Regulation of Hepatic Metabolism and Cell Growth by the ATF/CREB Family of Transcription Factors

Cui, Aoyuan; Ding, Dong; Liu, Yu

doi:10.2337/dbi20-0006

Cited by 45 publications

(37 citation statements)

References 121 publications

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“…Recent reports have highlighted that the ATF/CREB family is involved in regulating many aspects of lipid metabolism processes, including regulating critical enzymes and regulators involved in lipogenesis, fatty acid oxidation, and lipoprotein metabolism [ 23 ]. mRNA levels of members of the ATF/CREB family, such as Atf4 and 6 (Activating Transcription Factor 4 and 6) and Crebh (CAMP Responsive Element Binding Protein), show no significant regulation as a result of the MLN4924 treatment in the CD-HFD and 0.1% MCDD NAFLD mouse models ( Suppl.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, lipid homeostasis is regulated by many transcription factors in the liver that are altered in NAFLD [ 39 ]. For example, members of the ATF/CRBEH family have been shown to increase fatty acid oxidation [ 23 ]. Though we have not observed changes at the transcription level in the intermediates of this family, it should be considered that when we treated with MLN4924, we modify proteins post-translationally, and other regulatory mechanisms, such as cell localization and protein stability, might play a role.…”

Section: Discussionmentioning

confidence: 99%

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Neddylation inhibition ameliorates steatosis in NAFLD by boosting hepatic fatty acid oxidation via the DEPTOR-mTOR axis

Serrano‐Maciá

Simón

Gonzalez-Rellan

et al. 2021

Molecular Metabolism

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Objective Neddylation is a druggable and reversible ubiquitin-like post-translational modification upregulated in many diseases, including liver fibrosis, hepatocellular carcinoma, and more recently, non-alcoholic fatty liver disease (NAFLD). Herein, we propose to address the effects of neddylation inhibition and the underlying mechanisms in pre-clinical models of NAFLD. Methods Hepatic neddylation measured by immunohistochemical analysis and NEDD8 serum levels measured by ELISA assay were evaluated in NAFLD clinical and pre-clinical samples. The effects of neddylation inhibition by using a pharmacological small inhibitor, MLN4924, or molecular approaches were assessed in isolated mouse hepatocytes and pre-clinical mouse models of diet-induced NAFLD, male adult C57BL/6 mice, and the AlfpCre transgenic mice infected with AAV-DIO- shNedd8. Results Neddylation inhibition reduced lipid accumulation in oleic acid-stimulated mouse primary hepatocytes and ameliorated liver steatosis, preventing lipid peroxidation and inflammation in the mouse models of diet-induced NAFLD. Under these conditions, increased Deptor levels and the concomitant repression of mTOR signaling were associated with augmented fatty acid oxidation and reduced lipid content. Moreover, Deptor silencing in isolated mouse hepatocytes abolished the anti-steatotic effects mediated by neddylation inhibition. Finally, serum NEDD8 levels correlated with hepatic neddylation during the disease progression in the clinical and pre-clinical models Conclusions Overall, the upregulation of Deptor, driven by neddylation inhibition, is proposed as a novel effective target and therapeutic approach to tackle NAFLD.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Neddylation inhibition ameliorates steatosis in NAFLD by boosting hepatic fatty acid oxidation via the DEPTOR-mTOR axis

Serrano‐Maciá

Simón

Gonzalez-Rellan

et al. 2021

Molecular Metabolism

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“…These include CBP and p300, which have been implicated in hepatic insulin sensitivity. Under physiological conditions, insulin inhibits gluconeogenesis by selectively disrupting the interaction between CBP/p300 and the cyclic AMP-responsive element-binding protein (CREB), a TF involved in the expression of metabolic and gluconeogenic genes (129). In functional studies, p300 overexpression in mice was reported to cause hepatic steatosis, insulin resistance, and inflammation (27).…”

Section: Histone Acetyltransferases (Hats)mentioning

confidence: 99%

Epigenetics of Hepatic Insulin Resistance

2021

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Insulin resistance (IR) is largely recognized as a unifying feature that underlies metabolic dysfunction. Both lifestyle and genetic factors contribute to IR. Work from recent years has demonstrated that the epigenome may constitute an interface where different signals may converge to promote IR gene expression programs. Here, we review the current knowledge of the role of epigenetics in hepatic IR, focusing on the roles of DNA methylation and histone post-translational modifications. We discuss the broad epigenetic changes observed in the insulin resistant liver and its associated pathophysiological states and leverage on the wealth of ‘omics’ studies performed to discuss efforts in pinpointing specific loci that are disrupted by these changes. We envision that future studies, with increased genomic resolution and larger cohorts, will further the identification of biomarkers of early onset hepatic IR and assist the development of targeted interventions. Furthermore, there is growing evidence to suggest that persistent epigenetic marks may be acquired over prolonged exposure to disease or deleterious exposures, highlighting the need for preventative medicine and long-term lifestyle adjustments to avoid irreversible or long-term alterations in gene expression.

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“…Although it is known that production and secretion of OPN is induced in hepatocytes in NASH 21,25 , the mechanism of OPN in mediating the crosstalk beween hepatocytes and HSCs during fibrosis development in NASH remains largerly unknown. CREB/ATF bZIP transcription factor (CREBZF) is rapidly gaining interest as a key regulator in hepatic metabolism and cell growth 26,27 . CREBZF normally functions as a transcriptional inhibitor to regulate gene expression 27,28 .…”

Section: Introductionmentioning

confidence: 99%

“…CREB/ATF bZIP transcription factor (CREBZF) is rapidly gaining interest as a key regulator in hepatic metabolism and cell growth 26,27 . CREBZF normally functions as a transcriptional inhibitor to regulate gene expression 27,28 . During refeeding, CREBZF is induced by insulin to inhibit transcription levels of Insig-2a in the hepatocyte, leading to the activation of SREBP-1 and fatty acid synthesis 29 .…”

Section: Introductionmentioning

confidence: 99%

Hepatocyte CREBZF-osteopontin axis controls fibrosis in nonalcoholic steatohepatitis

Ma¹,

Liu²,

Hu³

et al. 2021

Preprint

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Nonalcoholic steatohepatitis (NASH) has emerged as a leading cause of chronic liver disease. The incomplete understanding of NASH fibrosis limits pharmacotherapy development. Here we report a molecular link between hepatocytes and hepatic stellate cells (HSCs) in regulating the progression of liver fibrosis via CREBZF-osteopontin (OPN) axis. Hepatocyte-specific CREBZF knockout (CREBZF LKO) mice and their wild-type littermates were divided into groups that were placed on AMLN, MCD or chow diet. Mouse primary hepatocytes were treated with 250 μM PA and 10 ng/ml TNFα, the conditioned medium was collected and then transferred to HSC-T6 cells for 24 hours. Adeno-associated virus-mediated overexpression of OPN or CREBZF was performed in mice via tail vail injection. Human studies have shown that deregulation of CREBZF is associated with pathogenesis of hepatic steatosis and dyslipidemia. Here, we show that CREBZF is markedly elevated in livers of NASH mice, whereas hepatocyte-specific CREBZF knockout mice are prevented from AMLN or MCD diet-induced hepatic inflammation, liver injury and fibrosis. In vivo and in vitro mechanistic studies revealed that a key mechanism linking hepatocyte CREBZF to NASH fibrosis is miR-6964-3p-mediated inhibition of OPN, an extracellular matrix protein that activates fibrogenic genes in hepatic stellate cells. Moreover, the reduction of NASH phenotypes in CREBZF LKO mice was reversed by adeno-associated virus-mediated overexpression of OPN. Thus, CREBZF-OPN axis represents a previously unrecognized intrahepatic crosstalk in the liver that triggers fibrosis progression and contributes to the severity of NASH.

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Regulation of Hepatic Metabolism and Cell Growth by the ATF/CREB Family of Transcription Factors

Cited by 45 publications

References 121 publications

Neddylation inhibition ameliorates steatosis in NAFLD by boosting hepatic fatty acid oxidation via the DEPTOR-mTOR axis

Neddylation inhibition ameliorates steatosis in NAFLD by boosting hepatic fatty acid oxidation via the DEPTOR-mTOR axis

Epigenetics of Hepatic Insulin Resistance

Hepatocyte CREBZF-osteopontin axis controls fibrosis in nonalcoholic steatohepatitis

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