Nonalcoholic fatty liver disease is a major risk factor for hepatocellular carcinoma (HCC). Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) augments lipid accumulation (steatosis), inflammation, and tumorigenesis, thereby promoting the whole spectrum of this disease process. Targeting AEG-1 is a potential interventional strategy for nonalcoholic steatohepatitis (NASH) and HCC. Thus, proper understanding of the regulation of this molecule is essential. We found that AEG-1 is palmitoylated at residue cysteine 75 (Cys75). Mutation of Cys75 to serine (Ser) completely abolished AEG-1 palmitoylation. We identified ZDHHC6 as a palmitoyltransferase catalyzing the process in HEK293T cells. To obtain insight into how palmitoylation regulates AEG-1 function, we generated knock-in mice by CRISPR/Cas9 in which Cys75 of AEG-1 was mutated to Ser (AEG-1-C75S). No developmental or anatomical abnormality was observed between AEG-1-wild type (AEG-1-WT) and AEG-1-C75S littermates. However, global gene expression analysis by RNA-sequencing unraveled that signaling pathways and upstream regulators, which contribute to cell proliferation, motility, inflammation, angiogenesis, and lipid accumulation, were activated in AEG-1-C75S hepatocytes compared to AEG-1-WT. These findings suggest that AEG-1-C75S functions as dominant positive and that palmitoylation restricts oncogenic and NASH-promoting functions of AEG-1. We thus identify a previously unknown regulatory mechanism of AEG-1, which might help design new therapeutic strategies for NASH and HCC.
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http://dx.doi.org/10.1021/acs.biochem.2c00583 | DOI Listing |
Front Cell Dev Biol
December 2024
Department of Ophthalmology, Laboratory of Optometry and Vision Sciences, Department of Optometry and Visual Science. West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Myopia, a major public health problem, involves axial elongation and thinning of all layers of the eye, including sclera, choroid and retina, which defocuses incoming light and thereby blurs vision. How the various populations of glia in the retina are involved in the disorder is unclear. Astrocytes and Müller cells provide structural support to the retina.
View Article and Find Full Text PDFZool Res
January 2025
Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea. E-mail:
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment and distinct neuropathological features, including amyloid-β plaques, neurofibrillary tangles, and reactive astrogliosis. Developing effective diagnostic, preventative, and therapeutic strategies for AD necessitates the establishment of animal models that accurately recapitulate the pathophysiological processes of the disease. Existing transgenic mouse models have significantly contributed to understanding AD pathology but often fail to replicate the complexity of human AD.
View Article and Find Full Text PDFBrain Behav Immun Integr
December 2024
Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
Maternal immune activation (MIA), a maternal stressor, increases risk for neuropsychiatric diseases, such as Major Depressive Disorder in offspring. MIA of toll-like receptor 7 (TLR7) initiates an immune response in mother and fetuses in a sex-selective manner. The paraventricular nucleus of the hypothalamus (PVN), a brain region that is sexually dimorphic and regulates hypothalamic-pituitary-adrenal (HPA) stress responses, have been tied to stress-related behaviors (i.
View Article and Find Full Text PDFSci Rep
January 2025
Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
Iron overload has been associated with cerebrovascular disease and cognitive impairment in β-thalassaemia patients, typically appearing earlier than in the general population. However, the mechanisms of iron overload on cerebrovascular pathology remain unclear. This study investigated the effects of heavy iron overload on the blood-brain barrier and neurohistology, particularly in the CA3 region of hippocampus and its contribution to cognitive impairment in β-thalassaemia mice.
View Article and Find Full Text PDFFront Aging Neurosci
December 2024
Department of Ophthalmology and Visual Sciences, Faculty of Medicine, Eye Care Centre, The University of British Columbia, Vancouver, BC, Canada.
Introduction: Apolipoprotein E (ApoE) plays a crucial role in lipid homeostasis, predominantly expressed in astrocytes and to a lesser extent in microglia within the central nervous system (CNS). While the allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), its precise role in AD pathogenesis remains elusive. -knockout (-ko) mice, mice expressing human , and human carriers exhibit similar deficits in lipid metabolism, cognitive and behavioral functions, and neurodegeneration.
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