scholarly journals Why Hepatic CYP2E1-Elevation by Itself Is Insufficient for Inciting NAFLD/NASH: Inferences from Two Genetic Knockout Mouse Models

Biology ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 419
Author(s):  
Maria Almira Correia ◽  
Doyoung Kwon
Keyword(s):  
Liver Disease ◽  
Mouse Models ◽  
Ubiquitin Ligase ◽  
Metabolic Diseases ◽  
E3 Ubiquitin Ligase ◽  
Metabolic Activation ◽  
Chow Diet ◽  
Hepatic Lipogenesis ◽  
Nonalcoholic Fatty Liver ◽  
Genetic Ablation

Hepatic cytochrome P450 CYP2E1 is an enzyme engaged in the metabolic biotransformation of various xenobiotics and endobiotics, resulting in both detoxification and/or metabolic activation of its substrates to more therapeutic or toxic products. Elevated hepatic CYP2E1 content is implicated in various metabolic diseases including alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), diabetes and obesity. While hepatic CYP2E1 elevation is considered essential to the pathogenesis of these liver diseases, our findings in two mouse models of E3 ubiquitin ligase genetic ablation fed a regular lab chow diet, argue that it is not sufficient for triggering NAFLD/NASH. Thus, albeit comparable hepatic CYP2E1 elevation and functional stabilization in these two models upon E3 ubiquitin ligase genetic ablation and consequent disruption of its ubiquitin-dependent proteasomal degradation, NAFLD/NASH was only observed in the mouse livers that exhibited concurrent SREBP1c-transcriptional upregulation of hepatic lipogenesis. These findings reinforce the critical complicity of an associated prolipogenic scenario induced by either an inherently upregulated hepatic lipogenesis or a high fat/high carbohydrate diet in CYP2E1-mediated NAFLD/NASH.

CBL mutations drive PI3K/AKT signaling via increased interaction with LYN and PIK3R1

Blood ◽  
2021 ◽  
Author(s):  
Roger Belizaire ◽  
Sebastian Hassan John Koochaki ◽  
Namrata D. Udeshi ◽  
Alexis Vedder ◽  
Lei Sun ◽  
...  
Keyword(s):  
Cell Lines ◽  
Ubiquitin Ligase ◽  
Therapeutic Potential ◽  
Mutant Cell ◽  
E3 Ubiquitin Ligase ◽  
Akt Signaling ◽  
Allelic Series ◽  
Genetic Ablation

CBL encodes an E3 ubiquitin ligase and signaling adaptor that regulates receptor and non-receptor tyrosine kinases. Recurrent CBL mutations occur in myeloid neoplasms, including 10-20% of chronic myelomonocytic leukemia (CMML) cases, and selectively disrupt the protein's E3 ubiquitin ligase activity. CBL mutations have been associated with poor prognosis, but the oncogenic mechanisms and therapeutic implications of CBL mutations remain incompletely understood. We combined functional assays and global mass spectrometry to define the phosphoproteome, CBL interactome, and mechanism of signaling activation in a panel of cell lines expressing an allelic series of CBL mutations. Our analyses revealed that increased LYN activation and interaction with mutant CBL are key drivers of enhanced CBL phosphorylation, PIK3R1 recruitment, and downstream PI3K/AKT signaling in CBL-mutant cells. Signaling adaptor domains of CBL, including the tyrosine-kinase binding domain, proline-rich region, and C-terminal phosphotyrosine sites, were all required for the oncogenic function of CBL mutants. Genetic ablation or dasatinib-mediated inhibition of LYN reduced CBL phosphorylation, CBL-PIK3R1 interaction, and PI3K/AKT signaling. Furthermore, we demonstrated in vitro and in vivo antiproliferative efficacy of dasatinib in CBL-mutant cell lines and primary CMML. Overall, these mechanistic insights into the molecular function of CBL mutations provide rationale to explore the therapeutic potential of LYN inhibition in CBL-mutant myeloid malignancies.

scholarly journals Targeted Nutrient Modifications in Purified Diets Differentially Affect Nonalcoholic Fatty Liver Disease and Metabolic Disease Development in Rodent Models

2020 ◽  
Vol 4 (6) ◽  
Author(s):  
Sridhar Radhakrishnan ◽  
Jia-Yu Ke ◽  
Michael A Pellizzon
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Metabolic Diseases ◽  
Complex Spectrum ◽  
Disease Development ◽  
Rodent Models ◽  
Nonalcoholic Fatty Liver ◽  
Time Frames

ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is a complex spectrum of disorders ranging from simple benign steatosis to more aggressive forms of nonalcoholic steatohepatitis (NASH) and fibrosis. Although not every patient with NAFLD/NASH develops liver complications, if left untreated it may eventually lead to cirrhosis and hepatocellular carcinoma. Purified diets formulated with specific nutritional components can drive the entire spectrum of NAFLD in rodent models. Although they may not perfectly replicate the clinical and histological features of human NAFLD, they provide a model to gain further understanding of disease progression in humans. Owing to the growing demand of diets for NAFLD research, and for our further understanding of how manipulation of dietary components can alter disease development, we outlined several commonly used dietary approaches for rodent models, including mice, rats, and hamsters, time frames required for disease development and whether other metabolic diseases commonly associated with NAFLD in humans occur.

scholarly journals Liver Proliferation Is an Essential Driver of Fibrosis in Mouse Models of Nonalcoholic Fatty Liver Disease

2019 ◽  
Vol 3 (8) ◽  
pp. 1036-1049 ◽  
Author(s):  
Ashley Cast ◽  
Meenasri Kumbaji ◽  
Amber D'Souza ◽  
Katherine Rodriguez ◽  
Anita Gupta ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Mouse Models ◽  
Fatty Liver Disease ◽  
Nonalcoholic Fatty Liver ◽  
Liver Proliferation

scholarly journals Gut Microbiota and Nonalcoholic Fatty Liver Disease: Insights on Mechanism and Therapy

2017 ◽  
Author(s):  
Junli Ma ◽  
Qihang Zhou ◽  
Houkai Li
Keyword(s):  
Liver Disease ◽  
Gut Microbiota ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Targeted Therapies ◽  
Fatty Liver Disease ◽  
Metabolic Diseases ◽  
Herbal Medicines ◽  
Active Components ◽  
Nonalcoholic Fatty Liver

Gut microbiota play critical roles in development of obese-related metabolic diseases such as nonalcoholic fatty liver disease (NAFLD), type 2 diabetes, and insulin resistance, which highlighted the potential of gut microbiota-targeted therapies on these diseases. There are various ways that can manipulate gut microbiota including probiotics, prebiotics, synbiotics, antibiotics and some active components from herbal medicines. In this review, we first reviewed the main roles of gut microbiota in mediating the development of NAFLD, and the advances in gut microbiota-targeted therapies on NAFLD in both the experimental and clinical studies, as well as the conclusions on the prospect of gut microbiota-targeted therapies in the future.

scholarly journals Gut Microbiota and Nonalcoholic Fatty Liver Disease: Insights on Mechanism and Therapy

2017 ◽  
Author(s):  
Junli Ma ◽  
Qihang Zhou ◽  
Houkai Li
Keyword(s):  
Liver Disease ◽  
Gut Microbiota ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Targeted Therapies ◽  
Fatty Liver Disease ◽  
Metabolic Diseases ◽  
Herbal Medicines ◽  
Active Components ◽  
Nonalcoholic Fatty Liver

Gut microbiota play critical roles in development of obese-related metabolic diseases such as nonalcoholic fatty liver disease (NAFLD), type 2 diabetes, and insulin resistance, which highlighted the potential of gut microbiota-targeted therapies on these diseases. There are various ways that can manipulate gut microbiota including probiotics, prebiotics, synbiotics, antibiotics and some active components from herbal medicines. In this review, we first described the main roles of gut microbiota in mediating the development of NAFLD, and the advances in gut microbiota-targeted therapies in NAFLD in both the experimental and clinical studies, as well as the conclusions on the prospect of gut microbiota-targeted therapies in the future.

Abstract 241: MDM2 E3 Ligase-mediated Ubiquitination and Degradation of HDAC1 in Vascular Calcification

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Hyun Kook ◽  
Duk-Hwa Kwon ◽  
Gwang Hyeon Eom ◽  
Hyun-Ki Min ◽  
Somy Yoon ◽  
...  
Keyword(s):  
Vascular Calcification ◽  
Ubiquitin Ligase ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Genetic Ablation ◽  
Histone Deacetylase 1 ◽  
Ubiquitination Pathway ◽  
Mdm2 Inhibitor

Vascular calcification (VC) is often associated with cardiovascular and metabolic diseases. However, the molecular mechanisms linking VC to these diseases have yet to be elucidated. Here we report that MDM2-induced ubiquitination of histone deacetylase 1 (HDAC1) mediates VC. Loss of HDAC1 activity via either chemical inhibitor or genetic ablation enhances VC. HDAC1 protein, but not mRNA, is reduced in cell and animal calcification models and in human calcified coronary artery. Under calcification-inducing conditions, proteasomal degradation of HDAC1 precedes VC and it is mediated by MDM2 E3 ubiquitin ligase that initiates HDAC1 K74 ubiquitination. Overexpression of MDM2 enhances VC, whereas loss of MDM2 blunts it. Decoy peptide spanning HDAC1 K74 and RG 7112, an MDM2 inhibitor, prevent VC in vivo and in vitro. These results uncover a previously unappreciated ubiquitination pathway and suggest MDM2-mediated HDAC1 ubiquitination as a new therapeutic target in VC.

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