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Editor’s note iNature is China’s largest academic official account.
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us
.
iNature non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, but there is no effective drug therapy available for clinical use
.
Non-alcoholic steatohepatitis (NASH) is the more serious stage of NAFLD
.
In this process, disorders of endoplasmic reticulum (ER) related pathways and proteins are one of the main signs
.
On July 17, 2021, Li Hongliang, Yuan Yufeng and Yang Hailong of Wuhan University jointly published a research result entitled "The E3 ubiquitin ligase RNF5 ameliorates nonalcoholic steatohepatitis via ubiquitin-mediated degradation of HRD1" in Hepatology (IF=17.
43).
The study first checked the expression level of RNF5 and found that RNF5 was significantly reduced in NASH livers of multiple species, including humans
.
Then, the study introduced the adenovirus used for Rnf5 overexpression or knockdown into primary mouse liver cells, and found that palmitic acid/oleic acid (PAOA) induced lipid accumulation and inflammation in liver cells were significantly reduced by Rnf5 overexpression.
But it was exacerbated by the silencing of the Rnf5 gene
.
Hepatocyte-specific Rnf5 knockout significantly aggravated liver steatosis, inflammatory response, and fibrosis in mice subjected to diet-induced NASH
.
In terms of mechanism, HRD1 was identified as a novel binding partner of RNF5 through systematic interactomics analysis
.
RNF5 directly binds to HRD1 and promotes the ubiquitination of its lysine 48 (K48) and K33 linkage and subsequent proteasomal degradation
.
In addition, Hrd1 overexpression significantly exacerbated PAOA-induced lipid accumulation and inflammation, while shRNA-mediated Hrd1 knockdown had the opposite effect
.
It is worth noting that Hrd1 knockdown significantly eliminated PAOA-induced lipid deposition and upregulation of related genes caused by Rnf5 ablation in hepatocytes
.
Taken together, these data indicate that RNF5 inhibits the progression of NASH through the targeted degradation of HRD1 through the ubiquitin-mediated proteasome pathway
.
Targeting the RNF5-HRD1 axis may provide new insights into the pathogenesis of NASH and pave the way for the development of new strategies for the prevention and treatment of NASH
.
On July 7, 2021, Li Hongliang, Yang Juan and Huang Zan of Wuhan University jointly published a research result entitled "FASN-suppressor screening identifies SNX8 as a novel therapeutic target for NAFLD" in Hepatology (IF=17.
43)
.
The study found that sorting connexin 8 (SNX8) is a new inhibitor of fatty acid synthesis through systematic screening, revealing the important function and mechanism of SNX8 in regulating non-alcoholic fatty liver disease (NAFLD) and providing a new target for NAFLD treatment And potential new strategies (click to read)
.
On June 16, 2021, Wuhan University Zhang Peng, Li Hongliang and Yang Hailong jointly published a research paper entitled "TNIP3 is a novel activator of Hippo-YAP signaling protecting against hepatic ischemia/reperfusion injury" in Hepatology (IF=14.
68) online The study found that TNIP3 of hepatocytes was significantly up-regulated in the livers of individuals and mice undergoing I/R surgery
.
In summary, the study found that TNIP3 is a new regulator of liver IR damage, reducing cell death and inflammation by assisting the ubiquitination and degradation of LATS2 and the resulting YAP activation
.
TNIP3 is a promising target for the treatment of liver I/R injury and can improve the prognosis of liver surgery (click to read)
.
On June 8, 2021, Li Hongliang, Bai Lan and Yuan Yufeng of Wuhan University published an online publication entitled "TMBIM1 is an inhibitor of adipogenesis and its depletion promotes adipocytehyperplasia and improves obesity-related metabolic disease" in Cell Metabolism (IF=21.
57) The research paper identified the lysosomal protein TMBIM1 as a new key factor in inhibiting adipogenesis for the first time through large-scale high-throughput screening, revealing the key negative regulatory effect of TMBIM1 on adipogenesis and obesity-related metabolic disorders, suggesting that TMBIM1 It is a potential molecular target for the treatment of obesity-related metabolic disorders (click to read)
.
On May 28, 2021, Li Hongliang’s team published "Nonalcoholic Fatty Liver Disease:An Emerging Driver of Cardiac Arrhythmia", which summarized and analyzed the clinical evidence and pathophysiological mechanism of NAFLD as a risk factor for arrhythmia; May 4, 2021, Li Hongliang’s team published "A kinome screen reveals that Nemo-like kinase is" in Cell Metabolism A key suppressor of hepaticgluconeogenesis" research paper, found for the first time that NLK is a key inhibitor of hepatic gluconeogenesis; on April 24, 2021, Li Hongliang’s team published "Hepatocyte SH3RF2 Deficiency is a Key Aggravator for Nonalcoholic Fatty Liver Disease" in Hepatology.
On April 7, 2021, Li Hongliang’s team published a review article "Therapeutic Potential of G Protein-Coupled Receptors against Nonalcoholic Steatohepatitis" in Hepatology, which was the first to identify the E3 ubiquitin ligase SH3RF2 targeting ACLY to improve the NAFLD process.
The latest research progress and application prospects of GPCR molecules in NASH; In February 2021, Li Hongliang’s team officially published the "Milk Fat Globule-Epidermal Growth Factor-Factor 8 Improves Hepatic Steatosis and Inflammation" research paper in Hepatology, revealing for the first time that MFGE8 passed is An important negative regulator of NASH; On January 5, 2021, Li Hongliang’s team published "The neutrophil-to-lymphocyte ratio determines clinical efficacy of corticosteroidtherapy in patients withCOVID-19" research paper, for the first time in the world to clarify the "use boundary" of glucocorticoids in the treatment of new coronary pneumonia; in January 2021, Li Hongliang's team officially published "Hepatic Regulator of G Protein Signaling 5 Ameliorates Nonalcoholic Fatty Liver Disease" in Hepatology.
by Suppressing Transforming Growth Factor Beta-ActivatedKinase 1-c-Jun-N-Terminal Kinase/p38 Signaling" research paper, for the first time it was found that RGS5 can significantly improve NASH by targeting TAK1 phosphorylation
.
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and its main feature is excessive lipid deposition in liver cells
.
With major changes in diet and life>
.
Non-alcoholic steatohepatitis (NASH) is a progressive form of NAFLD, which is characterized by severe liver steatosis, inflammatory infiltration and even liver fibrosis, which may eventually develop into cirrhosis or hepatocellular carcinoma (HCC)
.
Due to the complexity and heterogeneity of NASH, there are currently no effective FDA-approved drugs available for clinical use
.
Therefore, it is urgent to reveal the detailed mechanism of NASH and explore promising therapeutic targets or strategies
.
The endoplasmic reticulum (ER) is an important organelle for lipid synthesis in liver cells.
It is also widely involved in many physiological processes, such as protein post-translational processing, calcium homeostasis, lipid synthesis and inflammation
.
After exposure to extracellular stimuli, ER localization proteins are widely involved in a variety of pathological events, especially those mediated through pathways related to metabolic disorders
.
The unfolded protein response (UPR) is a conservative, conventional response involving the ER protein, which promotes protein and lipid imbalance during the progression of NASH
.
RNF5 is a member of the E3 ubiquitin ligase family and is mainly located in the ER
.
It is worth noting that RNF5 plays a crucial role in the negative regulation of ER stress and related biological processes
.
In addition, RNF5 effectively promotes the degradation of misfolded proteins and regulates the stability and clearance rate of proteins that play a role in various cellular processes (such as inflammation)
.
The function of RNF5 in regulating endoplasmic reticulum stress and inflammation suggests that it may be related to NASH
.
However, the role of RNF5 in the pathogenesis of NASH remains unknown
.
In this study, RNF5 was found to be significantly down-regulated in NASH
.
In vitro and in vivo, the ablation of RNF5 significantly aggravated liver steatosis, inflammation and fibrosis
.
In terms of mechanism, RNF5 promotes the ubiquitination of lysine 48 (K48) and K33 and the degradation of HMG-CoA reductase degradation protein 1 (HRD1), thereby improving liver steatosis
.
The results of this study indicate that RNF5 is a new modulator of NASH and a potential therapeutic target
.
Reference message: https://aasldpubs.
onlinelibrary.
wiley.
com/doi/10.
1002/hep.
32061
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us
.
iNature non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, but there is no effective drug therapy available for clinical use
.
Non-alcoholic steatohepatitis (NASH) is the more serious stage of NAFLD
.
In this process, disorders of endoplasmic reticulum (ER) related pathways and proteins are one of the main signs
.
On July 17, 2021, Li Hongliang, Yuan Yufeng and Yang Hailong of Wuhan University jointly published a research result entitled "The E3 ubiquitin ligase RNF5 ameliorates nonalcoholic steatohepatitis via ubiquitin-mediated degradation of HRD1" in Hepatology (IF=17.
43).
The study first checked the expression level of RNF5 and found that RNF5 was significantly reduced in NASH livers of multiple species, including humans
.
Then, the study introduced the adenovirus used for Rnf5 overexpression or knockdown into primary mouse liver cells, and found that palmitic acid/oleic acid (PAOA) induced lipid accumulation and inflammation in liver cells were significantly reduced by Rnf5 overexpression.
But it was exacerbated by the silencing of the Rnf5 gene
.
Hepatocyte-specific Rnf5 knockout significantly aggravated liver steatosis, inflammatory response, and fibrosis in mice subjected to diet-induced NASH
.
In terms of mechanism, HRD1 was identified as a novel binding partner of RNF5 through systematic interactomics analysis
.
RNF5 directly binds to HRD1 and promotes the ubiquitination of its lysine 48 (K48) and K33 linkage and subsequent proteasomal degradation
.
In addition, Hrd1 overexpression significantly exacerbated PAOA-induced lipid accumulation and inflammation, while shRNA-mediated Hrd1 knockdown had the opposite effect
.
It is worth noting that Hrd1 knockdown significantly eliminated PAOA-induced lipid deposition and upregulation of related genes caused by Rnf5 ablation in hepatocytes
.
Taken together, these data indicate that RNF5 inhibits the progression of NASH through the targeted degradation of HRD1 through the ubiquitin-mediated proteasome pathway
.
Targeting the RNF5-HRD1 axis may provide new insights into the pathogenesis of NASH and pave the way for the development of new strategies for the prevention and treatment of NASH
.
On July 7, 2021, Li Hongliang, Yang Juan and Huang Zan of Wuhan University jointly published a research result entitled "FASN-suppressor screening identifies SNX8 as a novel therapeutic target for NAFLD" in Hepatology (IF=17.
43)
.
The study found that sorting connexin 8 (SNX8) is a new inhibitor of fatty acid synthesis through systematic screening, revealing the important function and mechanism of SNX8 in regulating non-alcoholic fatty liver disease (NAFLD) and providing a new target for NAFLD treatment And potential new strategies (click to read)
.
On June 16, 2021, Wuhan University Zhang Peng, Li Hongliang and Yang Hailong jointly published a research paper entitled "TNIP3 is a novel activator of Hippo-YAP signaling protecting against hepatic ischemia/reperfusion injury" in Hepatology (IF=14.
68) online The study found that TNIP3 of hepatocytes was significantly up-regulated in the livers of individuals and mice undergoing I/R surgery
.
In summary, the study found that TNIP3 is a new regulator of liver IR damage, reducing cell death and inflammation by assisting the ubiquitination and degradation of LATS2 and the resulting YAP activation
.
TNIP3 is a promising target for the treatment of liver I/R injury and can improve the prognosis of liver surgery (click to read)
.
On June 8, 2021, Li Hongliang, Bai Lan and Yuan Yufeng of Wuhan University published an online publication entitled "TMBIM1 is an inhibitor of adipogenesis and its depletion promotes adipocytehyperplasia and improves obesity-related metabolic disease" in Cell Metabolism (IF=21.
57) The research paper identified the lysosomal protein TMBIM1 as a new key factor in inhibiting adipogenesis for the first time through large-scale high-throughput screening, revealing the key negative regulatory effect of TMBIM1 on adipogenesis and obesity-related metabolic disorders, suggesting that TMBIM1 It is a potential molecular target for the treatment of obesity-related metabolic disorders (click to read)
.
On May 28, 2021, Li Hongliang’s team published "Nonalcoholic Fatty Liver Disease:An Emerging Driver of Cardiac Arrhythmia", which summarized and analyzed the clinical evidence and pathophysiological mechanism of NAFLD as a risk factor for arrhythmia; May 4, 2021, Li Hongliang’s team published "A kinome screen reveals that Nemo-like kinase is" in Cell Metabolism A key suppressor of hepaticgluconeogenesis" research paper, found for the first time that NLK is a key inhibitor of hepatic gluconeogenesis; on April 24, 2021, Li Hongliang’s team published "Hepatocyte SH3RF2 Deficiency is a Key Aggravator for Nonalcoholic Fatty Liver Disease" in Hepatology.
On April 7, 2021, Li Hongliang’s team published a review article "Therapeutic Potential of G Protein-Coupled Receptors against Nonalcoholic Steatohepatitis" in Hepatology, which was the first to identify the E3 ubiquitin ligase SH3RF2 targeting ACLY to improve the NAFLD process.
The latest research progress and application prospects of GPCR molecules in NASH; In February 2021, Li Hongliang’s team officially published the "Milk Fat Globule-Epidermal Growth Factor-Factor 8 Improves Hepatic Steatosis and Inflammation" research paper in Hepatology, revealing for the first time that MFGE8 passed is An important negative regulator of NASH; On January 5, 2021, Li Hongliang’s team published "The neutrophil-to-lymphocyte ratio determines clinical efficacy of corticosteroidtherapy in patients withCOVID-19" research paper, for the first time in the world to clarify the "use boundary" of glucocorticoids in the treatment of new coronary pneumonia; in January 2021, Li Hongliang's team officially published "Hepatic Regulator of G Protein Signaling 5 Ameliorates Nonalcoholic Fatty Liver Disease" in Hepatology.
by Suppressing Transforming Growth Factor Beta-ActivatedKinase 1-c-Jun-N-Terminal Kinase/p38 Signaling" research paper, for the first time it was found that RGS5 can significantly improve NASH by targeting TAK1 phosphorylation
.
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and its main feature is excessive lipid deposition in liver cells
.
With major changes in diet and life>
.
Non-alcoholic steatohepatitis (NASH) is a progressive form of NAFLD, which is characterized by severe liver steatosis, inflammatory infiltration and even liver fibrosis, which may eventually develop into cirrhosis or hepatocellular carcinoma (HCC)
.
Due to the complexity and heterogeneity of NASH, there are currently no effective FDA-approved drugs available for clinical use
.
Therefore, it is urgent to reveal the detailed mechanism of NASH and explore promising therapeutic targets or strategies
.
The endoplasmic reticulum (ER) is an important organelle for lipid synthesis in liver cells.
It is also widely involved in many physiological processes, such as protein post-translational processing, calcium homeostasis, lipid synthesis and inflammation
.
After exposure to extracellular stimuli, ER localization proteins are widely involved in a variety of pathological events, especially those mediated through pathways related to metabolic disorders
.
The unfolded protein response (UPR) is a conservative, conventional response involving the ER protein, which promotes protein and lipid imbalance during the progression of NASH
.
RNF5 is a member of the E3 ubiquitin ligase family and is mainly located in the ER
.
It is worth noting that RNF5 plays a crucial role in the negative regulation of ER stress and related biological processes
.
In addition, RNF5 effectively promotes the degradation of misfolded proteins and regulates the stability and clearance rate of proteins that play a role in various cellular processes (such as inflammation)
.
The function of RNF5 in regulating endoplasmic reticulum stress and inflammation suggests that it may be related to NASH
.
However, the role of RNF5 in the pathogenesis of NASH remains unknown
.
In this study, RNF5 was found to be significantly down-regulated in NASH
.
In vitro and in vivo, the ablation of RNF5 significantly aggravated liver steatosis, inflammation and fibrosis
.
In terms of mechanism, RNF5 promotes the ubiquitination of lysine 48 (K48) and K33 and the degradation of HMG-CoA reductase degradation protein 1 (HRD1), thereby improving liver steatosis
.
The results of this study indicate that RNF5 is a new modulator of NASH and a potential therapeutic target
.
Reference message: https://aasldpubs.
onlinelibrary.
wiley.
com/doi/10.
1002/hep.
32061
