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Cao P, Jaeschke H, Ni HM, Ding WX. The Ways to Die: Cell Death in Liver Pathophysiology. Semin Liver Dis 2025. [PMID: 40199509 DOI: 10.1055/a-2576-4332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/10/2025]
Abstract
Liver diseases are closely associated with various cell death mechanisms, including apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis. Each process contributes uniquely to the pathophysiology of liver injury and repair. Importantly, these mechanisms are not limited to hepatocytes; they also significantly involve nonparenchymal cells. This review examines the molecular pathways and regulatory mechanisms underlying these forms of cell death in hepatocytes, emphasizing their roles in several liver diseases, such as ischemia-reperfusion injury, metabolic dysfunction-associated steatotic liver disease, drug-induced liver injury, and alcohol-associated liver disease. Recent insights into ferroptosis and pyroptosis may reveal novel therapeutic targets for managing liver diseases. This review aims to provide a comprehensive overview of these cell death mechanisms in the context of liver diseases, detailing their molecular signaling pathways and implications for potential treatment strategies.
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Affiliation(s)
- Peng Cao
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Hong-Min Ni
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
- Division of Gastroenterology, Hepatology and Mobility, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas
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2
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Ma X, Wei X, Niu M, Zhang C, Peng Z, Liu W, Yan J, Su X, Lu S, Cui W, Sesaki H, Zong WX, Ni HM, Ding WX. Disruption of Mitochondrial Dynamics and Stasis Leads to Liver Injury and Tumorigenesis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.11.637688. [PMID: 39990472 PMCID: PMC11844448 DOI: 10.1101/2025.02.11.637688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/25/2025]
Abstract
Background & Aims Mitochondrial dysfunction has been implicated in aging and various cancer development. As highly dynamic organelles, mitochondria constantly undergo fission, mediated by dynamin-related protein 1 (DRP1, gene name Dnm1l ), and fusion, regulated by mitofusin 1 (MFN1), MFN2, and optic atrophy 1 (OPA1). However, whether and how dysregulation of mitochondria dynamics would be involved in liver pathogenesis and tumorigenesis is unknown. Methods Dnm1l Flox/Flox ( Dnm1l F/F ), Mfn1 F/F and Mfn2 F/F mice were crossed with albumin-Cre mice to generate liver-specific Dnm1l knockout (L- Dnm1l KO), L- Mfn1 KO, L- Mfn2 KO, L- Mfn1, Mfn2 double KO (DKO), and L- Mfn1, Mfn2, Dnm1l triple KO (TKO) mice. These mice were housed for various periods up to 18 months. Some mice also received hydrodynamic tail vein injections of a Sleeping Beauty transposon-transposase plasmid system with c-MYC and YAP . Blood and liver tissues were harvested for biochemical and histological analysis. Results L- Dnm1l KO mice had elevated serum alanine aminotransferase levels and increased hepatic fibrosis as early as two months of age. By 12 to 18 months, male L- Dnm1l KO mice developed spontaneous liver tumors, primarily hepatocellular adenomas. While female L- Dnm1l KO mice also developed liver tumors, their incidence was much lower. In contrast, neither L- Mfn1 KO nor L- Mfn2 KO mice had notable liver injury or tumorigenesis. However, a small portion of DKO mice developed tumors at 15-18 month-old. Increased DNA damage, senescence and compensatory proliferation were observed in L- Dnm1l KO mice but were less evident in L- Mfn1 KO, L- Mfn2 KO or DKO mice, indicating that mitochondrial fission is more important to maintain hepatocyte homeostasis and prevent liver tumorigenesis. Interestingly, further deletion of Mfn1 and Mfn2 in L- Dnm1l KO mice markedly abolished liver injury, fibrosis, and both spontaneous and oncogene-induced tumorigenesis. RNA sequencing and metabolomics analysis revealed significant activation of the cGAS-STING-interferon pathway and alterations in the tumor microenvironment pathways, alongside increased pyrimidine synthesis and metabolism in the livers of L- Dnm1l KO mice. Notably, the changes in gene expression and pyrimidine metabolism were considerably corrected in the TKO mice. Conclusions Mitochondrial dynamics and stability are essential for maintaining hepatic mitochondrial homeostasis and hepatocyte functions. Loss of hepatic DRP1 promotes liver tumorigenesis by increasing pyrimidine metabolism and activating the cGAS-STING-mediated innate immune response.
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Cai H, Meng Z, Yu F. The involvement of ROS-regulated programmed cell death in hepatocellular carcinoma. Crit Rev Oncol Hematol 2024; 197:104361. [PMID: 38626849 DOI: 10.1016/j.critrevonc.2024.104361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 03/11/2024] [Accepted: 04/10/2024] [Indexed: 04/21/2024] Open
Abstract
Reactive oxidative species (ROS) is a crucial factor in the regulation of cellular biological activity and function, and aberrant levels of ROS can contribute to the development of a variety of diseases, particularly cancer. Numerous discoveries have affirmed that this process is strongly associated with "programmed cell death (PCD)," which refers to the suicide protection mechanism initiated by cells in response to external stimuli, such as apoptosis, autophagy, ferroptosis, etc. Research has demonstrated that ROS-induced PCD is crucial for the development of hepatocellular carcinoma (HCC). These activities serve a dual function in both facilitating and inhibiting cancer, suggesting the existence of a delicate balance within healthy cells that can be disrupted by the abnormal generation of reactive oxygen species (ROS), thereby influencing the eventual advancement or regression of a tumor. In this review, we summarize how ROS regulates PCD to influence the tumorigenesis and progression of HCC. Studying how ROS-induced PCD affects the progression of HCC at a molecular level can help develop better prevention and treatment methods and facilitate the design of more effective preventative and therapeutic strategies.
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Affiliation(s)
- Hanchen Cai
- The First Afliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, China
| | - Ziqi Meng
- The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, China; The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, China
| | - Fujun Yu
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, China.
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Wang X, Zhang W, Zeng S, Wang L, Wang B. Collagenase Type I and Probucol-Loaded Nanoparticles Penetrate the Extracellular Matrix to Target Hepatic Stellate Cells for Hepatic Fibrosis Therapy. Acta Biomater 2024; 175:262-278. [PMID: 38141933 DOI: 10.1016/j.actbio.2023.12.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Revised: 12/12/2023] [Accepted: 12/15/2023] [Indexed: 12/25/2023]
Abstract
Hepatic fibrosis is a common pathological process in chronic liver diseases, characterized by excessive reactive oxygen species (ROS), activated hepatic stellate cells (HSCs), and massive synthesis of extracellular matrix (ECM), which are important factors in the development of liver cirrhosis, liver failure, and liver cancer. During the development of hepatic fibrosis, ECM collagen produced by activated HSCs significantly hinders medication delivery to targeted cells and reduces the efficiency of pharmacological therapy. In this study, we designed a multifunctional hyaluronic acid polymeric nanoparticle (HA@PRB/COL NPs) based on autophagy inhibitor probucol (PRB) and collagenase type I (COL) modification, which could enhance ECM degradation and accurately target HSCs through specificity binding CD44 receptor in hepatic fibrosis therapy. Upon encountering excessive collagen I-deposition formed barrier, HA@PRB/COL NPs performed the nanodrill-like function to effectively degrade pericellular collagen I, leading to greater ECM penetration and prominent HSCs internalization capacity of delivered PRB. In mouse hepatic fibrosis model, HA@PRB/COL NPs were efficiently delivered to HSCs through binding CD44 receptor to achieve efficient accumulation in fibrotic liver. Further, we showed that HA@PRB/COL NPs executed the optimal anti-fibrotic activity by inhibiting autophagy and activation of HSCs. In conclusion, our novel dual-functional co-delivery system with degrading fibrotic ECM collagen and targeting activated HSCs exhibits great potentials in the treatment of hepatic fibrosis in clinic. STATEMENT OF SIGNIFICANCE: The excess release of extracellular matrix (ECM) such as collagen in hepatic fibrosis hinders medication delivery and decreases the efficiency of pharmacological drugs. We aimed to develop a nano-delivery carrier system with protein hydrolyzed surfaces and further encapsulated an autophagy inhibitor (PRB) to enhance fibrosis-related ECM degradation-penetration and hepatic stellate cells (HSCs) targeting in hepatic fibrosis niche (HA@PRB/COL NPs). The COL of HA@PRB/COL NPs successfully worked as a scavenger to promote the digestion of the ECM collagen I barrier for deeper penetration into fibroid liver tissue. It also accurately targeted HSCs through specifically binding to the CD44 receptor and subsequently released PRB to inhibit autolysosome and ROS generation, thus preventing HSCs activation. Our HA@PRB/COL NPs system provided a promising therapeutic strategy for hepatic fibrosis in a clinic setting.
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Affiliation(s)
- Xiaowei Wang
- Department of Biobank, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Wenjun Zhang
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Sheng Zeng
- Clinical Stem Cell Center, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China
| | - Liudi Wang
- Clinical Stem Cell Center, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China
| | - Bin Wang
- Clinical Stem Cell Center, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China.
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Yan H, Feng L, Li M. The Role of Traditional Chinese Medicine Natural Products in β-Amyloid Deposition and Tau Protein Hyperphosphorylation in Alzheimer's Disease. Drug Des Devel Ther 2023; 17:3295-3323. [PMID: 38024535 PMCID: PMC10655607 DOI: 10.2147/dddt.s380612] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 11/02/2023] [Indexed: 12/01/2023] Open
Abstract
Alzheimer's disease is a prevalent form of dementia among elderly individuals and is characterized by irreversible neurodegeneration. Despite extensive research, the exact causes of this complex disease remain unclear. Currently available drugs for Alzheimer's disease treatment are limited in their effectiveness, often targeting a single aspect of the disease and causing significant adverse effects. Moreover, these medications are expensive, placing a heavy burden on patients' families and society as a whole. Natural compounds and extracts offer several advantages, including the ability to target multiple pathways and exhibit high efficiency with minimal toxicity. These attributes make them promising candidates for the prevention and treatment of Alzheimer's disease. In this paper, we provide a summary of the common natural products used in Chinese medicine for different pathogeneses of AD. Our aim is to offer new insights and ideas for the further development of natural products in Chinese medicine and the treatment of AD.
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Affiliation(s)
- Huiying Yan
- Department of Neurology, the Third Affiliated Clinical Hospital of the Changchun University of Chinese Medicine, Changchun, Jilin Province, People’s Republic of China
| | - Lina Feng
- Shandong Key Laboratory of TCM Multi-Targets Intervention and Disease Control, the Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong Province, People’s Republic of China
| | - Mingquan Li
- Department of Neurology, the Third Affiliated Clinical Hospital of the Changchun University of Chinese Medicine, Changchun, Jilin Province, People’s Republic of China
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Liu S, Yao S, Yang H, Liu S, Wang Y. Autophagy: Regulator of cell death. Cell Death Dis 2023; 14:648. [PMID: 37794028 PMCID: PMC10551038 DOI: 10.1038/s41419-023-06154-8] [Citation(s) in RCA: 247] [Impact Index Per Article: 123.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 09/05/2023] [Accepted: 09/14/2023] [Indexed: 10/06/2023]
Abstract
Autophagy is the process by which cells degrade and recycle proteins and organelles to maintain intracellular homeostasis. Generally, autophagy plays a protective role in cells, but disruption of autophagy mechanisms or excessive autophagic flux usually leads to cell death. Despite recent progress in the study of the regulation and underlying molecular mechanisms of autophagy, numerous questions remain to be answered. How does autophagy regulate cell death? What are the fine-tuned regulatory mechanisms underlying autophagy-dependent cell death (ADCD) and autophagy-mediated cell death (AMCD)? In this article, we highlight the different roles of autophagy in cell death and discuss six of the main autophagy-related cell death modalities, with a focus on the metabolic changes caused by excessive endoplasmic reticulum-phagy (ER-phagy)-induced cell death and the role of mitophagy in autophagy-mediated ferroptosis. Finally, we discuss autophagy enhancement in the treatment of diseases and offer a new perspective based on the use of autophagy for different functional conversions (including the conversion of autophagy and that of different autophagy-mediated cell death modalities) for the clinical treatment of tumors.
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Affiliation(s)
- ShiZuo Liu
- School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, China
| | - ShuaiJie Yao
- School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, China
| | - Huan Yang
- The Second School of Clinical Medicine, Xinjiang Medical University, Urumqi, China
| | - ShuaiJie Liu
- School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, China
| | - YanJiao Wang
- Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, China.
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Qian H, Ding WX. SQSTM1/p62 and Hepatic Mallory-Denk Body Formation in Alcohol-Associated Liver Disease. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1415-1426. [PMID: 36906265 PMCID: PMC10642158 DOI: 10.1016/j.ajpath.2023.02.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 02/14/2023] [Accepted: 02/24/2023] [Indexed: 03/12/2023]
Abstract
Sequestosome 1 (SQSTM1/p62; hereafter p62) is an autophagy receptor protein for selective autophagy primarily due to its direct interaction with the microtubule light chain 3 protein that specifically localizes on autophagosome membranes. As a result, impaired autophagy leads to the accumulation of p62. p62 is also a common component of many human liver disease-related cellular inclusion bodies, such as Mallory-Denk bodies, intracytoplasmic hyaline bodies, α1-antitrypsin aggregates, as well as p62 bodies and condensates. p62 also acts as an intracellular signaling hub, and it involves multiple signaling pathways, including nuclear factor erythroid 2-related factor 2, NF-κB, and the mechanistic target of rapamycin, which are critical for oxidative stress, inflammation, cell survival, metabolism, and liver tumorigenesis. This review discusses the recent insights of p62 in protein quality control, including the role of p62 in the formation and degradation of p62 stress granules and protein aggregates as well as regulation of multiple signaling pathways in the pathogenesis of alcohol-associated liver disease.
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Affiliation(s)
- Hui Qian
- Department of Pharmacology, Toxicology, and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology, and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas; Department of Internal Medicine, The University of Kansas Medical Center, Kansas City, Kansas.
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8
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Li W, Jiang Y, Yu TT, Hao W, Wang G. Lycopene improves autophagy and attenuates carbon tetrachloride-induced hepatic fibrosis in rats. Croat Med J 2023; 64:243-255. [PMID: 37654036 PMCID: PMC10509677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 07/10/2023] [Indexed: 09/02/2023] Open
Abstract
AIM To evaluate the effect of lycopene on carbon tetrachloride (CCl4)-induced hepatic fibrosis and elucidate the underlying mechanism. METHODS Male rats were randomly assigned to the control group, CCl4 group, and lycopene group. The CCl4 group was intraperitoneally injected with CCl4 twice per week for 12 weeks to induce hepatic fibrosis. The control group was intraperitoneally injected with olive oil. Lycopene was orally administered during CCl4 treatment. Body weight and liver weight were recorded. Liver function was assessed. Biomarkers of oxidative stress and inflammatory factors were measured. Histological changes and collagen expression were evaluated. The expression of TGF-β1, α-SMA, HO-1, SIRT 1, REDD1, SHP2, P62, and LC3 in the liver was determined, as well as the levels of phosphorylated NF-κB and IκB α. RESULTS Lycopene significantly reduced the liver/body weight ratio, and AST (P=0.001) and ALT levels (P=0.009). It also significantly increased CAT and SOD activities (P<0.001) and decreased MDA content (P<0.001), IL-6 (P<0.001), and TNF-α (P=0.001). Histological analysis demonstrated that lycopene improved lobular architecture and decreased collagen expression. It also decreased the expression of TGF-β1, α-SMA, P62, and SHP2, and increased the ratio of LC3 II/I, as well as Beclin 1 and REDD1 expression. In addition, it reduced NF-κB and IκB-α phosphorylation, and elevated the levels of HO-1, SIRT 1, and PGC 1α. CONCLUSION Lycopene attenuates CCl4-induced hepatic fibrosis because of its effect on autophagy by reducing oxidative stress and inflammation.
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Affiliation(s)
| | | | | | | | - Guoguang Wang
- Guoguang Wang, 22# Wenchang West Road, Wuhu, Anhui, China,
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9
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Chen X, Qin W, Wang L, Jin Y, Tu J, Yuan X. Autophagy gene Atg7 regulates the development of radiation-induced skin injury and fibrosis of skin. Skin Res Technol 2023; 29:e13337. [PMID: 37357660 PMCID: PMC10230157 DOI: 10.1111/srt.13337] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 04/17/2023] [Indexed: 06/27/2023]
Abstract
BACKGROUND Radiation-induced skin injury, which may progress to fibrosis, is a severe side effect of radiotherapy in patients with cancer. However, currently, there is a lack of preventive or curative treatments for this injury. Meanwhile, the mechanisms underlying this injury remain poorly understood. Here, we elucidated whether autophagy is essential for the development of radiation-induced skin injury and the potential molecular pathways and mechanisms involved. METHODS AND RESULTS We used the myofibroblast-specific Atg7 knockout (namely, conditional Atg7 knockout) mice irradiated with a single electron beam irradiation dose of 30 Gy. Vaseline-based 0.2% rapamycin ointment was topically applied once daily from the day of irradiation for 30 days. On day 30 post irradiation, skin tissues were harvested for further analysis. In vitro, human foreskin fibroblast cells were treated with rapamycin (100 nM) for 24 h and pretreated with 3-MA (5 mM) for 12 h. Macroscopic skin manifestations, histological changes, and fibrosis markers at the mRNA and protein expression levels were measured. Post irradiation, the myofibroblast-specific autophagy-deficient (Atg7Flox/Flox Cre+ ) mice had increased fibrosis marker (COL1A1, CTGF, TGF-β1, and α-SMA) levels in the irradiated area and had more severe macroscopic skin manifestations than the control group (Atg7Flox/Flox Cre- ) mice. Treatment with an autophagy agonist rapamycin attenuated macroscopic skin injury scores and skin fibrosis marker levels with decreased epidermal thickness and dermal collagen deposition in Atg7Flox/Flox Cre+ mice compared with the vehicle control. Moreover, in vitro experiment results were consistent with the in vivo results. Together with studies at the molecular level, we found that these changes involved the Akt/mTOR pathway. In addition, this phenomenon might also relate to Nrf2-autophagy signaling pathway under oxidative stress conditions. CONCLUSION In conclusion, Atg7 and autophagy-related mechanisms confer radioprotection, and reactivation of the autophagy process can be a novel therapeutic strategy to reduce and prevent the occurrence of radiodermatitis, particularly skin fibrosis, in patients with cancer.
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Affiliation(s)
- Xinyi Chen
- Department of OncologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina
| | - Wan Qin
- Department of OncologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina
| | - Lu Wang
- Department of OncologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina
| | - Yu Jin
- Department of OncologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina
| | - Jingyao Tu
- Department of OncologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina
| | - Xianglin Yuan
- Department of OncologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina
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Chen F, Sheng L, Zhou T, Yan L, Loveless R, Li H, Teng Y, Cai Y. Loss of Ufl1/Ufbp1 in hepatocytes promotes liver pathological damage and carcinogenesis through activating mTOR signaling. J Exp Clin Cancer Res 2023; 42:110. [PMID: 37131258 PMCID: PMC10155312 DOI: 10.1186/s13046-023-02681-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 04/21/2023] [Indexed: 05/04/2023] Open
Abstract
BACKGROUND Ufm1-specific ligase 1 (Ufl1) and Ufm1-binding protein 1 (Ufbp1), as putative targets of ubiquitin-fold modifier 1 (Ufm1), have been implicated in several pathogenesis-related signaling pathways. However, little is known about their functional roles in liver disease. METHODS Hepatocyte-specific Ufl1Δ/Δhep and Ufbp1Δ/Δhep mice were used to study their role in liver injury. Fatty liver disease and liver cancer were induced by high-fat diet (HFD) and diethylnitrosamine (DEN) administration, respectively. iTRAQ analysis was employed to screen for downstream targets affected by Ufbp1 deletion. Co-immunoprecipitation was used to determine the interactions between the Ufl1/Ufbp1 complex and the mTOR/GβL complex. RESULTS Ufl1Δ/Δhep or Ufbp1Δ/Δhep mice exhibited hepatocyte apoptosis and mild steatosis at 2 months of age and hepatocellular ballooning, extensive fibrosis, and steatohepatitis at 6-8 months of age. More than 50% of Ufl1Δ/Δhep and Ufbp1Δ/Δhep mice developed spontaneous hepatocellular carcinoma (HCC) by 14 months of age. Moreover, Ufl1Δ/Δhep and Ufbp1Δ/Δhep mice were more susceptible to HFD-induced fatty liver and DEN-induced HCC. Mechanistically, the Ufl1/Ufbp1 complex directly interacts with the mTOR/GβL complex and attenuates mTORC1 activity. Ablation of Ufl1 or Ufbp1 in hepatocytes dissociates them from the mTOR/GβL complex and activates oncogenic mTOR signaling to drive HCC development. CONCLUSIONS These findings reveal the potential role of Ufl1 and Ufbp1 as gatekeepers to prevent liver fibrosis and subsequent steatohepatitis and HCC development by inhibiting the mTOR pathway.
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Affiliation(s)
- Fanghui Chen
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Le Sheng
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Tianci Zhou
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Li Yan
- Department of Radiation Oncology, Linyi People Hospital, Linyi, 276000, China
| | - Reid Loveless
- Department of Oral Biology and Diagnostic Sciences, Georgia Cancer Center, Augusta University, Augusta, GA, 30912, USA
| | - Honglin Li
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Yong Teng
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, 30322, USA.
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA, 30322, USA.
| | - Yafei Cai
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
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Kouroumalis E, Tsomidis I, Voumvouraki A. Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy. Biomedicines 2023; 11:1166. [PMID: 37189787 PMCID: PMC10135776 DOI: 10.3390/biomedicines11041166] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 04/09/2023] [Accepted: 04/12/2023] [Indexed: 05/17/2023] Open
Abstract
The pathogenesis of hepatocellular carcinoma (HCC) is a multifactorial process that has not yet been fully investigated. Autophagy and apoptosis are two important cellular pathways that are critical for cell survival or death. The balance between apoptosis and autophagy regulates liver cell turnover and maintains intracellular homeostasis. However, the balance is often dysregulated in many cancers, including HCC. Autophagy and apoptosis pathways may be either independent or parallel or one may influence the other. Autophagy may either inhibit or promote apoptosis, thus regulating the fate of the liver cancer cells. In this review, a concise overview of the pathogenesis of HCC is presented, with emphasis on new developments, including the role of endoplasmic reticulum stress, the implication of microRNAs and the role of gut microbiota. The characteristics of HCC associated with a specific liver disease are also described and a brief description of autophagy and apoptosis is provided. The role of autophagy and apoptosis in the initiation, progress and metastatic potential is reviewed and the experimental evidence indicating an interplay between the two is extensively analyzed. The role of ferroptosis, a recently described specific pathway of regulated cell death, is presented. Finally, the potential therapeutic implications of autophagy and apoptosis in drug resistance are examined.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, PAGNI University Hospital, University of Crete School of Medicine, 71500 Heraklion, Crete, Greece
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
| | - Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Central Macedonia, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Central Macedonia, Greece
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12
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Bai Y, Liu T, Cui YH, Li ZZ, Zhou XF, Cheng Y, Wang JH, Guo JR. Autologous blood transfusion promotes autophagy and inhibits hepatocellular carcinoma progression through HIF-1α signalling pathway. J Cell Mol Med 2023; 27:1353-1361. [PMID: 37038623 PMCID: PMC10183710 DOI: 10.1111/jcmm.17736] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 03/14/2023] [Accepted: 03/22/2023] [Indexed: 04/12/2023] Open
Abstract
To explore the molecular mechanism of autologous blood transfusion promoting autophagy of hepatocellular carcinoma (HCC) cells and inhibiting the HCC progression through HIF-1α signalling pathway. This is a research paper. Rat hepatocellular carcinoma model and HepG2 cell model were built. The rats with HCC were conducted a surgery, and their blood was collected for detection to detect the recurrence and metastasis of the rats. Western blot was used to analysed the expression of HIF-1α, TP53, MDM2, ATG5 and ATG14 protein. The apoptosis rate of HepG2 cells was detected by flow cytometry, and autophagosomes were observed by transmission electron microscopy. HIF-1α expression was measured by immunofluorescence assay. The expressions of HIF-1α, TP53, MDM2, ATG5 and ATG14 protein were highest in model + autoblood group compared with the model group. HIF-1α content of model group was higher, but content of TP53, MDM2, ATG5 and ATG14 in the model group is the second. The highest apoptosis rate was found in HepG2 + autoblood group. The number of autophagosomes in HepG2 + autoblood was obviously larger than that of HepG2 + autoblood + inhibitor. HIF-1α expression of immunofluorescence assay showed that high expression of HIF-1α was clearly observed in HepG2 and HepG2 + autoblood group from confocal observation. However, there was no HIF-1α protein expression in HepG2 + autoblood + inhibitor group. The migration rate in HepG2 group, HepG2 + autoblood group and HepG2 + autoblood + inhibitor group was 85.71 ± 7.38%, 14.36 ± 6.54% and 61.25 ± 5.39%, respectively. Autologous blood transfusion promotes autophagy of HCC cells through HIF-1α signalling pathway, which further inhibits HCC migration and erosion.
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Affiliation(s)
- Yu Bai
- Graduate School of Wannan Medical College, Wuhu, Anhui, China
- Department of Anesthesiology, Shanghai Gongli Hospital, Naval Military Medical University, Shanghai, China
| | - Tong Liu
- Graduate School of Wannan Medical College, Wuhu, Anhui, China
- Department of Anesthesiology, Shanghai Gongli Hospital, Naval Military Medical University, Shanghai, China
| | - Ying-Hui Cui
- Graduate School of Wannan Medical College, Wuhu, Anhui, China
- Department of Anesthesiology, Shanghai Gongli Hospital, Naval Military Medical University, Shanghai, China
| | - Zhen-Zhou Li
- Department of Anesthesiology, Shanghai Gongli Hospital, Naval Military Medical University, Shanghai, China
| | - Xiao-Fang Zhou
- Department of Anesthesiology, Shanghai Gongli Hospital, Naval Military Medical University, Shanghai, China
| | - Yong Cheng
- Department of Anesthesiology, Shanghai Gongli Hospital, Naval Military Medical University, Shanghai, China
| | - Jin-Huo Wang
- Department of Anesthesiology, Shanghai Gongli Hospital, Naval Military Medical University, Shanghai, China
| | - Jian-Rong Guo
- Department of Anesthesiology, Shanghai Gongli Hospital, Naval Military Medical University, Shanghai, China
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13
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Wu Y, Tan HWS, Lin JY, Shen HM, Wang H, Lu G. Molecular mechanisms of autophagy and implications in liver diseases. LIVER RESEARCH 2023; 7:56-70. [PMID: 39959698 PMCID: PMC11792062 DOI: 10.1016/j.livres.2023.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 11/03/2022] [Accepted: 02/15/2023] [Indexed: 02/22/2023]
Abstract
Autophagy is a highly conserved process in which cytosolic contents are degraded by the lysosome, which plays an important role in energy and nutrient balance, and protein or organelle quality control. The liver is the most important organ for metabolism. Studies to date have revealed a significant role of autophagy in the maintenance of liver homeostasis under basal and stressed conditions, and the impairment of autophagy has been closely linked to various liver diseases. Therefore, a comprehensive understanding of the roles of autophagy in liver diseases may help in the development of therapeutic strategies via targeting autophagy. In this review, we will summarize the latest understanding of the molecular mechanisms of autophagy and systematically discuss its implications in various liver diseases, including alcohol-related liver disease, non-alcoholic fatty liver disease, viral hepatitis, hepatocellular carcinoma, and acetaminophen-induced liver injury.
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Affiliation(s)
- Yuankai Wu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hayden Weng Siong Tan
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Jin-Yi Lin
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Han-Ming Shen
- Department of Biomedical Sciences, Faculty of Health Sciences, Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Macau, China
| | - Haihe Wang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Guang Lu
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
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14
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He Y, Su Y, Duan C, Wang S, He W, Zhang Y, An X, He M. Emerging role of aging in the progression of NAFLD to HCC. Ageing Res Rev 2023; 84:101833. [PMID: 36565959 DOI: 10.1016/j.arr.2022.101833] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 12/10/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022]
Abstract
With the aging of global population, the incidence of nonalcoholic fatty liver disease (NAFLD) has surged in recent decades. NAFLD is a multifactorial disease that follows a progressive course, ranging from simple fatty liver, nonalcoholic steatohepatitis (NASH) to liver cirrhosis and hepatocellular carcinoma (HCC). It is well established that aging induces pathological changes in liver and potentiates the occurrence and progression of NAFLD, HCC and other age-related liver diseases. Studies of senescent cells also indicate a pivotal engagement in the development of NAFLD via diverse mechanisms. Moreover, nicotinamide adenine dinucleotide (NAD+), silence information regulator protein family (sirtuins), and mechanistic target of rapamycin (mTOR) are three vital and broadly studied targets involved in aging process and NAFLD. Nevertheless, the crucial role of these aging-associated factors in aging-related NAFLD remains underestimated. Here, we reviewed the current research on the roles of aging, cellular senescence and three aging-related factors in the evolution of NAFLD to HCC, aiming at inspiring promising therapeutic targets for aging-related NAFLD and its progression.
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Affiliation(s)
- Yongyuan He
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yinghong Su
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chengcheng Duan
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Siyuan Wang
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei He
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China; School of Basic Medicine, Kunming Medical University, China
| | - Yingting Zhang
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaofei An
- Department of Endocrinology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
| | - Ming He
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China.
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15
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Chen A, Ding WX, Ni HM. Scramblases as Regulators of Autophagy and Lipid Homeostasis: Implications for NAFLD. AUTOPHAGY REPORTS 2022; 1:143-160. [PMID: 35509327 PMCID: PMC9066413 DOI: 10.1080/27694127.2022.2055724] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Equilibration of phospholipids between the two monolayers of the lipid bilayer of cellular membranes is mediated by scramblases acting as phospholipid shuttling proteins that are critical for cellular function, particularly during inter-organelle contact. Recent work has identified several protein scramblases, including TMEM41B, VMP1 and ATG9 that are critical in autophagy. More recently, ATG9, TMEM41B, and VMP1 have also been discovered to be important regulators of cellular lipid homeostasis. In vivo mouse models involving ablation of TMEM41B in liver have shown that knockout of these proteins can lead to rapid development of non-alcoholic steatohepatitis (NASH) and systemic dyslipidemia, though this has not been explored yet with ATG9. The resulting phenotype is likely due to the combined effects of a severe lipid secretion defect caused by stalled neutral lipids export from the endoplasmic reticulum (ER) membrane bilayer coupled with increased lipogenesis. Here we briefly discuss recent exciting findings on the topic of scramblases in autophagy, their relevance to human non-alcoholic fatty liver disease (NAFLD)/NASH, as well as future directions in this research.
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Affiliation(s)
- Allen Chen
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, USA
- Department of Internal Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Hong-Min Ni
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, USA
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16
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Wu X, Liu XQ, Liu ZN, Xia GQ, Zhu H, Zhang MD, Wu BM, Lv XW. CD73 aggravates alcohol-related liver fibrosis by promoting autophagy mediated activation of hepatic stellate cells through AMPK/AKT/mTOR signaling pathway. Int Immunopharmacol 2022; 113:109229. [DOI: 10.1016/j.intimp.2022.109229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/30/2022] [Accepted: 09/01/2022] [Indexed: 11/05/2022]
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17
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Chao X, Williams SN, Ding WX. Role of mechanistic target of rapamycin in autophagy and alcohol-associated liver disease. Am J Physiol Cell Physiol 2022; 323:C1100-C1111. [PMID: 36062877 PMCID: PMC9550572 DOI: 10.1152/ajpcell.00281.2022] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/26/2022] [Accepted: 08/26/2022] [Indexed: 11/22/2022]
Abstract
Mechanistic target of rapamycin (mTOR) is a serine-threonine kinase and a cellular sensor for nutrient and energy status, which is critical in regulating cell metabolism and growth by governing the anabolic (protein and lipid synthesis) and catabolic process (autophagy). Alcohol-associated liver disease (ALD) is a major chronic liver disease worldwide that carries a huge financial burden. The spectrum of the pathogenesis of ALD includes steatosis, fibrosis, inflammation, ductular reaction, and eventual hepatocellular carcinoma, which is closely associated with metabolic changes that are regulated by mTOR. In this review, we summarized recent progress of alcohol consumption on the changes of mTORC1 and mTORC2 activity, the potential mechanisms and possible impact of the mTORC1 changes on autophagy in ALD. We also discussed the potential beneficial effects and limitations of targeting mTORC1 against ALD.
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Affiliation(s)
- Xiaojuan Chao
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas
| | - Sha Neisha Williams
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas
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18
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Morishita H, Komatsu M. Role of autophagy in liver diseases. CURRENT OPINION IN PHYSIOLOGY 2022. [DOI: 10.1016/j.cophys.2022.100594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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19
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Wang S, Chao X, Jiang X, Wang T, Rodriguez Y, Yang L, Pacher P, Ni HM, Ding WX. Loss of acinar cell VMP1 triggers spontaneous pancreatitis in mice. Autophagy 2022; 18:1572-1582. [PMID: 34709991 PMCID: PMC9298442 DOI: 10.1080/15548627.2021.1990672] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 09/30/2021] [Accepted: 10/04/2021] [Indexed: 12/19/2022] Open
Abstract
The pathogenesis of pancreatitis has been linked to disruption of organelle homeostasis including macroautophagy/autophagy dysfunction and endoplasmic reticulum (ER) stress. However, the direct impact of aberrant organelle function on pancreatitis initiation and progression is largely unknown. Recently an ER membrane protein, VMP1 (vacuole membrane protein 1), has been reported to play a crucial role in autophagosome formation. Notably, we found that VMP1 is downregulated in both human chronic pancreatitis (CP) and experimental mouse acute pancreatitis (AP). Pancreatic acinar cell-specific vmp1 deletion promotes inflammation, acinar-to-ductal metaplasia, and fibrosis in mice, sharing histological similarities with human CP. Mechanistically, loss of pancreatic VMP1 leads to defective autophagic degradation and ER stress as well as activation of the NFE2L2/Nrf2 pathway. Genetic ablation of NFE2L2 attenuated pancreatitis in VMP1-deficient mice. Our data highlight the importance of VMP1 in modulating an integrated organelle stress response and its functional role in maintaining pancreas homeostasis in the context of CP.Abbreviations: AMY: amylase; ADM: acinar-to-ductal metaplasia; AP: acute pancreatitis; CASP3: caspase 3; CP: chronic pancreatitis; DDIT3/CHOP: DNA damage inducible transcript 3; DKO, double knockout; ER: endoplasmic reticulum; GCLC: glutamate-cysteine ligase catalytic subunit; GCLM: glutamate-cysteine ligase modifier subunit; HSPA5/BIP: heat shock protein family A (Hsp70) member 5; KO: knockout; KRT19/CK19: keratin 19; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MPO: myeloperoxidase; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; ND: normal donor; NQO1: NAD(P)H quinone dehydrogenase 1; PCNA: proliferating cell nuclear antigen; RIPA: radio-immunoprecipitation; SQSTM1/p62: sequestosome 1; SOX9: SRY-box transcription factor 9; TAP: trypsinogen activation peptide; TFEB: transcription factor EB; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; UB: ubiquitin; VMP1: vacuole membrane protein 1; XBP1: X-box binding protein 1; YAP1, Yes1 associated transcriptional regulator; ZG: zymogen granule.
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Affiliation(s)
- Shaogui Wang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
- International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Xiaojuan Chao
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Xiaoxiao Jiang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Tiantian Wang
- International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Yssa Rodriguez
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Ling Yang
- Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Hong-Min Ni
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
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20
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Ma X, Williams SN, Ding WX. Linking of Senescence to Autophagy Deficiency in Chronic Liver Disease. Cell Mol Gastroenterol Hepatol 2022; 14:405-406. [PMID: 35605640 PMCID: PMC9304967 DOI: 10.1016/j.jcmgh.2022.04.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 04/18/2022] [Accepted: 04/26/2022] [Indexed: 12/10/2022]
Affiliation(s)
| | | | - Wen-Xing Ding
- Correspondence Address correspondence to: Wen-Xing Ding, PhD, Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, MS 1018, 3901 Rainbow Boulevard, Kansas City, Kansas 66160.
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21
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Yang C, Su C, Iyaswamy A, Krishnamoorthi SK, Zhu Z, Yang S, Tong BC, Liu J, Sreenivasmurthy SG, Guan X, Kan Y, Wu AJ, Huang AS, Tan J, Cheung K, Song J, Li M. Celastrol enhances transcription factor EB (TFEB)-mediated autophagy and mitigates Tau pathology: Implications for Alzheimer’s disease therapy. Acta Pharm Sin B 2022; 12:1707-1722. [PMID: 35847498 PMCID: PMC9279716 DOI: 10.1016/j.apsb.2022.01.017] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 12/11/2021] [Accepted: 12/16/2021] [Indexed: 02/06/2023] Open
Abstract
Alzheimer's disease (AD), characterized by the accumulation of protein aggregates including phosphorylated Tau aggregates, is the most common neurodegenerative disorder with limited therapeutic agents. Autophagy plays a critical role in the degradation of phosphorylated Tau aggregates, and transcription factor EB (TFEB) is a master regulator of autophagy and lysosomal biogenesis. Thus, small-molecule autophagy enhancers targeting TFEB hold promise for AD therapy. Here, we found that celastrol, an active ingredient isolated from the root extracts of Tripterygium wilfordii (Lei Gong Teng in Chinese) enhanced TFEB-mediated autophagy and lysosomal biogenesis in vitro and in mouse brains. Importantly, celastrol reduced phosphorylated Tau aggregates and attenuated memory dysfunction and cognitive deficits in P301S Tau and 3xTg mice, two commonly used AD animal models. Mechanistical studies suggest that TFEB-mediated autophagy-lysosomal pathway is responsible for phosphorylated Tau degradation in response to celastrol. Overall, our findings indicate that Celastrol is a novel TFEB activator that promotes the degradation of phosphorylated Tau aggregates and improves memory in AD animal models. Therefore, Celastrol shows potential as a novel agent for the treatment and/or prevention of AD and other tauopathies.
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22
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Zhang H, Su X, Burley SK, Zheng XFS. mTOR regulates aerobic glycolysis through NEAT1 and nuclear paraspeckle-mediated mechanism in hepatocellular carcinoma. Theranostics 2022; 12:3518-3533. [PMID: 35547764 PMCID: PMC9065186 DOI: 10.7150/thno.72581] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 04/06/2022] [Indexed: 11/12/2022] Open
Abstract
Background: Hepatocellular Carcinoma (HCC) is a major form of liver cancer and a leading cause of cancer-related death worldwide. New insights into HCC pathobiology and mechanism of drug actions are urgently needed to improve patient outcomes. HCC undergoes metabolic reprogramming of glucose metabolism from respiration to aerobic glycolysis, a phenomenon known as the 'Warburg Effect' that supports rapid cancer cell growth, survival, and invasion. mTOR is known to promote Warburg Effect, but the underlying mechanism(s) remains poorly defined. The aim of this study is to understand the mechanism(s) and significance of mTOR regulation of aerobic glycolysis in HCC. Methods: We profiled mTORC1-dependent long non-coding RNAs (lncRNAs) by RNA-seq of HCC cells treated with rapamycin. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were used to explore the transcriptional regulation of NEAT1 by mTORC1. [U-13C]-glucose labeling and metabolomic analysis, extracellular acidification Rate (ECAR) by Seahorse XF Analyzer, and glucose uptake assay were used to investigate the role of mTOR-NEAT1-NONO signaling in the regulation of aerobic glycolysis. RNA immunoprecipitation (RIP) and NONO-binding motif scanning were performed to identify the regulatory mechanism of pre-mRNA splicing by mTOR-NEAT1. Myristoylated AKT1 (mAKT1)/NRASV12-driven HCC model developed by hydrodynamic transfection (HDT) was employed to explore the significance of mTOR-NEAT1 signaling in HCC tumorigenesis and mTOR-targeted therapy. Results: mTOR regulates lncRNA transcriptome in HCC and that NEAT1 is a major mTOR transcriptional target. Interestingly, although both NEAT1_1 and NEAT1_2 are down-regulated in HCC, only NEAT1_2 is significantly correlated with poor overall survival of HCC patients. NEAT1_2 is the organizer of nuclear paraspeckles that sequester the RNA-binding proteins NONO and SFPQ. We show that upon oncogenic activation, mTORC1 suppresses NEAT1_2 expression and paraspeckle biogenesis, liberating NONO/SFPQ, which in turn, binds to U5 within the spliceosome, stimulating mRNA splicing and expression of key glycolytic enzymes. This series of actions lead to enhanced glucose transport, aerobic glycolytic flux, lactate production, and HCC growth both in vitro and in vivo. Furthermore, the paraspeckle-mediated mechanism is important for the anticancer action of US FDA-approved drugs rapamycin/temsirolimus. Conclusions: These findings reveal a molecular mechanism by which mTOR promotes the 'Warburg Effect', which is important for the metabolism and development of HCC, and anticancer response of mTOR-targeted therapy.
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Affiliation(s)
- Hong Zhang
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA.,Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854, USA
| | - Xiaoyang Su
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA.,Department of Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 125 Paterson Street, New Brunswick, NJ 08901
| | - Stephen K Burley
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA.,RCSB Protein Data Bank and Institute for Quantitative Biomedicine, Rutgers, The State University of New Jersey, Piscataway, 174 Frelinghuysen Road, NJ 08854 USA.,Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 174 Frelinghuysen Road, Piscataway, NJ 08854 USA.,RCSB Protein Data Bank, Skaggs School of Pharmacy and Pharmaceutical Sciences and San Diego Supercomputing Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093 USA
| | - X F Steven Zheng
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA.,Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854, USA
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23
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Li Y, Cheng Y, Zhou Y, Du H, Zhang C, Zhao Z, Chen Y, Zhou Z, Mei J, Wu W, Chen M. High fat diet-induced obesity leads to depressive and anxiety-like behaviors in mice via AMPK/mTOR-mediated autophagy. Exp Neurol 2021; 348:113949. [PMID: 34902357 DOI: 10.1016/j.expneurol.2021.113949] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 12/02/2021] [Accepted: 12/07/2021] [Indexed: 12/28/2022]
Abstract
Depression is one of the most common mental illnesses in modern society. In recent years, several studies show that there are disturbances in lipid metabolism in depressed patients. High-fat diet may lead to anxiety and depression, but the mechanisms involved remain unclear. In our study, we found that 8 weeks of high-fat feeding effectively induced metabolic disorders, including obesity and hyperlipidemia in mice. Interestingly, the mice also showed depressive and anxiety-like behaviors. We further found activated microglia and astrocyte, increased neuroinflammation, decreased autophagy and BDNF levels in mice after high-fat feeding. Besides, high-fat feeding can also inhibit AMPK phosphorylation and induce mTOR phosphorylation. After treating with the mTOR inhibitor rapamycin, autophagy and BDNF levels were elevated. The number of activated microglia and astrocyte, and pro-inflammation levels were reduced. Besides, rapamycin can also reduce the body weight and serum lipid level in high fat feeding mice. Depressive and anxiety-like behaviors were also ameliorated to some extent after rapamycin treatment. In summary, these results suggest that high-fat diet-induced obesity may lead to depressive and anxiety-like behaviors in mice by inhibiting AMPK phosphorylation and promoting mTOR shift to phosphorylation to inhibit autophagy. Therefore, improving lipid metabolism or enhancing autophagy through the AMPK/mTOR pathway could be potential targets for the treatment of obesity depression.
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Affiliation(s)
- Yong Li
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
| | - Yujie Cheng
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
| | - Yuan Zhou
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
| | - Hongmei Du
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
| | - Cui Zhang
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
| | - Zhentao Zhao
- Department of Otorhinolaryngology, Head and Neck Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China
| | - Yuenan Chen
- Department of Clinical Pharmacy, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Zhongnan Zhou
- Department of Clinical Pharmacy, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Jinyu Mei
- Department of Otorhinolaryngology, Head and Neck Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China.
| | - Wenning Wu
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China.
| | - Ming Chen
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China.
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24
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Qian H, Bai Q, Yang X, Akakpo JY, Ji L, Yang L, Rülicke T, Zatloukal K, Jaeschke H, Ni HM, Ding WX. Dual roles of p62/SQSTM1 in the injury and recovery phases of acetaminophen-induced liver injury in mice. Acta Pharm Sin B 2021; 11:3791-3805. [PMID: 35024307 PMCID: PMC8727897 DOI: 10.1016/j.apsb.2021.11.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 11/05/2021] [Accepted: 11/08/2021] [Indexed: 12/15/2022] Open
Abstract
Acetaminophen (APAP) overdose can induce liver injury and is the most frequent cause of acute liver failure in the United States. We investigated the role of p62/SQSTM1 (referred to as p62) in APAP-induced liver injury (AILI) in mice. We found that the hepatic protein levels of p62 dramatically increased at 24 h after APAP treatment, which was inversely correlated with the hepatic levels of APAP-adducts. APAP also activated mTOR at 24 h, which is associated with increased cell proliferation. In contrast, p62 knockout (KO) mice showed increased hepatic levels of APAP-adducts detected by a specific antibody using Western blot analysis but decreased mTOR activation and cell proliferation with aggravated liver injury at 24 h after APAP treatment. Surprisingly, p62 KO mice recovered from AILI whereas the wild-type mice still sustained liver injury at 48 h. We found increased number of infiltrated macrophages in p62 KO mice that were accompanied with decreased hepatic von Willebrand factor (VWF) and platelet aggregation, which are associated with increased cell proliferation and improved liver injury at 48 h after APAP treatment. Our data indicate that p62 inhibits the late injury phase of AILI by increasing autophagic selective removal of APAP-adducts and mitochondria but impairs the recovery phase of AILI likely by enhancing hepatic blood coagulation.
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Key Words
- 4EBP-1, translational initiation factor 4E binding protein-1
- AILI, APAP-induced liver injury
- ALT, alanine aminotransferase
- APAP, acetaminophen
- APAP-AD, APAP-adducts
- Autophagy
- CLEC-2, C-type lectin-like receptor
- CYP2E1, cytochrome P450 2E
- Coagulation
- DILI
- GCL, glutamate cysteine ligase
- GSH, glutathione
- H&E, hematoxylin and eosin
- Hepatotoxicity
- KC, Kupffer cells
- KEAP1, Kelch-like ECH-associated protein-1
- KIR, KEAP1-interacting region
- KO, knockout
- LC3, microtubule-associated light chain 3
- Liver regeneration
- Macrophage
- NAC, N-acetylcysteine
- NAPQI, N-acetyl-p-benzoquinone imine
- NF-κB, nuclear factor-κB
- NPCs, non-parenchymal cells
- NQO1, NADPH quinone dehydrogenase 1
- NRF2, nuclear factor erythroid 2-related factor 2
- Platelet
- S6, ribosomal protein S6 kinase
- TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling
- VWF, von Willebrand factor
- WT, wild type
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Affiliation(s)
- Hui Qian
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Qingyun Bai
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- School of Chemistry and Bioengineering, Yichun University, Yichun 336000, China
| | - Xiao Yang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jephte Y. Akakpo
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Lili Ji
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Li Yang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Thomas Rülicke
- Department of Biomedical Sciences, University of Veterinary Medicine Vienna Veterinärplatz, Vienna 1210, Austria
| | - Kurt Zatloukal
- The Institute of Pathology, Medical University of Graz, Graz A-8036, Austria
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Hong-Min Ni
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
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Wang K, Chen X. Autophagic tumor-associated macrophages promote the endothelial mesenchymal transition in lung adenocarcinomas through the FUT4/p-ezrin pathway. J Thorac Dis 2021; 13:5973-5985. [PMID: 34795945 PMCID: PMC8575842 DOI: 10.21037/jtd-21-1519] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 10/16/2021] [Indexed: 12/24/2022]
Abstract
Background Lung adenocarcinoma is one of the most common malignant tumors with high morbidity and mortality, but the effect of Tumor-associated macrophages (TAMs) on lung adenocarcinoma has not been studied clearly now. Methods In this study, TAMs were stably transfected with Atg5 silence or overexpression lentiviral vectors to inhibit or induce autophagy of TAMs. In addition, the expression of fucosyltransferase IV (FUT4) or Ezrin were interfered in TAMs with autophagy. The above treated TAMs were then co-cultured with A549 or H1299 cells. The expressions of genes were detected by qPCR, western blotting, cell immunofluorescence, and enzyme-linked immunosorbent assay. Meanwhile, cell migration and invasion were analyzed by Transwell assay and wound healing assay. Furthermore, the effects of TAMs with autophagy were explored in lung adenocarcinoma xenograft model of mice. Results The results showed that overexpression of autophagy-related gene 5 (ATG5) induced autophagy in TAMs, which increased the expression of FUT4, TGF-β1, and p-ezrin, and promoted epithelial-mesenchymal transition (EMT) in lung adenocarcinoma cells. However, FUT4 silencing partially reversed the effects of TAM autophagy, specifically, the expression of TGF-β1 and p-ezrin was inhibited and EMT in lung adenocarcinoma cells was suppressed. Notably, ezrin deletion in autophagic TAMs induced by rapamycin reduced TGF-β1 expression and suppressed EMT in lung adenocarcinoma cells. Consistently, in vivo experiments also revealed that autophagic TAMs increased the expression of FUT4, TGF-β1, and p-ezrin, and promoted EMT in lung adenocarcinomas. Similarly, FUT4 silencing partially reversed the effects of autophagic TAMs on EMT in lung adenocarcinomas. Conclusions In conclusion, autophagic TAMs promoted TGF-β1 secretion through the FUT4/p-ezrin pathway and induced EMT in co-cultured lung adenocarcinoma cells.
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Affiliation(s)
- Kangwu Wang
- Department of Thoracic Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Xiao Chen
- Department of Geriatrics, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
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Lu X, Xuan W, Li J, Yao H, Huang C, Li J. AMPK protects against alcohol-induced liver injury through UQCRC2 to up-regulate mitophagy. Autophagy 2021; 17:3622-3643. [PMID: 33719895 PMCID: PMC8632272 DOI: 10.1080/15548627.2021.1886829] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 01/22/2021] [Accepted: 02/03/2021] [Indexed: 02/06/2023] Open
Abstract
Recent reports indicated that mitophagy protects against alcohol-induced liver injury, which helps remove damaged mitochondria to reduce the accumulation of reactive oxygen species (ROS). AMP-activated protein kinase (AMPK) has been recently used in ALD (alcoholic liver disease) and mitochondrial dysfunction research. However, the inner mechanism, whether AMPK can regulate mitophagy in ALD, remains unknown. Here we found that AMPK can significantly reduce alcohol-induced liver injury and enhances hepatocytes' mitophagy level. Next, we identified that AMPK rescued alcohol-induced low expression of UQCRC2 (ubiquinol-cytochrome c reductase core protein 2). Interestingly, UQCRC2 knockdown (KD) treatment causes impaired mitophagy, whereas UQCRC2 overexpression (OE) can significantly increase mitophagy to attenuate liver injury. Also, we identified that AMPK indirectly upregulates UQCRC2 protein level, and RNA-seq, chromatin immunoprecipitation (ChIP) assay, bioinformatics, and luciferase assays helped us understand that AMPK enhanced UQCRC2 gene transcription through activating NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2). Our results demonstrate that AMPK regulating UQCRC2 is a significant mitochondrial event in mitophagy. It identifies a new signaling axis, AMPK-NFE2L2-UQCRC2, in the regulation of mitophagy levels in the liver, suggesting a possible therapeutic strategy to treat ALD.Abbreviations: AAV: AENO-associated virus; ALD: alcoholic liver disease; AMPK: AMP-activated protein kinase; BUN: blood urea nitrogen; H&E: hematoxylin and eosin; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; ChIP: chromatin immunoprecipitation assay; CO-IP: co-immunoprecipitation; COPD: chronic obstructive pulmonary disease; EM: electron microscope; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic-pyruvic transaminase; IF: immunofluorescence; IHC: immunohistochemistry; KD: knockdown; MAP1LC3/LC3: microtubule associated protein 1 light chain protein 3; MTDR: MitoTracker Deep Red; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; mtDNA: mitochondrial DNA; MTRC: MitoTracker Red CMXRos; OCR: Oxygen consumption rate; OE: overexpress; PINK1: PTEN induced kinase 1; qRT-PCR: quantitative real-time PCR; ROS: reactive oxygen species; SD: standard deviation; SOD2: superoxide dismutase 2; UQCRC2: ubiquinol-cytochrome c reductase core protein 2; WB: western blot; ΔΨ: mitochondrial membrane potential.
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Affiliation(s)
- Xinyi Lu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
| | - Wenting Xuan
- Department of Anesthesiology, Drum Tower Hospital, Medical College of Nanjing University, Nanjing, China
| | - Juanjuan Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
| | - Hongwei Yao
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
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Involvement of Autophagy in Ageing and Chronic Cholestatic Diseases. Cells 2021; 10:cells10102772. [PMID: 34685751 PMCID: PMC8534511 DOI: 10.3390/cells10102772] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/05/2021] [Accepted: 10/13/2021] [Indexed: 01/18/2023] Open
Abstract
Autophagy is a “housekeeping” lysosomal degradation process involved in numerous physiological and pathological processes in all eukaryotic cells. The dysregulation of hepatic autophagy has been described in several conditions, from obesity to diabetes and cholestatic disease. We review the role of autophagy, focusing on age-related cholestatic diseases, and discuss its therapeutic potential and the molecular targets identified to date. The accumulation of toxic BAs is the main cause of cell damage in cholestasis patients. BAs and their receptor, FXR, have been implicated in the regulation of hepatic autophagy. The mechanisms by which cholestasis induces liver damage include mitochondrial dysfunction, oxidative stress and ER stress, which lead to cell death and ultimately to liver fibrosis as a compensatory mechanism to reduce the damage. The stimulation of autophagy seems to ameliorate the liver damage. Autophagic activity decreases with age in several species, whereas its basic extends lifespan in animals, suggesting that it is one of the convergent mechanisms of several longevity pathways. No strategies aimed at inducing autophagy have yet been tested in cholestasis patients. However, its stimulation can be viewed as a novel therapeutic strategy that may reduce ageing-dependent liver deterioration and also mitigate hepatic steatosis.
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28
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Dong XC, Chowdhury K, Huang M, Kim HG. Signal Transduction and Molecular Regulation in Fatty Liver Disease. Antioxid Redox Signal 2021; 35:689-717. [PMID: 33906425 PMCID: PMC8558079 DOI: 10.1089/ars.2021.0076] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Significance: Fatty liver disease is a major liver disorder in the modern societies. Comprehensive understanding of the pathophysiology and molecular mechanisms is essential for the prevention and treatment of the disease. Recent Advances: Remarkable progress has been made in the recent years in basic and translational research in the field of fatty liver disease. Multiple signaling pathways have been implicated in the development of fatty liver disease, including AMP-activated protein kinase, mechanistic target of rapamycin kinase, endoplasmic reticulum stress, oxidative stress, inflammation, transforming growth factor β, and yes1-associated transcriptional regulator/transcriptional coactivator with PDZ-binding motif (YAP/TAZ). In addition, critical molecular regulations at the transcriptional and epigenetic levels have been linked to the pathogenesis of fatty liver disease. Critical Issues: Some critical issues remain to be solved so that research findings can be translated into clinical applications. Robust and reliable biomarkers are needed for diagnosis of different stages of the fatty liver disease. Effective and safe molecular targets remain to be identified and validated. Prevention strategies require solid scientific evidence and population-wide feasibility. Future Directions: As more data are generated with time, integrative approaches are needed to comprehensively understand the disease pathophysiology and mechanisms at multiple levels from population, organismal system, organ/tissue, to cell. The interactions between genes and environmental factors require deeper investigation for the purposes of prevention and personalized treatment of fatty liver disease. Antioxid. Redox Signal. 35, 689-717.
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Affiliation(s)
- Xiaocheng Charlie Dong
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.,Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, USA.,Department of BioHealth Informatics, School of Informatics and Computing, Indiana University Purdue University Indianapolis, Indianapolis, Indiana, USA
| | - Kushan Chowdhury
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Menghao Huang
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Hyeong Geug Kim
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
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29
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Wang F, He Q, Gao Z, Redington AN. Atg5 knockdown induces age-dependent cardiomyopathy which can be rescued by repeated remote ischemic conditioning. Basic Res Cardiol 2021; 116:47. [PMID: 34319513 PMCID: PMC8316897 DOI: 10.1007/s00395-021-00888-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 07/15/2021] [Indexed: 01/02/2023]
Abstract
Altered autophagy is implicated in several human cardiovascular diseases. Remote ischemic conditioning (RIC) is cardioprotective in multiple cardiovascular injury models and modifies autophagy signaling, but its effect in cardiomyopathy induced by gene manipulation has not been reported. To investigate the cardiac effects of chronically reduced autophagy as a result of Atg5 knockdown and assess whether RIC can rescue the phenotype. Atg5 knockdown was induced with tamoxifen for 14 days in cardiac-specific conditional Atg5 flox mice. Autophagy proteins and cardiac function were evaluated by Western blot and echocardiography, respectively. RIC was induced by cyclical hindlimb ischemia and reperfusion using a tourniquet. RIC or sham procedure was performed daily during tamoxifen induction and, in separate experiments, chronically 3 times per week for 8 weeks. Cardiac responses were assessed by end of the study. Cardiac-specific knockdown of Atg5 reduced protein levels by 70% and was associated with a significant increase in mTOR, a reduction of LC3-II and increased upstream autophagy proteins including LC3-I, P62, and Beclin. The changes in biochemical markers were associated with development of an age-related cardiomyopathy during the 17-month follow-up indicated by increased heart weight body weight ratio, progressive decline in cardiac function, and premature death. RIC increased cardiac ATG5 and rescued some of the Atg5 knockdown-induced cardiomyopathy phenotype and associated morphological remodeling. We conclude that cardiac-specific Atg5 knockdown leads to the development of age-related cardiomyopathy. RIC reverses the molecular and structural phenotype when administered both acutely and chronically.
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Affiliation(s)
- Fangfei Wang
- The Heart Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA
| | - Quan He
- The Heart Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA
| | - Zhiqian Gao
- The Heart Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA
| | - Andrew N Redington
- The Heart Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA.
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30
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Jiao L, Eickhoff R, Egners A, Jumpertz S, Roth J, Erdem M, Kroh A, Duimel H, López-Iglesias C, Caro P, Heij LR, Schmeding M, Meierhofer D, Neumann UP, Cramer T. Deletion of mTOR in liver epithelial cells enhances hepatic metastasis of colon cancer. J Pathol 2021; 255:270-284. [PMID: 34309874 DOI: 10.1002/path.5768] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 07/02/2021] [Accepted: 07/21/2021] [Indexed: 12/21/2022]
Abstract
Activation of the mechanistic target of rapamycin (mTOR) pathway is frequently found in cancer, but mTOR inhibitors have thus far failed to demonstrate significant antiproliferative efficacy in the majority of cancer types. Besides cancer cell-intrinsic resistance mechanisms, it is conceivable that mTOR inhibitors impact on non-malignant host cells in a manner that ultimately supports resistance of cancer cells. Against this background, we sought to analyze the functional consequences of mTOR inhibition in hepatocytes for the growth of metastatic colon cancer. To this end, we established liver epithelial cell (LEC)-specific knockout (KO) of mTOR (mTORLEC ) mice. We used these mice to characterize the growth of colorectal liver metastases with or without partial hepatectomy to model different clinical settings. Although the LEC-specific loss of mTOR remained without effect on metastasis growth in intact liver, partial liver resection resulted in the formation of larger metastases in mTORLEC mice compared with wildtype controls. This was accompanied by significantly enhanced inflammatory activity in LEC-specific mTOR KO livers after partial liver resection. Analysis of NF-ĸB target gene expression and immunohistochemistry of p65 displayed a significant activation of NF-ĸB in mTORLEC mice, suggesting a functional importance of this pathway for the observed inflammatory phenotype. Taken together, we show an unexpected acceleration of liver metastases upon deletion of mTOR in LECs. Our results support the notion that non-malignant host cells can contribute to resistance against mTOR inhibitors and encourage testing whether anti-inflammatory drugs are able to improve the efficacy of mTOR inhibitors for cancer therapy. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Long Jiao
- Department of General, Visceral- and Transplantation Surgery, RWTH University Hospital, Aachen, Germany
| | - Roman Eickhoff
- Department of General, Visceral- and Transplantation Surgery, RWTH University Hospital, Aachen, Germany
| | - Antje Egners
- Department of General, Visceral- and Transplantation Surgery, RWTH University Hospital, Aachen, Germany
| | - Sandra Jumpertz
- Department of General, Visceral- and Transplantation Surgery, RWTH University Hospital, Aachen, Germany
| | - Johanna Roth
- Department of General, Visceral- and Transplantation Surgery, RWTH University Hospital, Aachen, Germany
| | - Merve Erdem
- Department of General, Visceral- and Transplantation Surgery, RWTH University Hospital, Aachen, Germany
| | - Andreas Kroh
- Department of General, Visceral- and Transplantation Surgery, RWTH University Hospital, Aachen, Germany
| | - Hans Duimel
- Microscopy Core Lab, FHML and M4I Maastricht Multimodal Molecular Imaging Institute, Maastricht University, Maastricht, The Netherlands
| | - Carmen López-Iglesias
- Microscopy Core Lab, FHML and M4I Maastricht Multimodal Molecular Imaging Institute, Maastricht University, Maastricht, The Netherlands
| | - Pilar Caro
- Department of General, Visceral- and Transplantation Surgery, RWTH University Hospital, Aachen, Germany
| | - Lara R Heij
- Department of General, Visceral- and Transplantation Surgery, RWTH University Hospital, Aachen, Germany.,Pathology, RWTH University Hospital, Aachen, Germany
| | - Maximilian Schmeding
- Department of General, Visceral- and Transplantation Surgery, RWTH University Hospital, Aachen, Germany
| | | | - Ulf P Neumann
- Department of General, Visceral- and Transplantation Surgery, RWTH University Hospital, Aachen, Germany.,ESCAM - European Surgery Center Aachen Maastricht, Aachen, Germany.,ESCAM - European Surgery Center Aachen Maastricht, Maastricht, The Netherlands.,Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Thorsten Cramer
- Department of General, Visceral- and Transplantation Surgery, RWTH University Hospital, Aachen, Germany.,ESCAM - European Surgery Center Aachen Maastricht, Aachen, Germany.,NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
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Qian H, Chao X, Williams J, Fulte S, Li T, Yang L, Ding WX. Autophagy in liver diseases: A review. Mol Aspects Med 2021; 82:100973. [PMID: 34120768 DOI: 10.1016/j.mam.2021.100973] [Citation(s) in RCA: 215] [Impact Index Per Article: 53.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 05/29/2021] [Accepted: 05/30/2021] [Indexed: 02/07/2023]
Abstract
The liver is a highly dynamic metabolic organ that plays critical roles in plasma protein synthesis, gluconeogenesis and glycogen storage, cholesterol metabolism and bile acid synthesis as well as drug/xenobiotic metabolism and detoxification. Research from the past decades indicate that autophagy, the cellular catabolic process mediated by lysosomes, plays an important role in maintaining cellular and metabolic homeostasis in the liver. Hepatic autophagy fluctuates with hormonal cues and the availability of nutrients that respond to fed and fasting states as well as circadian activities. Dysfunction of autophagy in liver parenchymal and non-parenchymal cells can lead to various liver diseases including non-alcoholic fatty liver diseases, alcohol associated liver disease, drug-induced liver injury, cholestasis, viral hepatitis and hepatocellular carcinoma. Therefore, targeting autophagy may be a potential strategy for treating these various liver diseases. In this review, we will discuss the current progress on the understanding of autophagy in liver physiology. We will also discuss several forms of selective autophagy in the liver and the molecular signaling pathways in regulating autophagy of different cell types and their implications in various liver diseases.
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Affiliation(s)
- Hui Qian
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
| | - Xiaojuan Chao
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
| | - Jessica Williams
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
| | - Sam Fulte
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
| | - Tiangang Li
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Ling Yang
- Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA.
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Sun H, Ni HM, McCracken JM, Akakpo JY, Fulte S, McKeen T, Jaeschke H, Wang H, Ding WX. Liver-specific deletion of mechanistic target of rapamycin does not protect against acetaminophen-induced liver injury in mice. LIVER RESEARCH 2021; 5:79-87. [PMID: 34504721 PMCID: PMC8425470 DOI: 10.1016/j.livres.2021.03.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Acetaminophen (APAP) overdose can cause liver injury and liver failure, which is one of the most common causes of drug-induced liver injury in the United States. Pharmacological activation of autophagy by inhibiting mechanistic target of rapamycin (mTOR) protects against APAP-induced liver injury likely via autophagic removal of APAP-adducts and damaged mitochondria. In the present study, we aimed to investigate the role of genetic ablation of mTOR pathways in mouse liver in APAP-induced liver injury and liver repair/regeneration. METHODS Albumin-Cre (Alb-Cre) mice, mTORf/f and Raptorf/f mice (C57BL/6J background) were crossbred to produce liver-specific mTOR knockout (L-mTOR KO, Alb Cre+/-, mTORf/f) and liver-specific Raptor KO (L-Raptor, Alb Cre+/-, Raptor f/f) mice. Alb-Cre littermates were used as wild-type (WT) mice. These mice were treated with APAP for various time points for up to 48 h. Liver injury, cell proliferation, autophagy and mTOR activation were determined. RESULTS We found that genetic deletion of neither Raptor, an important adaptor protein in mTOR complex 1, nor mTOR, in the mouse liver significantly protected against APAP-induced liver injury despite increased hepatic autophagic flux. Genetic deletion of Raptor or mTOR in mouse livers did not affect APAP metabolism and APAP-induced c-Jun N-terminal kinase (JNK) activation, but slightly improved mouse survival likely due to increased hepatocyte proliferation. CONCLUSIONS Our results indicate that genetic ablation of mTOR in mouse livers does not protect against APAP-induced liver injury but may slightly improve liver regeneration and mouse survival after APAP overdose.
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Affiliation(s)
- Hua Sun
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS, USA,Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hong-Min Ni
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS, USA
| | - Jennifer M. McCracken
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS, USA
| | - Jephte Y Akakpo
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS, USA
| | - Sam Fulte
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS, USA
| | - Tara McKeen
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS, USA
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS, USA
| | - Hua Wang
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS, USA,Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS, USA,Corresponding author. Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS, USA. (W.-X. Ding)
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Inokuchi S, Yoshizumi T, Toshima T, Itoh S, Yugawa K, Harada N, Mori H, Fukuhara T, Matsuura Y, Mori M. Suppression of optineurin impairs the progression of hepatocellular carcinoma through regulating mitophagy. Cancer Med 2021; 10:1501-1514. [PMID: 33600074 PMCID: PMC7940236 DOI: 10.1002/cam4.3519] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 09/11/2020] [Accepted: 09/19/2020] [Indexed: 12/28/2022] Open
Abstract
Autophagy removes damaged organelles to inhibit malignant transformation during tumor initiation. Once a cancer matures, it uses the autophagic pathway as an energy source. Optineurin (OPTN) is an autophagy adaptor protein that recruits microtubule‐associated protein 1 light chain 3, an autophagosome marker, to the autophagosome. Despite studies of the relation between cancer progression and autophagy adaptor proteins, there are no reports to our knowledge of a correlation between hepatocellular carcinoma (HCC) and OPTN. We aimed here to investigate the effects of OPTN expression on HCC progression through autophagy. Immunohistochemistry was used to measure the OPTN expression in the tissues of 141 Japanese patients with HCC. The effects of OPTN expression on HCC progression and mitophagy were assessed using an OPTN knockout (KO) cell line in vitro. We used this KO cell line to establish and exploit a mouse model of HCC to determine the effects of OPTN expression on tumor progression. Immunohistochemical analysis showed that patients with elevated expression of OPTN experienced shorter overall survival (OS) and recurrence‐free survival (RFS). OPTN KO cells proliferated relatively slower versus wild‐type (WT) cells in vitro. Western blot analysis showed that mitophagy was suppressed in OPTN KO cells, and ATP synthesis and beta‐oxidation were reduced. The mouse model of HCC showed that OPTN KO cells formed smaller tumors versus WT cells less 10 weeks after implantation. Overall, the present findings suggest that OPTN is a key mediator of mitophagy that contributes to HCC progression through mitochondrial energy production.
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Affiliation(s)
- Shoichi Inokuchi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeo Toshima
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinji Itoh
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kyohei Yugawa
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Noboru Harada
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hiroyuki Mori
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Fukuoka, Japan
| | - Takasuke Fukuhara
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Fukuoka, Japan
| | - Yoshiharu Matsuura
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Fukuoka, Japan
| | - Masaki Mori
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Ahn JH, Jegal H, Choi MS, Kim S, Park SM, Ahn J, Han HY, Cho HS, Yoon S, Oh JH. TNFα enhances trovafloxacin-induced in vitro hepatotoxicity by inhibiting protective autophagy. Toxicol Lett 2021; 342:73-84. [PMID: 33609687 DOI: 10.1016/j.toxlet.2021.02.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 02/09/2021] [Accepted: 02/12/2021] [Indexed: 12/12/2022]
Abstract
Trovafloxacin (TVX) is associated with idiosyncratic drug-induced liver injury (iDILI) and inflammation-mediated hepatotoxicity. However, the inflammatory stress-regulated mechanisms in iDILI remain unclear. Herein, we elucidated the novel role of tumor-necrosis factor alpha (TNFα), an inflammatory stress factor, in TVX-induced in vitro hepatotoxicity and synergistic toxicity. TVX specifically induced synergistic toxicity in HepG2 cells with TNFα, which inhibits autophagy. TVX-treated HepG2 cells induced protective autophagy by inhibiting the expression of mTOR signaling proteins, while ATG5 knockdown in HepG2 cells, responsible for the impairment of autophagy, enhanced TVX-induced toxicity due to the increase in cytochrome C release and JNK pathway activation. Interestingly, the expression of mTOR signal proteins, which were suppressed by TVX, disrupted the negative feedback of the PI3K/AKT pathway and TNFα rebounded p70S6K phosphorylation. Co-treatment with TVX and TNFα inhibited protective autophagy by maintaining p70S6K activity, which enhanced TVX-induced cytotoxicity. Phosphorylation of p70S6K was inhibited by siRNA knockdown and rapamycin to restore TNFα-inhibited autophagy, which prevented the synergistic effect on TVX-induced cytotoxicity. These results indicate that TVX activates protective autophagy in HepG2 cells exposed to toxicity and an imbalance in negative feedback regulation of autophagy by TNFα synergistically enhanced the toxicity. The finding from this study may contribute to a better understanding of the mechanisms underlying iDILI associated with inflammatory stress.
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Affiliation(s)
- Jun-Ho Ahn
- Department of Predictive Toxicology, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea; Bio Medical Research Center, Bio Medical & Health Division, Korea Testing Laboratory (KTL), Seoul, 08389, Republic of Korea
| | - Hyun Jegal
- Department of Predictive Toxicology, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea; Department of Human and Environmental Toxicology, University of Science & Technology, Daejeon, 34113, Republic of Korea
| | - Mi-Sun Choi
- Department of Predictive Toxicology, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea
| | - Soojin Kim
- Department of Predictive Toxicology, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea
| | - Se-Myo Park
- Department of Predictive Toxicology, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea
| | - Jaehwan Ahn
- Department of Predictive Toxicology, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea
| | - Hyoung-Yun Han
- Department of Predictive Toxicology, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea
| | - Hyun-Soo Cho
- Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
| | - Seokjoo Yoon
- Department of Predictive Toxicology, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea; Department of Human and Environmental Toxicology, University of Science & Technology, Daejeon, 34113, Republic of Korea.
| | - Jung-Hwa Oh
- Department of Predictive Toxicology, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea; Department of Human and Environmental Toxicology, University of Science & Technology, Daejeon, 34113, Republic of Korea.
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35
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Kouroumalis E, Voumvouraki A, Augoustaki A, Samonakis DN. Autophagy in liver diseases. World J Hepatol 2021; 13:6-65. [PMID: 33584986 PMCID: PMC7856864 DOI: 10.4254/wjh.v13.i1.6] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 12/10/2020] [Accepted: 12/26/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is the liver cell energy recycling system regulating a variety of homeostatic mechanisms. Damaged organelles, lipids and proteins are degraded in the lysosomes and their elements are re-used by the cell. Investigations on autophagy have led to the award of two Nobel Prizes and a health of important reports. In this review we describe the fundamental functions of autophagy in the liver including new data on the regulation of autophagy. Moreover we emphasize the fact that autophagy acts like a two edge sword in many occasions with the most prominent paradigm being its involvement in the initiation and progress of hepatocellular carcinoma. We also focused to the implication of autophagy and its specialized forms of lipophagy and mitophagy in the pathogenesis of various liver diseases. We analyzed autophagy not only in well studied diseases, like alcoholic and nonalcoholic fatty liver and liver fibrosis but also in viral hepatitis, biliary diseases, autoimmune hepatitis and rare diseases including inherited metabolic diseases and also acetaminophene hepatotoxicity. We also stressed the different consequences that activation or impairment of autophagy may have in hepatocytes as opposed to Kupffer cells, sinusoidal endothelial cells or hepatic stellate cells. Finally, we analyzed the limited clinical data compared to the extensive experimental evidence and the possible future therapeutic interventions based on autophagy manipulation.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71110, Greece
| | - Argryro Voumvouraki
- 1 Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54636, Greece
| | - Aikaterini Augoustaki
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece
| | - Dimitrios N Samonakis
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece.
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36
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Gao J, Wei B, de Assuncao TM, Liu Z, Hu X, Ibrahim S, Cooper SA, Cao S, Shah VH, Kostallari E. Hepatic stellate cell autophagy inhibits extracellular vesicle release to attenuate liver fibrosis. J Hepatol 2020; 73:1144-1154. [PMID: 32389810 PMCID: PMC7572579 DOI: 10.1016/j.jhep.2020.04.044] [Citation(s) in RCA: 206] [Impact Index Per Article: 41.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 04/29/2020] [Accepted: 04/30/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Autophagy plays a crucial role in hepatic homeostasis and its deregulation has been associated with chronic liver disease. However, the effect of autophagy on the release of fibrogenic extracellular vesicles (EVs) by platelet-derived growth factor (PDGF)-stimulated hepatic stellate cells (HSCs) remains unknown. Herein, we aimed to elucidate the role of autophagy, specifically relating to fibrogenic EV release, in fibrosis. METHODS In vitro experiments were conducted in primary human and murine HSCs as well as LX2 cells. Small EVs were purified by differential ultracentrifugation. Carbon tetrachloride (CCl4) or bile duct ligation (BDL) were used to induce fibrosis in our mouse model. Liver lysates from patients with cirrhosis or healthy controls were compared by RNA sequencing. RESULTS In vitro, PDGF and its downstream molecule SHP2 (Src homology 2-containing protein tyrosine phosphatase 2) inhibited autophagy and increased HSC-derived EV release. We used this PDGF/SHP2 model to further investigate how autophagy affects fibrogenic EV release. RNA sequencing identified an mTOR (mammalian target of rapamycin) signaling molecule that was regulated by SHP2 and PDGF. Disruption of mTOR signaling abolished PDGF-dependent EV release. Activation of mTOR signaling induced the release of multivesicular body-derived exosomes (by inhibiting autophagy) and microvesicles (by activating ROCK1 signaling). These mTOR-dependent EVs promoted in vitro HSC migration. To assess the importance of this mechanism in vivo, SHP2 was selectively deleted in HSCs, which attenuated CCl4- or BDL-induced liver fibrosis. Furthermore, in the CCl4 model, mice receiving circulating EVs derived from mice with HSC-specific Shp2 deletion had less fibrosis than mice receiving EVs from control mice. Correspondingly, SHP2 was upregulated in patients with liver cirrhosis. CONCLUSION These results demonstrate that autophagy in HSCs attenuates liver fibrosis by inhibiting the release of fibrogenic EVs. LAY SUMMARY During liver fibrosis and cirrhosis, activated hepatic stellate cells (HSCs) are the key cell type responsible for fibrotic tissue deposition. Recently, we demonstrated that activated HSCs release nano-sized vesicles enriched with fibrogenic proteins. In the current study, we unveil the mechanism by which these fibrogenic vesicles are released, moving a step closer to the long-term goal of therapeutically targeting this process.
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Affiliation(s)
- Jinhang Gao
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN,Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041 China
| | - Bo Wei
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN,Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041 China
| | | | - Zhikui Liu
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Xiao Hu
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Samar Ibrahim
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Shawna A. Cooper
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN,Biochemistry and Molecular Biology Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN
| | - Sheng Cao
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Vijay H. Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States.
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37
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Szekerczés T, Gógl A, Illyés I, Mandl J, Borka K, Kiss A, Schaff Z, Lendvai G, Werling K. Autophagy, Mitophagy and MicroRNA Expression in Chronic Hepatitis C and Autoimmune Hepatitis. Pathol Oncol Res 2020; 26:2143-2151. [PMID: 32124227 PMCID: PMC7471137 DOI: 10.1007/s12253-020-00799-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 02/11/2020] [Indexed: 12/13/2022]
Abstract
Although the role of autophagy has been implicated in several forms of chronic hepatitis, it is still not fully understood. Active autophagy eliminates damaged molecules and organelles (such as mitochondria) by lysosomal degradation. In the present study, we aimed to examine and compare autophagy activity in chronic hepatitis C (CHC) and autoimmune hepatitis (AIH) by detecting the expression of autophagy (LC3 and p62) and mitochondrium-related (TOMM20) proteins, as well as the levels of selected microRNAs (miR-101, -155, -204 and - 224) known to be involved in the regulation of autophagy. In addition, the expression levels were related to pathohistological parameters. Liver biopsy samples, including 45 CHC and 18 AIH cases, were immunohistochemically stained for LC3, p62 and TOMM20 and the expression of miRNAs was determined using real-time PCR. We found elevated LC3 and p62 in AIH samples as compared with CHC ones, indicating an activated autophagy that is impaired in AIH as no degradation of p62 seemed to occur. Moreover, p62 showed strong correlation with necroinflammatory grades in the AIH group. The observed elevated levels of TOMM20 and p62 suggest a less efficient elimination of damaged mitochondria in AIH as opposed to CHC, in which autophagy seems to have a more active function. The level of miR-101 was increased in case of CHC as compared with AIH, however, miR-155, -204 and 224 resulted in no expressional. Furthermore, miR-224 level correlated with steatosis and miR-155 expression with fibrosis stage in CHC. In conclusion, dissimilar autophagic activity was observed in CHC and AIH, suggesting a close association between impaired autophagy and severity of necroinflammation. This impairment may not be regulated by the analyzed miRNAs. Nevertheless, miR-224 and - 155 seem to be associated with CHC progression.
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MESH Headings
- Adolescent
- Adult
- Aged
- Autophagy
- Biomarkers, Tumor/genetics
- Disease Progression
- Female
- Follow-Up Studies
- Gene Expression Regulation, Neoplastic
- Hepatitis C, Chronic/genetics
- Hepatitis C, Chronic/metabolism
- Hepatitis C, Chronic/pathology
- Hepatitis C, Chronic/surgery
- Hepatitis, Autoimmune/genetics
- Hepatitis, Autoimmune/metabolism
- Hepatitis, Autoimmune/pathology
- Hepatitis, Autoimmune/surgery
- Humans
- Male
- MicroRNAs/genetics
- Middle Aged
- Mitophagy
- Prognosis
- Retrospective Studies
- Survival Rate
- Young Adult
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Affiliation(s)
- Tímea Szekerczés
- 2nd Department of Pathology, Semmelweis University, Üllői 93, 1091, Budapest, Hungary
| | - Alíz Gógl
- 2nd Department of Pathology, Semmelweis University, Üllői 93, 1091, Budapest, Hungary
| | - Ildikó Illyés
- 2nd Department of Pathology, Semmelweis University, Üllői 93, 1091, Budapest, Hungary
| | - József Mandl
- Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1094, Budapest, Hungary
| | - Katalin Borka
- 2nd Department of Pathology, Semmelweis University, Üllői 93, 1091, Budapest, Hungary
| | - András Kiss
- 2nd Department of Pathology, Semmelweis University, Üllői 93, 1091, Budapest, Hungary
| | - Zsuzsa Schaff
- 2nd Department of Pathology, Semmelweis University, Üllői 93, 1091, Budapest, Hungary
| | - Gábor Lendvai
- 2nd Department of Pathology, Semmelweis University, Üllői 93, 1091, Budapest, Hungary.
| | - Klára Werling
- 2nd Department of Internal Medicine, Semmelweis University, 1088, Budapest, Hungary
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38
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Chao X, Qian H, Wang S, Fulte S, Ding WX. Autophagy and liver cancer. Clin Mol Hepatol 2020; 26:606-617. [PMID: 33053934 PMCID: PMC7641568 DOI: 10.3350/cmh.2020.0169] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 07/31/2020] [Accepted: 08/01/2020] [Indexed: 02/07/2023] Open
Abstract
Autophagy is a highly conserved catabolic process that degrades cytosolic proteins and organelles via formation of autophagosomes that fuse with lysosomes to form autolysosomes, whereby autophagic cargos are degraded. Numerous studies have demonstrated that autophagy plays a critical role in the regulation of liver physiology and homeostasis, and impaired autophagy leads to the pathogenesis of various liver diseases such as viral hepatitis, alcohol associated liver diseases (AALD), non-alcoholic fatty liver diseases (NAFLD), and liver cancer. Recent evidence indicates that autophagy may play a dual role in liver cancer: inhibiting early tumor initiation while promoting progression and malignancy of already formed liver tumors. In this review, we summarized the progress of current understanding of how hepatic viral infection, alcohol consumption and diet-induced fatty liver diseases impair hepatic autophagy. We also discussed how impaired autophagy promotes liver tumorigenesis, and paradoxically how autophagy is required to promote the malignancy and progression of liver cancer. Understanding the molecular mechanisms underlying how autophagy differentially affects liver cancer development and progression may help to design better therapeutic strategies for prevention and treatment of liver cancer.
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Affiliation(s)
- Xiaojuan Chao
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Hui Qian
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Shaogui Wang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Sam Fulte
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
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39
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Pathological Consequences of Hepatic mTORC1 Dysregulation. Genes (Basel) 2020; 11:genes11080896. [PMID: 32764389 PMCID: PMC7465966 DOI: 10.3390/genes11080896] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 07/30/2020] [Accepted: 08/02/2020] [Indexed: 12/28/2022] Open
Abstract
The mammalian target of rapamycin complex 1 (mTORC1) is a central regulator of metabolism that integrates environmental inputs, including nutrients, growth factors, and stress signals. mTORC1 activation upregulates anabolism of diverse macromolecules, such as proteins, lipids, and nucleic acids, while downregulating autolysosomal catabolism. mTORC1 dysregulation is often found in various diseases, including cancer, cardiovascular and neurodegenerative diseases, as well as metabolic syndromes involving obesity and type II diabetes. As an essential metabolic organ, the liver requires proper regulation of mTORC1 for maintaining homeostasis and preventing pathologies. For instance, aberrant hyper- or hypoactivation of mTORC1 disrupts hepatocellular homeostasis and damages the structural and functional integrity of the tissue, leading to prominent liver injury and the development of hepatocellular carcinogenesis. Proper regulation of mTORC1 during liver diseases may be beneficial for restoring liver function and ameliorating the detrimental consequences of liver failure.
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40
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Li Y, Liu R, Wu J, Li X. Self-eating: friend or foe? The emerging role of autophagy in fibrotic diseases. Am J Cancer Res 2020; 10:7993-8017. [PMID: 32724454 PMCID: PMC7381749 DOI: 10.7150/thno.47826] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 06/16/2020] [Indexed: 01/18/2023] Open
Abstract
Fibrosis occurs in most human organs including the liver, lung, heart and kidney, and is crucial for the progression of most chronic diseases. As an indispensable catabolic process for intracellular quality control and homeostasis, autophagy occurs in most mammalian cells and is implicated in many biological processes including fibrogenesis. Although advances have been made in understanding autophagy process, the potential role of autophagy in fibrotic diseases remains controversial and has recently attracted a great deal of attention. In the current review, we summarize the commonalities of autophagy affecting different types of fibrosis in different organs, including the liver, lung, heart, and kidney as well as in cystic fibrosis, systematically outline the contradictory results and highlight the distinct role of autophagy during the various stages of fibrosis. In summary, the exact role autophagy plays in fibrogenesis depends on specific cell types and different stimuli, and identifying and evaluating the pathogenic contribution of autophagy in fibrogenesis will promote the discovery of novel therapeutic strategies for the clinical management of these fibrotic diseases.
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41
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Tan Q, Liu Y, Deng X, Chen J, Tsai PJ, Chen PH, Ye M, Guo J, Su Z. Autophagy: a promising process for the treatment of acetaminophen-induced liver injury. Arch Toxicol 2020; 94:2925-2938. [PMID: 32529281 DOI: 10.1007/s00204-020-02780-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 05/07/2020] [Indexed: 12/13/2022]
Abstract
Toxicity from drugs has become an important cause of acute liver failure. Acetaminophen, a commonly used analgesic, can cause severe acute liver injury that can worsen into acute liver failure. Autophagy, a protective cell programme, has been reported to have protective effects in a variety of diseases such as cancer, immune diseases, neurodegenerative diseases, and inflammatory diseases. In this review, we describe how an excess of acetaminophen causes liver injury step by step, from the formation of the initial protein adduct to the final hepatocyte necrosis, as well as the induction of autophagy and its beneficial effects on diseases. Emphasis is placed on the potential effect of autophagy on improving the damage of acetaminophen to hepatocytes. Finally, we are committed to providing insights into the treatment of acute liver failure through the mechanism of acetaminophen induced liver injury, the mechanism of autophagy, and the link between autophagy and liver injury.
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Affiliation(s)
- Qiuhua Tan
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou, China.,Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yongjian Liu
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou, China.,Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xiaoyi Deng
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou, China.,Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jiajia Chen
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou, China.,Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Ping-Ju Tsai
- King-Prebiotics Biotechnology (TW) CO., Ltd., New Taipei City, Taiwan, ROC
| | - Pei-Hsuan Chen
- King-Prebiotics Biotechnology (TW) CO., Ltd., New Taipei City, Taiwan, ROC
| | - Manxiang Ye
- New Francisco (Yunfu City) Biotechnology CO. Ltd., Yunfu, China
| | - Jiao Guo
- Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China.
| | - Zhengquan Su
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou, China.
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42
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He F, Antonucci L, Yamachika S, Zhang Z, Taniguchi K, Umemura A, Hatzivassiliou G, Roose-Girma M, Reina-Campos M, Duran A, Diaz-Meco MT, Moscat J, Sun B, Karin M. NRF2 activates growth factor genes and downstream AKT signaling to induce mouse and human hepatomegaly. J Hepatol 2020; 72:1182-1195. [PMID: 32105670 PMCID: PMC8054878 DOI: 10.1016/j.jhep.2020.01.023] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 01/02/2020] [Accepted: 01/16/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Hepatomegaly can be triggered by insulin and insulin-unrelated etiologies. Insulin acts via AKT, but how other challenges cause hepatomegaly is unknown. METHODS Since many hepatomegaly-inducing toxicants and stressors activate NRF2, we examined the effect of NRF2 activation on liver size and metabolism using a conditional allele encoding a constitutively active NRF2 variant to generate Nrf2Act-hep mice in which NRF2 is selectively activated in hepatocytes. We also used adenoviruses encoding variants of the autophagy adaptor p62/SQSTM1, which activates liver NRF2, as well as liver-specific ATG7-deficient mice (Atg7Δhep) and liver specimens from patients with hepatic sinusoidal obstruction syndrome (HSOS) and autoimmune hepatitis (AIH). RNA sequencing and cell signaling analyses were used to determine cellular consequences of NRF2 activation and diverse histological analyses were used to study effects of the different manipulations on liver and systemic pathophysiology. RESULTS Hepatocyte-specific NRF2 activation, due to p62 accumulation or inhibition of KEAP1 binding, led to hepatomegaly associated with enhanced glycogenosis, steatosis and G2/M cell cycle arrest, fostering hyperplasia without cell division. Surprisingly, all manipulations that led to NRF2 activation also activated AKT, whose inhibition blocked NRF2-induced hepatomegaly and glycogenosis, but not NRF2-dependent antioxidant gene induction. AKT activation was linked to NRF2-mediated transcriptional induction of PDGF and EGF receptor ligands that signaled through their cognate receptors in an autocrine manner. Insulin and insulin-like growth factors were not involved. The NRF2-AKT signaling axis was also activated in human HSOS- and AIH-related hepatomegaly. CONCLUSIONS NRF2, a transcription factor readily activated by xenobiotics, oxidative stress and autophagy disruptors, may be a common mediator of hepatomegaly; its effects on hepatic metabolism can be reversed by AKT/tyrosine kinase inhibitors. LAY SUMMARY Hepatomegaly can be triggered by numerous etiological factors, including infections, liver cancer, metabolic disturbances, toxicant exposure, as well as alcohol abuse or drug-induced hepatitis. This study identified the oxidative stress response transcription factor NRF2 as a common mediator of hepatomegaly. NRF2 activation results in elevated expression of several growth factors. These growth factors are made by hepatocytes and activate their receptors in an autocrine fashion to stimulate the accumulation of glycogen and lipids that lead to hepatocyte and liver enlargement. The protein kinase AKT plays a key role in this process and its inhibition leads to reversal of hepatomegaly.
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Affiliation(s)
- Feng He
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Laura Antonucci
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Shinichiro Yamachika
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Zechuan Zhang
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, Jiangsu Province, China
| | - Koji Taniguchi
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Atsushi Umemura
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | | | | | - Miguel Reina-Campos
- Cancer Metabolism and Signaling Networks Program, Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Angeles Duran
- Cancer Metabolism and Signaling Networks Program, Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Maria T Diaz-Meco
- Cancer Metabolism and Signaling Networks Program, Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Jorge Moscat
- Cancer Metabolism and Signaling Networks Program, Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Beicheng Sun
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, Jiangsu Province, China.
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Pathology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
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The HMGB1-RAGE axis modulates the growth of autophagy-deficient hepatic tumors. Cell Death Dis 2020; 11:333. [PMID: 32382012 PMCID: PMC7206028 DOI: 10.1038/s41419-020-2536-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 04/08/2020] [Accepted: 04/09/2020] [Indexed: 02/07/2023]
Abstract
Autophagy is an intracellular lysosomal degradative pathway important for tumor surveillance. Autophagy deficiency can lead to tumorigenesis. Autophagy is also known to be important for the aggressive growth of tumors, yet the mechanism that sustains the growth of autophagy-deficient tumors is not unclear. We previously reported that progression of hepatic tumors developed in autophagy-deficient livers required high mobility group box 1 (HMGB1), which was released from autophagy-deficient hepatocytes. In this study we examined the pathological features of the hepatic tumors and the mechanism of HMGB1-mediated tumorigenesis. We found that in liver-specific autophagy-deficient (Atg7ΔHep) mice the tumors cells were still deficient in autophagy and could also release HMGB1. Histological analysis using cell-specific markers suggested that fibroblast and ductular cells were present only outside the tumor whereas macrophages were present both inside and outside the tumor. Genetic deletion of Hmgb1 or one of its receptors, receptor for advanced glycated end product (Rage), retarded liver tumor development. HMGB1 and RAGE enhanced the proliferation capability of the autophagy-deficient hepatocytes and tumors. However, RAGE expression was only found on ductual cells and Kupffer’s cells but not on hepatoctyes, suggesting that HMGB1 might promote hepatic tumor growth through a paracrine mode, which altered the tumor microenvironment. Finally, RNAseq analysis of the tumors indicated that HMGB1 induced a much broad changes in tumors. In particular, genes related to mitochondrial structures or functions were enriched among those differentially expressed in tumors in the presence or absence of HMGB1, revealing a potentially important role of mitochondria in sustaining the growth of autophagy-deficient liver tumors via HMGB1 stimulation.
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Römermann D, Ansari N, Schultz-Moreira AR, Michael A, Marhenke S, Hardtke-Wolenski M, Longerich T, Manns MP, Wedemeyer H, Vogel A, Buitrago-Molina LE. Absence of Atg7 in the liver disturbed hepatic regeneration after liver injury. Liver Int 2020; 40:1225-1238. [PMID: 32141704 DOI: 10.1111/liv.14425] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 02/25/2020] [Accepted: 02/27/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIMS Autophagy is a critical process in cell survival and the maintenance of homeostasis. However, the implementation of therapeutic approaches based on autophagy mechanisms after liver damage is still challenging. METHODS We used a hepatospecific Atg7-deficient murine model to address this question. RESULTS We showed that the proliferation and regeneration capacity of Atg7-deficient hepatocytes was impaired. On the one hand, Atg7-deficient hepatocytes showed steady-state hyperproliferation. On the other hand, external triggers such as partial hepatectomy (PHx) or cell transplantation did not induce hepatocellular proliferation or liver repopulation. After PHx, hepatocyte proliferation was strongly decreased, accompanied by high mortality. This increase in mortality could be overcome by pharmacological mTOR inhibition. In accordance with hepatocyte hypoproliferation after damage, Atg7-deficient hepatocytes failed to repopulate the liver in a hepatic injury model. Atg7-deficient mice showed hepatic hypertrophy, transient cellular hypertrophy, and high transaminase levels followed by strong perisinusoidal/pericellular fibrosis with age. Their elevated modified hepatic activity index (mHAI) was almost exclusively due to apoptosis without any inflammation. These parameters were associated with variations in the triglyceride content and compromised lipid droplet formation after PHx. Mechanistically, we also observed a modulation of HGF, PAK4, NOTCH3 and YES1, which are proteins involved in cell cycle regulation. CONCLUSION We demonstrated the important role of autophagy in the regeneration capacity of hepatocytes. We showed the causative relationship between autophagy and triglycerides that is essential for promoting liver recovery. Finally, pharmacological mTOR inhibition overcame the impact of autophagy deficiency after liver damage and prevented mortality.
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Affiliation(s)
- Dorothee Römermann
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany
| | - Nadiea Ansari
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany
| | - Adriana Rita Schultz-Moreira
- Department of Gastroenterology and Hepatology, Essen University Hospital, University Duisburg-Essen, Essen, Germany
| | - Alina Michael
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany
| | - Silke Marhenke
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany
| | - Matthias Hardtke-Wolenski
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Gastroenterology and Hepatology, Essen University Hospital, University Duisburg-Essen, Essen, Germany
| | - Thomas Longerich
- Institute of Pathology, University of Heidelberg, Heidelberg, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Gastroenterology and Hepatology, Essen University Hospital, University Duisburg-Essen, Essen, Germany
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany
| | - Laura Elisa Buitrago-Molina
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Gastroenterology and Hepatology, Essen University Hospital, University Duisburg-Essen, Essen, Germany
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Ma X, McKeen T, Zhang J, Ding WX. Role and Mechanisms of Mitophagy in Liver Diseases. Cells 2020; 9:cells9040837. [PMID: 32244304 PMCID: PMC7226762 DOI: 10.3390/cells9040837] [Citation(s) in RCA: 168] [Impact Index Per Article: 33.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/23/2020] [Accepted: 03/28/2020] [Indexed: 12/12/2022] Open
Abstract
The mitochondrion is an organelle that plays a vital role in the regulation of hepatic cellular redox, lipid metabolism, and cell death. Mitochondrial dysfunction is associated with both acute and chronic liver diseases with emerging evidence indicating that mitophagy, a selective form of autophagy for damaged/excessive mitochondria, plays a key role in the liver’s physiology and pathophysiology. This review will focus on mitochondrial dynamics, mitophagy regulation, and their roles in various liver diseases (alcoholic liver disease, non-alcoholic fatty liver disease, drug-induced liver injury, hepatic ischemia-reperfusion injury, viral hepatitis, and cancer) with the hope that a better understanding of the molecular events and signaling pathways in mitophagy regulation will help identify promising targets for the future treatment of liver diseases.
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Affiliation(s)
- Xiaowen Ma
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA; (X.M.); (T.M.)
| | - Tara McKeen
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA; (X.M.); (T.M.)
| | - Jianhua Zhang
- Department of Pathology, Division of Molecular Cellular Pathology, University of Alabama at Birmingham, 901 19th street South, Birmingham, AL 35294, USA;
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA; (X.M.); (T.M.)
- Correspondence: ; Tel.: +1-913-588-9813
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Yan S, Khambu B, Hong H, Liu G, Huda N, Yin XM. Autophagy, Metabolism, and Alcohol-Related Liver Disease: Novel Modulators and Functions. Int J Mol Sci 2019; 20:ijms20205029. [PMID: 31614437 PMCID: PMC6834312 DOI: 10.3390/ijms20205029] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 10/02/2019] [Accepted: 10/09/2019] [Indexed: 02/06/2023] Open
Abstract
Alcohol-related liver disease (ALD) is caused by over-consumption of alcohol. ALD can develop a spectrum of pathological changes in the liver, including steatosis, inflammation, cirrhosis, and complications. Autophagy is critical to maintain liver homeostasis, but dysfunction of autophagy has been observed in ALD. Generally, autophagy is considered to protect the liver from alcohol-induced injury and steatosis. In this review, we will summarize novel modulators of autophagy in hepatic metabolism and ALD, including autophagy-mediating non-coding RNAs (ncRNAs), and crosstalk of autophagy machinery and nuclear factors. We will also discuss novel functions of autophagy in hepatocytes and non-parenchymal hepatic cells during the pathogenesis of ALD and other liver diseases.
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Affiliation(s)
- Shengmin Yan
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Bilon Khambu
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Honghai Hong
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Gang Liu
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Nazmul Huda
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Xiao-Ming Yin
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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