scholarly journals MyD88 in Hepatic Stellate Cells Promotes the Development of Alcoholic Fatty Liver via the AKT Pathway

2021 ◽  
Author(s):  
Yukun Li ◽  
Miaomiao Wei ◽  
Qi Yuan ◽  
Yu Liu ◽  
Tian Tian ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Signaling Pathway ◽  
Hepatic Stellate Cells ◽  
Adaptor Protein ◽  
Stellate Cells ◽  
Primary Response ◽  
Potential Candidate ◽  
Alcoholic Fatty Liver ◽  
Ethanol Feeding

Abstract Myeloid differentiation primary response gene 88 (MyD88), an adaptor protein in the TLRs signaling pathway, is expressed in various liver cells including hepatocytes, Kupffer cells and hepatic stellate cells (HSCs). However, the specific role of MyD88 in HSCs in alcoholic fatty liver (AFL) has not been well investigated. Here, to study the role of MyD88 in HSCs in the development of AFL and its related molecular mechanism, chronic-binge ethanol mice models were established in mice with specific MyD88 knockout in quiescent (MyD88GFAP−KO) and activated HSCs (MyD88SMA−KO), respectively. The results showed that the expression of MyD88 in HSCs was significantly increased in ethanol-induced liver tissues of wild-type mice. MyD88 deficiency in quiescent HSCs inhibited inflammation and lipogenesis, but in activated HSCs it only inhibited inflammation under the ethanol feeding condition. Further mechanism studies found that MyD88 promoted the osteopontin (OPN) secretion of HSCs, which further activated the AKT signaling pathway of hepatocytes and upregulated lipogenic gene expression to promote fat accumulation. In addition, OPN also promotes inflammation by activating p-STAT1. Thus, MyD88 may represent a potential candidate target for the prevention and targeted therapy in AFL, and MyD88 inhibitor can be also applied in inhibiting adipogenesis.

scholarly journals Role of G Protein-Coupled Receptors in Hepatic Stellate Cells and Approaches to Anti-Fibrotic Treatment of Non-Alcoholic Fatty Liver Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Takefumi Kimura ◽  
Simran Singh ◽  
Naoki Tanaka ◽  
Takeji Umemura
Keyword(s):  
Liver Disease ◽  
Hepatic Fibrosis ◽  
Hepatic Stellate Cells ◽  
Fatty Liver Disease ◽  
Stellate Cells ◽  
G Protein Coupled Receptors ◽  
Alcoholic Fatty Liver ◽  
G Protein Coupled ◽  
Alcoholic Fatty Liver Disease

The prevalence of non-alcoholic fatty liver disease (NAFLD) is globally increasing. Gaining control over disease-related events in non-alcoholic steatohepatitis (NASH), an advanced form of NAFLD, is currently an unmet medical need. Hepatic fibrosis is a critical prognostic factor in NAFLD/NASH. Therefore, a better understanding of the pathophysiology of hepatic fibrosis and the development of related therapies are of great importance. G protein-coupled receptors (GPCRs) are cell surface receptors that mediate the function of a great variety of extracellular ligands. GPCRs represent major drug targets, as indicated by the fact that about 40% of all drugs currently used in clinical practice mediate their therapeutic effects by acting on GPCRs. Like many other organs, various GPCRs play a role in regulating liver function. It is predicted that more than 50 GPCRs are expressed in the liver. However, our knowledge of how GPCRs regulate liver metabolism and fibrosis in the different cell types of the liver is very limited. In particular, a better understanding of the role of GPCRs in hepatic stellate cells (HSCs), the primary cells that regulate liver fibrosis, may lead to the development of drugs that can improve hepatic fibrosis in NAFLD/NASH. In this review, we describe the functions of multiple GPCRs expressed in HSCs, their roles in liver fibrogenesis, and finally speculate on the development of novel treatments for NAFLD/NASH.

scholarly journals The Role of Notch Signaling Pathway in Non-Alcoholic Fatty Liver Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
Hao Xu ◽  
Lin Wang
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Fatty Liver Disease ◽  
Notch Signaling Pathway ◽  
Alcoholic Fatty Liver ◽  
New Evidence ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and progressive NAFLD can develop into non-alcoholic steatohepatitis (NASH), liver cirrhosis, or hepatocellular carcinoma (HCC). NAFLD is a kind of metabolic disordered disease, which is commonly associated with lipid metabolism, insulin resistance, oxidative stress, inflammation, and fibrogenesis, as well as autophagy. Growing studies have shown Notch signaling pathway plays a pivotal role in the regulation of NAFLD progression. Here, we review the profile of the Notch signaling pathway, new evidence of Notch signaling involvement in NAFLD, and describe the potential of Notch as a biomarker and therapeutic target for NAFLD treatment.

scholarly journals Ultrastructural Changes of Hepatic Stellate Cells in the Space of Disse in Alcoholic Fatty Liver

2001 ◽  
Vol 16 (3) ◽  
pp. 160-166 ◽  
Author(s):  
Nam Ik Han ◽  
Kyu Won Chung ◽  
Byung Min Ahn ◽  
Sang Wook Choi ◽  
Young Sok Lee ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Ultrastructural Changes ◽  
Alcoholic Fatty Liver ◽  
Space Of Disse

The role of cytochrome P-4502E1 in the progression of alcoholic and non-alcoholic fatty liver

2010 ◽  
Vol 48 (08) ◽  
Author(s):  
H Qin ◽  
K Glassen ◽  
G Millonig ◽  
KB Linhart ◽  
H Bartsch ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Alcoholic Fatty Liver

scholarly journals The Role of the Transsulfuration Pathway in Non-Alcoholic Fatty Liver Disease

2021 ◽  
Vol 10 (5) ◽  
pp. 1081
Author(s):  
Mikkel Parsberg Werge ◽  
Adrian McCann ◽  
Elisabeth Douglas Galsgaard ◽  
Dorte Holst ◽  
Anne Bugge ◽  
...  
Keyword(s):  
Liver Disease ◽  
Animal Models ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Alcoholic Fatty Liver ◽  
Precise Control ◽  
Transsulfuration Pathway ◽  
Global Population ◽  
Alcoholic Fatty Liver Disease

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing and approximately 25% of the global population may have NAFLD. NAFLD is associated with obesity and metabolic syndrome, but its pathophysiology is complex and only partly understood. The transsulfuration pathway (TSP) is a metabolic pathway regulating homocysteine and cysteine metabolism and is vital in controlling sulfur balance in the organism. Precise control of this pathway is critical for maintenance of optimal cellular function. The TSP is closely linked to other pathways such as the folate and methionine cycles, hydrogen sulfide (H2S) and glutathione (GSH) production. Impaired activity of the TSP will cause an increase in homocysteine and a decrease in cysteine levels. Homocysteine will also be increased due to impairment of the folate and methionine cycles. The key enzymes of the TSP, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), are highly expressed in the liver and deficient CBS and CSE expression causes hepatic steatosis, inflammation, and fibrosis in animal models. A causative link between the TSP and NAFLD has not been established. However, dysfunctions in the TSP and related pathways, in terms of enzyme expression and the plasma levels of the metabolites (e.g., homocysteine, cystathionine, and cysteine), have been reported in NAFLD and liver cirrhosis in both animal models and humans. Further investigation of the TSP in relation to NAFLD may reveal mechanisms involved in the development and progression of NAFLD.

scholarly journals Role of Insulin Resistance in MAFLD

2021 ◽  
Vol 22 (8) ◽  
pp. 4156
Author(s):  
Yoshitaka Sakurai ◽  
Naoto Kubota ◽  
Toshimasa Yamauchi ◽  
Takashi Kadowaki
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
De Novo Lipogenesis ◽  
Hepatic Insulin Resistance ◽  
Metabolic Dysfunction ◽  
Alcoholic Fatty Liver ◽  
Fat Accumulation

Many studies have reported that metabolic dysfunction is closely involved in the complex mechanism underlying the development of non-alcoholic fatty liver disease (NAFLD), which has prompted a movement to consider renaming NAFLD as metabolic dysfunction-associated fatty liver disease (MAFLD). Metabolic dysfunction in this context encompasses obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and metabolic syndrome, with insulin resistance as the common underlying pathophysiology. Imbalance between energy intake and expenditure results in insulin resistance in various tissues and alteration of the gut microbiota, resulting in fat accumulation in the liver. The role of genetics has also been revealed in hepatic fat accumulation and fibrosis. In the process of fat accumulation in the liver, intracellular damage as well as hepatic insulin resistance further potentiates inflammation, fibrosis, and carcinogenesis. Increased lipogenic substrate supply from other tissues, hepatic zonation of Irs1, and other factors, including ER stress, play crucial roles in increased hepatic de novo lipogenesis in MAFLD with hepatic insulin resistance. Herein, we provide an overview of the factors contributing to and the role of systemic and local insulin resistance in the development and progression of MAFLD.

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