Browse
Submit Data
Databases
API
Help

Dataset Information

25 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Rev-erbα exacerbates hepatic steatosis in alcoholic liver diseases through regulating autophagy.

ABSTRACT:

Background and aims

Alcoholic fatty liver (AFL) is a liver disease caused by long-term excessive drinking and is characterized by hepatic steatosis. Understanding the regulatory mechanism of steatosis is essential for the treatment of AFL. Rev-erbα is a member of the Rev-erbs family of nuclear receptors, playing an important role in regulating lipid metabolism. However, its functional role in AFL and its underlying mechanism remains unclear.

Results

Rev-erbα was upregulated in the liver of EtOH-fed mice and EtOH-treated L-02 cells. Further, Rev-erbα activation exacerbates steatosis in L-02 cells. Inhibition/downexpression of Rev-erbα improved steatosis. Mechanistically, autophagy activity was inhibited in vivo and vitro. Interestingly, inhibition/downexpression of Rev-erbα enhanced autophagy. Furthermore, silencing of Rev-erbα up-regulated the nuclear expression of Bmal1. Autophagy activity was inhibited and steatosis was deteriorated after EtOH-treated L-02 cells were cotransfected with Rev-erbα shRNA and Bmal1 siRNA.

Conclusions

Rev-erbα induces liver steatosis, which promotes the progression of AFL. Our study reveals a novel steatosis regulatory mechanism in AFL and suggest that Rev-erbα might be a potential therapeutic target for AFL.

SUBMITTER: Liu Q

PROVIDER: S-EPMC8272374 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Nighttime light exposure enhances Rev-erbα-targeting microRNAs and contributes to hepatic steatosis.

Project description:OBJECTIVE:The exposure to artificial light at night (ALAN) disrupts the biological rhythms and has been associated with the development of metabolic syndrome. MicroRNAs (miRNAs) display a critical role in fine-tuning the circadian system and energy metabolism. In this study, we aimed to assess whether altered miRNAs expression in the liver underlies metabolic disorders caused by disrupted biological rhythms. RESULTS:We found that C3H/HePas mice exposed to ALAN developed obesity, and hepatic steatosis, which was paralleled by decreased expression of Rev-erbα and up-regulation of its lipogenic targets ACL and FAS in liver. Furthermore, the expression of Rev-erbα-targeting miRNAs, miR-140-5p, 185-5p, 326-5p and 328-5p were increased in this group. Consistently, overexpression of these miRNAs in primary hepatocytes reduced Rev-erbα expression at the mRNA and protein levels. Importantly, overexpression of Rev-erbα-targeting miRNAs increased mRNA levels of Acly and Fasn. CONCLUSION:Thus, altered miRNAs profile is an important mechanism underlying the disruption of the peripheral clock caused by exposure to ALAN, which could lead to hepatic steatosis.

| S-EPMC6145802 | biostudies-literature

REV-ERBα and REV-ERBβ function as key factors regulating Mammalian Circadian Output.

Project description:The circadian clock regulates behavioural and physiological processes in a 24-h cycle. The nuclear receptors REV-ERBα and REV-ERBβ are involved in the cell-autonomous circadian transcriptional/translational feedback loops as transcriptional repressors. A number of studies have also demonstrated a pivotal role of REV-ERBs in regulation of metabolic, neuronal, and inflammatory functions including bile acid metabolism, lipid metabolism, and production of inflammatory cytokines. Given the multifunctional role of REV-ERBs, it is important to elucidate the mechanism through which REV-ERBs exert their functions. To this end, we established a Rev-erbα/Rev-erbβ double-knockout mouse embryonic stem (ES) cell model and analyzed the circadian clock and clock-controlled output gene expressions. A comprehensive mRNA-seq analysis revealed that the double knockout of both Rev-erbα and Rev-erbβ does not abrogate expression rhythms of E-box-regulated core clock genes but drastically changes a diverse set of other rhythmically-expressed output genes. Of note, REV-ERBα/β deficiency does not compromise circadian expression rhythms of PER2, while REV-ERB target genes, Bmal1 and Npas2, are significantly upregulated. This study highlight the relevance of REV-ERBs as pivotal output mediators of the mammalian circadian clock.

| S-EPMC6629614 | biostudies-literature

Impaired hepatic autophagy exacerbates hepatotoxin induced liver injury.

Project description:Hepatotoxins activate the hepatic survival pathway, but it is unclear whether impaired survival pathways contribute to liver injury caused by hepatotoxins. We investigated the role of hepatic autophagy, a cellular survival pathway, in cholestatic liver injury driven by a hepatotoxin. Here we demonstrate that hepatotoxin contained DDC diet impaired autophagic flux, resulting in the accumulation of p62-Ub-intrahyaline bodies (IHBs) but not the Mallory Denk-Bodies (MDBs). An impaired autophagic flux was associated with a deregulated hepatic protein-chaperonin system and significant decline in Rab family proteins. Additionally, p62-Ub-IHB accumulation activated the NRF2 pathway rather than the proteostasis-related ER stress signaling pathway and suppressed the FXR nuclear receptor. Moreover, we demonstrate that heterozygous deletion of Atg7, a key autophagy gene, aggravated the IHB accumulation and cholestatic liver injury. Conclusion: Impaired autophagy exacerbates hepatotoxin-induced cholestatic liver injury. The promotion of autophagy may represent a new therapeutic approach for hepatotoxin-induced liver damage.

| S-EPMC9944334 | biostudies-literature

REV-ERBα Activates C/EBP Homologous Protein to Control Small Heterodimer Partner-Mediated Oscillation of Alcoholic Fatty Liver.

Project description:The small heterodimer partner (SHP) nuclear receptor is an important regulator of nonalcoholic fatty liver disease. However, little is known about the role of SHP in alcoholic fatty liver. In this study, we used a modified chronic ethanol-binge model to examine cyclic alterations of lipid metabolism in wild-type (WT) and Shp-/- mice over a 24-hour period after binge. The serum and hepatic lipid profiles, as well as the expression of lipid synthesis genes and markers of endoplasmic reticulum stress, exhibited distinct variations in WT and Shp-/- mice in response to ethanol diet plus ethanol binge (ED+E) and control diet plus maltose binge. ED+E induced steatosis in WT mice, which correlated with a marked up-regulation of activating transcription factor 4 protein (ATF4) but down-regulation of C/EBP homologous protein (CHOP) and sterol regulatory element-binding transcription factor 1c protein (SREBP-1c). On the contrary, the control diet plus maltose binge caused lipid accumulation in Shp-/- mice, which was accompanied by a sharp elevation of CHOP, SREBP-1c, and REV-ERBα proteins but a diminished ATF4. REV-ERBα activated CHOP promoter activity and gene transcription, which were inhibited by SHP. Knockdown Rev-Erbα in Shp-/- mice prevented steatosis induced by ED+E. Our study revealed a critical role of SHP and REV-ERBα in controlling rhythmic CHOP expression in alcoholic fatty liver.

| S-EPMC5222961 | biostudies-literature

NIK links inflammation to hepatic steatosis by suppressing PPAR? in alcoholic liver disease.

Project description:Background: Inflammation and steatosis are the main pathological features of alcoholic liver disease (ALD), in which, inflammation is one of the critical drivers for the initiation and development of alcoholic steatosis. NIK, an inflammatory pathway component activated by inflammatory cytokines, was suspected to link inflammation to hepatic steatosis during ALD. However, the underlying pathogenesis is not well-elucidated. Methods: Alcoholic steatosis was induced in mice by chronic-plus-binge ethanol feeding. Both the loss- and gain-of-function experiments by the hepatocyte-specific deletion, pharmacological inhibition and adenoviral transfection of NIK were utilized to elucidate the role of NIK in alcoholic steatosis. Rate of fatty acid oxidation was assessed in vivo and in vitro. PPAR? agonists or antagonists of MEK1/2 and ERK1/2 were used to identify the NIK-induced regulation of PPAR?, MEK1/2, and ERK1/2. The potential interactions between NIK, MEK1/2, ERK1/2 and PPAR? and the phosphorylation of PPAR? were clarified by immunoprecipitation, immunoblotting and far-western blotting analysis. Results: Hepatocyte-specific deletion of NIK protected mice from alcoholic steatosis by sustaining hepatic fatty acid oxidation. Moreover, overexpression of NIK contributed to hepatic lipid accumulation with disrupted fatty acid oxidation. The pathological effect of NIK in ALD may be attributed to the suppression of PPAR?, the main controller of fatty acid oxidation in the liver, because PPAR? agonists reversed NIK-mediated hepatic steatosis and malfunction of fatty acid oxidation. Mechanistically, NIK recruited MEK1/2 and ERK1/2 to form a complex that catalyzed the inhibitory phosphorylation of PPAR?. Importantly, pharmacological intervention against NIK significantly attenuated alcoholic steatosis in ethanol-fed mice. Conclusions: NIK targeting PPAR? via MEK1/2 and ERK1/2 disrupts hepatic fatty acid oxidation and exhibits high value in ALD therapy.

| S-EPMC7069072 | biostudies-literature

Hepatic Inactivation of the Type 2 Deiodinase Confers Resistance to Alcoholic Liver Steatosis.

Project description:BackgroundA mouse with hepatocyte-specific deiodinase type II inactivation (Alb-D2KO) is resistant to diet-induced obesity, hepatic steatosis, and hypertriglyceridemia due to perinatal epigenetic modifications in the liver. This phenotype is linked to low levels of Zfp125, a hepatic transcriptional repressor that promotes liver steatosis by inhibiting genes involved in packaging and secretion of very-low-density lipoprotein.MethodsHere, we used chronic and binge ethanol (EtOH) in mice to cause liver steatosis.ResultsThe EtOH treatment causes a 2.3-fold increase in hepatic triglyceride content; Zfp125 levels were approximately 50% higher in these animals. In contrast, Alb-D2KO mice did not develop EtOH-induced liver steatosis. They also failed to elevate Zfp125 to the same levels, despite being on the EtOH-containing diet for the same period of time. Their phenotype was associated with 1.3- to 2.9-fold up-regulation of hepatic genes involved in lipid transport and export that are normally repressed by Zfp125, that is, Mttp, Abca1, Ldlr, Apoc1, Apoc3, Apoe, Apoh, and Azgp1. Furthermore, genes involved in the EtOH metabolic pathway, that is, Aldh2 and Acss2, were also 1.6- to 3.1-fold up-regulated in Alb-D2KO EtOH mice compared with control animals kept on EtOH.ConclusionsEtOH consumption elevates expression of Zfp125. Alb-D2KO animals, which have lower levels of Zfp125, are much less susceptible to EtOH-induced liver steatosis.

| S-EPMC6602874 | biostudies-literature

HNF6 and Rev-erbα integrate hepatic lipid metabolism by overlapping and distinct transcriptional mechanisms.

Project description:Hepatocyte nuclear factor 6 (HNF6) is required for liver development, but its role in adult liver metabolism is not known. Here we show that deletion of HNF6 in livers of adult C57Bl/6 mice leads to hepatic steatosis in mice fed normal laboratory chow. Although HNF6 is known mainly as a transcriptional activator, hepatic loss of HNF6 up-regulated many lipogenic genes bound directly by HNF6. Many of these genes are targets of the circadian nuclear receptor Rev-erbα, and binding of Rev-erbα at these sites was lost when HNF6 was ablated in the liver. While HNF6 and Rev-erbα coordinately regulate hepatic lipid metabolism, each factor also affects additional gene sets independently. These findings highlight a novel mechanism of transcriptional repression by HNF6 and demonstrate how overlapping and distinct mechanisms of transcription factor function contribute to the integrated physiology of the liver.

| S-EPMC4973293 | biostudies-literature

Liquid Biopsy for the Diagnosis of Viral Hepatitis, Fatty Liver Steatosis, and Alcoholic Liver Diseases.

Project description:During the progression from hepatitis to fibrosis, cirrhosis, and liver failure, the accumulation of stressed/damaged hepatocyte elements associated with liver inflammation is critical. The causes of hepatocyte injuries include viral hepatitis infections, alcoholic hepatitis, and non-alcoholic fatty liver disease. Hepatocyte-derived extracellular vesicles (Hep-EVs) released from stressed/damaged hepatocytes are partly responsible for liver disease progression and liver damage because they activate non-parenchymal cells and infiltrate inflammatory cells within the liver, which are in turn are an important source of EVs. This cell-to-cell signaling is prevalent during inflammation in many liver diseases. Accordingly, special emphasis should be placed on liquid biopsy methods for the long-term monitoring of chronic liver diseases. In the present review, we have highlighted various aspects of current liquid biopsy research into chronic liver diseases. We have also reviewed recent progress on liquid biopsies that focus on cell-free DNA (cfDNA), long non-coding RNA (lncRNA), and the proteins in EVs as potential diagnostic tools and novel therapeutic targets in patients with viral hepatitis, fatty liver steatosis, and alcoholic liver diseases.

| S-EPMC7279404 | biostudies-literature

Lack of hepatic autophagy promotes severity of liver injury but not steatosis.

Project description: Not available

| S-EPMC10046991 | biostudies-literature

Adipokines and Endotoxemia Correlate with Hepatic Steatosis in Non-Alcoholic Fatty Liver Disease (NAFLD).

Project description:(1) Background: The etiology of non-alcoholic fatty liver disease (NAFLD) is multifactorial. Dietary composition has been implicated as a factor modulating intestinal barrier and could affect disease severity. The aim of this study was to evaluate dietary intake and markers of intestinal permeability in patients with NAFLD. (2) Methods: We enrolled 63 patients with NAFLD and compared them to age-matched controls. (3) Results: body mass index (BMI) and leptin to adiponectin ratio-the latter being an indicator of abdominal fat accumulation-correlated with the degree of hepatic steatosis being accompanied with rising levels of fasting insulin. Furthermore, endotoxin plasma levels and markers of inflammation were significantly higher in NAFLD compared to controls and increased with the severity of hepatic steatosis. Despite comparable intake of total energy and macronutrients, intake of fiber was lower in all patients with NAFLD compared to controls and were negatively related to disease severity. (4) Conclusions: Taken together, results of the present study suggest that fiber intake in patients is negatively related to steatosis degree and bacterial endotoxin levels, further suggesting that dietary fiber intake may be a target in NAFLD treatment (NCT: 02366052 and 03482284).

| S-EPMC7146245 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data