-
Categories
-
Pharmaceutical Intermediates
-
Active Pharmaceutical Ingredients
-
Food Additives
- Industrial Coatings
- Agrochemicals
- Dyes and Pigments
- Surfactant
- Flavors and Fragrances
- Chemical Reagents
- Catalyst and Auxiliary
- Natural Products
- Inorganic Chemistry
-
Organic Chemistry
-
Biochemical Engineering
- Analytical Chemistry
- Cosmetic Ingredient
-
Pharmaceutical Intermediates
Promotion
ECHEMI Mall
Wholesale
Weekly Price
Exhibition
News
-
Trade Service
iNature Although nonalcoholic steatohepatitis (NASH) can lead to serious clinical consequences, including cirrhosis and hepatocellular carcinoma, there are currently no effective treatments for this disease
.
Growing evidence suggests that hepatic sinusoidal endothelial cells (LSEC) play a key role in the pathogenesis of NASH; however, the mechanisms involved in LSEC-mediated NASH remain to be fully elucidated
.
On January 10, 2022, Wang Lin and Dou Guorui of Air Force Military Medical University jointly published a research paper titled "Notch-triggered maladaptation of liver sinusoidal endothelium aggravates nonalcoholic steatohepatitis through eNOS" in Hepatology (IF=17).
LSEC homeostasis is disrupted and LSEC-specific gene profiles are altered in a methionine-choline deficient (MCD) diet-induced mouse model of NASH
.
Importantly, Notch signaling was found to be activated in the LSEC of NASH mice
.
Then to investigate the role of endothelial Notch in NASH progression, mouse lines with endothelial-specific NICD overexpression or RBP-J knockout were generated to activate or inhibit Notch signaling in endothelial cells, respectively
.
Notably, endothelial-specific overexpression of NICD accelerates LSEC maladaptation and exacerbates NASH, whereas EC-specific inhibition of Notch signaling restores LSEC homeostasis and improves NASH phenotype
.
Furthermore, this study demonstrates that endothelial-specific Notch activation exacerbates NASH by inhibiting eNOS transcription, while administration of the pharmacological eNOS activator YC-1 attenuates hepatic steatosis and lipid accumulation caused by Notch activation
.
Finally, to explore the therapeutic potential of Notch inhibitors in the treatment of NASH, this study applied two γ-secretase inhibitors, DAPT and LY3039478, in a mouse model of MCD diet-induced NASH and found that both inhibitors could Effectively improve liver steatosis, inflammation and liver fibrosis
.
In conclusion, this study found that endothelial-specific Notch activation triggers LSEC maladaptation and exacerbates the NASH phenotype in an eNOS-dependent manner
.
Genetic and pharmacological inhibition of Notch signaling effectively restores LSEC homeostasis and improves NASH progression
.
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide
.
It is estimated that NAFLD affects one quarter of the global population and the incidence is increasing rapidly year by year
.
NAFLD presents a natural progression and can be divided into three stages according to pathological characteristics, namely non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), and finally develops into cirrhosis
.
In recent years, abnormal lipid metabolism, inflammation, fibrosis, apoptosis, insulin resistance, and the gut-liver axis have all been associated with NASH progression
.
However, there are currently no effective treatments for this disease
.
Hepatocyte steatosis is the main pathological change in the liver of NASH patients
.
Therefore, most studies have focused on the role of hepatocytes in the development of NASH
.
However, the importance of hepatic non-parenchymal cells (NPCs), including hepatic sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), and macrophages, in the pathophysiology of NASH has been increasingly recognized
.
LSECs constitute the largest proportion of NPCs in hepatic sinusoids and have been found to play a particularly critical role in NASH
.
LSECs are highly specialized ECs lining hepatic sinusoids
.
Differentiated LSECs are characterized by the presence of fenestrations, which establish channels for the exchange of lipids, lipoproteins, and macromolecules between hepatocytes and blood
.
In addition, LSEC can transfer lipids through endocytosis
.
Under pathological conditions, hepatic sinusoidal homeostasis is prone to disruption, and LSECs undergo a series of morphological and functional changes, such as reduced fenestration numbers and impaired endocytosis, which largely disrupt the interaction between hepatocytes and blood.
lipid exchange, leading to NASH progression
.
Therefore, maintaining LSEC homeostasis is expected to slow the development of NASH
.
Notch signaling is a highly conserved developmental pathway involving diverse ligands
.
Cleavage of the Notch receptor by γ-secretase results in the release and nuclear translocation of the Notch intracellular domain (NICD)
.
In the nucleus, NICD interacts with recombinant signal-binding protein (RBP-J) in the kappa J region of immunoglobulins, leading to the recruitment of other transcriptional coactivators and activation of downstream target genes such as HES1/5 and HESR1/2
.
Aberrant activation of Notch signaling can lead to diseases such as Alagille syndrome and leukoencephalopathy (CADASIL)
.
Notch signaling has recently been reported to be activated in hepatocytes during NASH, and is also known to play multiple roles in NASH-related lipid metabolism, inflammation, and fibrosis
.
However, relatively few studies have highlighted the importance of endothelial-derived Notch signaling in the development of NASH
.
Sinusoidal homeostasis is disrupted in nonalcoholic steatohepatitis (NASH) (figure from Hepatology) It is well known that Notch signaling is a key regulator of angiogenesis
.
In the liver, endothelial Notch signaling is necessary for the prevention of hepatic vascular malformations
.
Conditional knockout of Notch/RBP-J results in impaired LSEC homeostasis and interferes with liver regeneration
.
Endothelial-specific Notch activation aggravates CCl4-induced liver fibrosis and impairs liver regeneration
.
Collectively, these findings suggest that endothelial Notch signaling is essential for maintaining LSEC homeostasis and thus recovery from liver injury
.
Here, the study found that LSEC homeostasis was disrupted and endothelial-derived Notch signaling was reactivated in methionine-choline deficient (MCD) diet-induced NASH mice
.
Forced activation of endothelial Notch signaling exacerbates NASH in an eNOS-dependent manner, whereas RBP-J deletion or pharmacological inhibition of Notch signaling causes the opposite effect
.
Taken together, these findings highlight the therapeutic potential of endothelial-specific Notch inhibition in the treatment of NASH and NAFLD
.
Reference message: https://aasldpubs.
onlinelibrary.
wiley.
com/doi/10.
1002/hep.
32332
.
Growing evidence suggests that hepatic sinusoidal endothelial cells (LSEC) play a key role in the pathogenesis of NASH; however, the mechanisms involved in LSEC-mediated NASH remain to be fully elucidated
.
On January 10, 2022, Wang Lin and Dou Guorui of Air Force Military Medical University jointly published a research paper titled "Notch-triggered maladaptation of liver sinusoidal endothelium aggravates nonalcoholic steatohepatitis through eNOS" in Hepatology (IF=17).
LSEC homeostasis is disrupted and LSEC-specific gene profiles are altered in a methionine-choline deficient (MCD) diet-induced mouse model of NASH
.
Importantly, Notch signaling was found to be activated in the LSEC of NASH mice
.
Then to investigate the role of endothelial Notch in NASH progression, mouse lines with endothelial-specific NICD overexpression or RBP-J knockout were generated to activate or inhibit Notch signaling in endothelial cells, respectively
.
Notably, endothelial-specific overexpression of NICD accelerates LSEC maladaptation and exacerbates NASH, whereas EC-specific inhibition of Notch signaling restores LSEC homeostasis and improves NASH phenotype
.
Furthermore, this study demonstrates that endothelial-specific Notch activation exacerbates NASH by inhibiting eNOS transcription, while administration of the pharmacological eNOS activator YC-1 attenuates hepatic steatosis and lipid accumulation caused by Notch activation
.
Finally, to explore the therapeutic potential of Notch inhibitors in the treatment of NASH, this study applied two γ-secretase inhibitors, DAPT and LY3039478, in a mouse model of MCD diet-induced NASH and found that both inhibitors could Effectively improve liver steatosis, inflammation and liver fibrosis
.
In conclusion, this study found that endothelial-specific Notch activation triggers LSEC maladaptation and exacerbates the NASH phenotype in an eNOS-dependent manner
.
Genetic and pharmacological inhibition of Notch signaling effectively restores LSEC homeostasis and improves NASH progression
.
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide
.
It is estimated that NAFLD affects one quarter of the global population and the incidence is increasing rapidly year by year
.
NAFLD presents a natural progression and can be divided into three stages according to pathological characteristics, namely non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), and finally develops into cirrhosis
.
In recent years, abnormal lipid metabolism, inflammation, fibrosis, apoptosis, insulin resistance, and the gut-liver axis have all been associated with NASH progression
.
However, there are currently no effective treatments for this disease
.
Hepatocyte steatosis is the main pathological change in the liver of NASH patients
.
Therefore, most studies have focused on the role of hepatocytes in the development of NASH
.
However, the importance of hepatic non-parenchymal cells (NPCs), including hepatic sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), and macrophages, in the pathophysiology of NASH has been increasingly recognized
.
LSECs constitute the largest proportion of NPCs in hepatic sinusoids and have been found to play a particularly critical role in NASH
.
LSECs are highly specialized ECs lining hepatic sinusoids
.
Differentiated LSECs are characterized by the presence of fenestrations, which establish channels for the exchange of lipids, lipoproteins, and macromolecules between hepatocytes and blood
.
In addition, LSEC can transfer lipids through endocytosis
.
Under pathological conditions, hepatic sinusoidal homeostasis is prone to disruption, and LSECs undergo a series of morphological and functional changes, such as reduced fenestration numbers and impaired endocytosis, which largely disrupt the interaction between hepatocytes and blood.
lipid exchange, leading to NASH progression
.
Therefore, maintaining LSEC homeostasis is expected to slow the development of NASH
.
Notch signaling is a highly conserved developmental pathway involving diverse ligands
.
Cleavage of the Notch receptor by γ-secretase results in the release and nuclear translocation of the Notch intracellular domain (NICD)
.
In the nucleus, NICD interacts with recombinant signal-binding protein (RBP-J) in the kappa J region of immunoglobulins, leading to the recruitment of other transcriptional coactivators and activation of downstream target genes such as HES1/5 and HESR1/2
.
Aberrant activation of Notch signaling can lead to diseases such as Alagille syndrome and leukoencephalopathy (CADASIL)
.
Notch signaling has recently been reported to be activated in hepatocytes during NASH, and is also known to play multiple roles in NASH-related lipid metabolism, inflammation, and fibrosis
.
However, relatively few studies have highlighted the importance of endothelial-derived Notch signaling in the development of NASH
.
Sinusoidal homeostasis is disrupted in nonalcoholic steatohepatitis (NASH) (figure from Hepatology) It is well known that Notch signaling is a key regulator of angiogenesis
.
In the liver, endothelial Notch signaling is necessary for the prevention of hepatic vascular malformations
.
Conditional knockout of Notch/RBP-J results in impaired LSEC homeostasis and interferes with liver regeneration
.
Endothelial-specific Notch activation aggravates CCl4-induced liver fibrosis and impairs liver regeneration
.
Collectively, these findings suggest that endothelial Notch signaling is essential for maintaining LSEC homeostasis and thus recovery from liver injury
.
Here, the study found that LSEC homeostasis was disrupted and endothelial-derived Notch signaling was reactivated in methionine-choline deficient (MCD) diet-induced NASH mice
.
Forced activation of endothelial Notch signaling exacerbates NASH in an eNOS-dependent manner, whereas RBP-J deletion or pharmacological inhibition of Notch signaling causes the opposite effect
.
Taken together, these findings highlight the therapeutic potential of endothelial-specific Notch inhibition in the treatment of NASH and NAFLD
.
Reference message: https://aasldpubs.
onlinelibrary.
wiley.
com/doi/10.
1002/hep.
32332
