ pathway in alcoholic liver injury

A novel approach combining network pharmacology and experimental validation to study the protective effect of ginsenoside Rb1 against cantharidin‐induced hepatotoxicity in mice

Dysregulated hepatic lipid metabolism and gut microbiota associated with early-stage NAFLD in ASPP2-deficiency mice

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