The Race to Bash NASH: Emerging Targets and Drug Development in a Complex Liver Disease

Romero, F. Anthony; Jones, Christopher T.; Xu, Yinchuan; Fenaux, Martijn; Halcomb, Randall L.

doi:10.1021/acs.jmedchem.9b01701

Cited by 76 publications

(66 citation statements)

References 336 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…NAFLD refers to excessive fat deposition in the liver in the absence of ethanol and other clear causes. The main characteristics of this disease are accumulation and diffuse fatty degeneration of hepatocytes (3,4). NAFLD is the most common chronic liver disease (4,5), and NAFLD has become a worldwide public health problem that endangers human health.…”

Section: Introductionmentioning

confidence: 99%

CML/RAGE Signal Bridges a Common Pathogenesis Between Atherosclerosis and Non-alcoholic Fatty Liver

et al. 2020

View full text Add to dashboard Cite

Non-alcoholic fatty liver disease (NAFLD) has become a common chronic disease in the world. NAFLD is not only a simple intrahepatic lesion, but also affects the occurrence of a variety of extrahepatic complications. In particular, cardiovascular complications are particularly serious, which is the main cause of death in patients with NAFLD. To study the relationship between NAFLD and AS may be a new way to improve the quality of life in patients with NAFLD. As we all known, inflammatory response plays an important role in the occurrence and development of NAFLD and AS. In this study, we found that the accumulation of Nε-carboxymethyllysine (CML) in the liver leads to hepatic steatosis. CML can induce the expression of interleukin (IL-1β), interleukin (IL-6), tumor necrosis factor (TNF-α), C-reactionprotein (CRP) by binding with advanced glycosylation end-product receptor (RAGE) and accelerate the development of AS. After silencing RAGE expression, the expression of pro-inflammatory cytokines was inhibited and liver and aorta pathological changes were relieved. In conclusion, CML/RAGE signal promotes the progression of non-alcoholic fatty liver disease and atherosclerosis. We hope to provide new ideas for the study of liver vascular dialogue in multi organ communication.

show abstract

Section: Introductionmentioning

confidence: 99%

CML/RAGE Signal Bridges a Common Pathogenesis Between Atherosclerosis and Non-alcoholic Fatty Liver

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In order to determine the expression characteristics of disease-related clinically significant genes in different cell types/subtypes, we analyzed the gene expression of a series of blood markers and drug targets for NASH diagnosis and therapy in each cell type. Cytokeratin 18 (CK18) is a blood marker of apoptosis and fibrosis for diagnosis of NASH (40). We found that Krt18 , which encodes CK18, is specifically high expressed in cholangiocytes and obviously increased in subtype Cho3 in HF-MCD group (Supplementary Figure S5E and F), suggesting that NASH is accompanied by significant injury and apoptosis of cholangiocytes, especially subtype Cho3, and cholangiocytes may associate with the mechanism of NASH.…”

Section: Resultsmentioning

confidence: 99%

A single-cell transcriptomic atlas characterizes liver non-parenchymal cells in healthy and diseased mice

Wang

Qian

et al. 2021

Preprint

View full text Add to dashboard Cite

The heterogeneity of liver non-parenchymal cells (NPCs) is essential for liver structure and function. However, the current understanding of liver NPCs, especially in different liver diseases, remains incompletely elucidated. Here, a single-cell transcriptome atlas of 171,814 NPCs from healthy and 5 typical liver disease mouse models, including alcoholic liver disease, nonalcoholic steatohepatitis (NASH), drug-induced liver injury, cholestatic, and ischemia-reperfusion liver injury is constructed. The inter- and intra-group heterogeneity of 12 types (and numerous subtypes) of NPCs involving endothelial cells, hepatic stellate cells (HSCs), neutrophils, T cells, and mononuclear phagocytes (MPs) are summarized. A protective subtype of neutrophils characterized by Chil3high is validated and found significantly increasing only in drug-induced and cholestatic liver injury models. Transcriptional regulatory network analysis reveals disease-specific transcriptional reprogramming. Metabolic activity analysis indicates that fibrosis is accompanied by increases in glycolysis and retinol metabolism in activated HSCs and MPs. Moreover, we found that cell-cell interactions between cholangiocytes and immune cells contribute more to cholestatic liver fibrosis compared with NASH, while HSCs are more important for NASH fibrosis. Our atlas, together with an interactive website provides a systematic view of highly heterogeneous NPCs and a valuable resource to better understand pathological mechanisms underlying liver diseases.

show abstract

“…Currently, no specific drug has been approved for clinical use to treat patients with NASH. There are many promising candidates in the drug development pipeline, and some have shown very useful for improving NASH by controlling inflammation in clinical trials (Table 2), such as dual CCR2/5 inhibitor, apoptosis signal-regulating kinase 1 (ASK1) inhibitor, and caspase inhibitor (Romero et al, 2020). Unfortunately, the latest clinic outcomes of selonsertib (an ASK1 inhibitor) and emricasan (a pan-caspase inhibitor) are not satisfied (Loomba et al, 2018;Harrison et al, 2020;Ratziu et al, 2020;Romero et al, 2020).…”

Section: Therapeutic Perspectivesmentioning

confidence: 99%

Targeting Liver Sinusoidal Endothelial Cells: An Attractive Therapeutic Strategy to Control Inflammation in Nonalcoholic Fatty Liver Disease

Wang

Peng

2021

Front. Pharmacol.

View full text Add to dashboard Cite

Nonalcoholic fatty liver disease (NAFLD), especially its advanced stage nonalcoholic steatohepatitis (NASH), has become a threatened public health problem worldwide. However, no specific drug has been approved for clinical use to treat patients with NASH, though there are many promising candidates against NAFLD in the drug development pipeline. Recently, accumulated evidence showed that liver sinusoidal endothelial cells (LSECs) play an essential role in the occurrence and development of liver inflammation in patients with NAFLD. LSECs, as highly specialized endothelial cells with unique structure and anatomical location, contribute to the maintenance of liver homeostasis and could be a promising therapeutic target to control liver inflammation of NAFLD. In this review, we outline the pathophysiological roles of LSECs related to inflammation of NAFLD, highlight the pro-inflammatory and anti-inflammatory effects of LSECs, and discuss the potential drug development strategies against NAFLD based on targeting to LSECs.

show abstract

The Race to Bash NASH: Emerging Targets and Drug Development in a Complex Liver Disease

Cited by 76 publications

References 336 publications

CML/RAGE Signal Bridges a Common Pathogenesis Between Atherosclerosis and Non-alcoholic Fatty Liver

CML/RAGE Signal Bridges a Common Pathogenesis Between Atherosclerosis and Non-alcoholic Fatty Liver

A single-cell transcriptomic atlas characterizes liver non-parenchymal cells in healthy and diseased mice

Targeting Liver Sinusoidal Endothelial Cells: An Attractive Therapeutic Strategy to Control Inflammation in Nonalcoholic Fatty Liver Disease

Contact Info

Product

Resources

About