Transcriptional Regulation of Hepatic Autophagy by Nuclear Receptors

Kim, Eun Young; Lee, Jae Man

doi:10.3390/cells11040620

Cited by 11 publications

(7 citation statements)

References 220 publications

(248 reference statements)

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“…The autophagosomes engulf the nucleus and then fuse with lysosomes, which contain hydrolytic enzymes that break down the contents of the autophagosomes [ 18 ]. Autophagy shows involvement in various cellular processes, such as the DNA damage response, cellular senescence, and cellular metabolism regulation [ 19 , 20 , 21 , 22 ]. Additionally, it implicates in the onset of several diseases, including cancer [ 23 ] and neurodegenerative disorders [ 24 , 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

The Absence of Gasdermin D Reduces Nuclear Autophagy in a Cecal Ligation and Puncture-Induced Sepsis-Associated Encephalopathy Mouse Model

Xie

Bai

et al. 2023

Brain Sciences

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Sepsis-associated encephalopathy (SAE) is a common complication of sepsis, which is a life-threatening condition resulting from a dysregulated host response to infection. Pyroptosis, a pro-inflammatory mode of lytic cell death mediated by GSDMD (Gasdermin D), is involved in the pathogenesis of SAE. While autophagy has been extensively studied in SAE, the role of nuclear autophagy is not yet well understood. In this study, we aimed to investigate the involvement of pyroptosis and neural nuclear autophagy in the pathogenesis of SAE. We analyzed a CLP (cecal ligation and puncture)-induced SAE model in wild-type and GSDMD−/− mice to gain insights into the underlying mechanisms. Here, we show that in sepsis, neural nuclear autophagy is extremely activated, and nuclear LaminB decreases and is accompanied by an increase in the ratio of LC3BII/I. These effects can be reversed in GSDMD−/− mice. The behavioral outcomes of septic wild-type mice are impaired by the evidence from the novel object recognition test (NORT) and open field test (OFT), but are improved in septic GSDMD−/− mice. In conclusion, our study demonstrates the activation of neural nuclear autophagy in SAE. The absence of GSDMD inhibits nuclear autophagy and improves the behavioral outcomes of SAE.

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Section: Introductionmentioning

confidence: 99%

The Absence of Gasdermin D Reduces Nuclear Autophagy in a Cecal Ligation and Puncture-Induced Sepsis-Associated Encephalopathy Mouse Model

Xie

Bai

et al. 2023

Brain Sciences

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“…In addition, PXR may be a promising target for the prevention and treatment of liver disease based on its transcriptional regulation in inflammation, liver injury, and maintenance of homeostasis. PXR has also been shown to regulate liver autophagy and apoptosis pathways, thus having hepatoprotective effects in various liver injuries ( 44 , 45 ). PXR-null mice were reported to have more severe liver damage and suppressed autophagy flow in mice ( 46 ).…”

Section: Discussionmentioning

confidence: 99%

Role of nuclear pregnane X receptor in Cu-induced lipid metabolism and xenobiotic responses in largemouth bass (Micropterus salmoides)

Gong

Wang

et al. 2022

Front. Endocrinol.

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The pregnane X receptor (PXR) is a master xenobiotic-sensing receptor in response to toxic byproducts, as well as a key regulator in intermediary lipid metabolism. Therefore, the present study was conducted to investigate the potential role of PXR in mediating the lipid dysregulation and xenobiotic responses under Cu-induced stress in largemouth bass (Micropterus salmoides). Four groups of largemouth bass (52.66 ± 0.03 g) were treated with control, Cu waterborne (9.44 μmol/L), Cu+RIF (Rifampicin, 100 mg/kg, PXR activator), and Cu+KET (Ketoconazole, 20 mg/kg, PXR inhibitor) for 48 h. Results showed that Cu exposure significantly elevated the plasma stress indicators and triggered antioxidant systems to counteract Cu-induced oxidative stress. Acute Cu exposure caused liver steatosis, as indicated by the significantly higher levels of plasma triglycerides (TG), lipid droplets, and mRNA levels of lipogenesis genes in the liver. Liver injuries were detected, as shown by hepatocyte vacuolization and severe apoptotic signals after Cu exposure. Importantly, Cu exposure significantly stimulated mRNA levels of PXR, suggesting the response of this regulator in the xenobiotic response. The pharmacological intervention of PXR by the agonist and antagonist significantly altered hepatic mRNA levels of PXR, implying that RIF and KET were effective agents of PXR in largemouth bass. Administration of RIF significantly exacerbated liver steatosis, and such alterations were dependent on the regulations on pparγ and cd36 rather than srebp1 signaling, which suggested that PXR-PPARγ might be another pathway for Cu-induced lipid deposition in fish. Whereas, KET administration showed reverse effects on lipid metabolism as indicated by the lower hepatic TG levels, suppressed mRNA levels of pparγ and cd36. Activation of PXR stimulated autophagy and inhibited apoptosis, leading to lower hepatic vacuolization; while inhibition of PXR showed higher apoptotic signals, inhibition of autophagic genes and stimulation of apoptotic genes. Taken together, PXR played a cytoprotective role in Cu-induced hepatotoxicity through regulations on autophagy and apoptosis. Overall, our data has demonstrated for the first time on the dual roles of PXR as a co-regulator in mediating xenobiotic responses and lipid metabolism in fish, which implying the potential of PXR as a therapy target for xenobiotics-induced lipid dysregulation and hepatotoxicity.

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“…This regulation influences various cellular processes, including endocytosis, lysosomal function, exocytosis, autophagy, and phagocytosis. 54 Research on nanoparticle drug delivery has shown that when nanocarriers enter cells through the endocytic pathway, they are transported to lysosomes as endosomes become more acidic and mature. As a result, the drugs enclosed within the nanocarriers are vulnerable to degradation by digestive enzymes.…”

Section: Cluster Analysis Of Protein Expression Patternsmentioning

confidence: 99%

Molecular Mechanisms of Iron Transport and Homeostasis Regulated by Antarctic Krill-Derived Heptapeptide–Iron Complex

Hu,

Lin,

et al. 2024

J. Agric. Food Chem.

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In this study, the molecular mechanisms of iron transport and homeostasis regulated by the Antarctic krill-derived heptapeptide−iron (LVDDHFL−iron) complex were explored. LVDDHFL−iron significantly increased the hemoglobin, serum iron, total iron binding capacity levels, and iron contents in the liver and spleen to normal levels, regulated the gene expressions of iron homeostasis, and enhanced in vivo antioxidant capacity in iron-deficiency anemia mice (P < 0.05). The results revealed that iron ions within LVDDHFL−iron can be transported via the heme transporter and divalent metal transporter-1, and the absorption of LVDDHFL−iron involved receptor-mediated endocytosis. We also found that the transport of LVDDHFL−iron across cells via phagocytosis was facilitated by the up-regulation of the high mobility group protein, heat shock protein β, and V-type proton ATPase subunit, accompanied by the regulatory mechanism of autophagy. These findings provided deeper understandings of the mechanism of LVDDHFL−iron facilitating iron absorption.

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Transcriptional Regulation of Hepatic Autophagy by Nuclear Receptors

Cited by 11 publications

References 220 publications

The Absence of Gasdermin D Reduces Nuclear Autophagy in a Cecal Ligation and Puncture-Induced Sepsis-Associated Encephalopathy Mouse Model

The Absence of Gasdermin D Reduces Nuclear Autophagy in a Cecal Ligation and Puncture-Induced Sepsis-Associated Encephalopathy Mouse Model

Role of nuclear pregnane X receptor in Cu-induced lipid metabolism and xenobiotic responses in largemouth bass (Micropterus salmoides)

Molecular Mechanisms of Iron Transport and Homeostasis Regulated by Antarctic Krill-Derived Heptapeptide–Iron Complex

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