scholarly journals The therapeutic potential of C-C chemokine receptor antagonists in nonalcoholic steatohepatitis

2020 ◽  
Vol 1 (4) ◽  
pp. 170-183
Author(s):  
Michael Doulberis ◽  
Kasiani Papadimitriou ◽  
Apostolis Papaefthymiou ◽  
Jannis Kountouras ◽  
Stergios A. Polyzos
Keyword(s):  
Kupffer Cells ◽  
Chemokine Receptor ◽  
Nonalcoholic Steatohepatitis ◽  
Therapeutic Potential ◽  
Hepatic Inflammation ◽  
Dual Inhibitor ◽  
Nonalcoholic Fatty Liver ◽  
Pooled Prevalence ◽  
Immunodeficiency Virus ◽  
Monocytes And Macrophages

Pooled prevalence of nonalcoholic fatty liver disease (NAFLD) globally is about 25%. Nonalcoholic steatohepatitis (NASH) with advanced fibrosis has been linked with substantial morbidity and mortality, without having to-date any licensed treatment. C-C chemokine receptor (CCR) antagonists have been investigated as candidates for the treatment of NASH. Inhibition of CCR2 is expected to mitigate hepatic inflammation, through reducing the activation of Kupffer cells, as well as the infiltration of monocytes and macrophages into the liver. Inhibition of CCR5 is expected to mitigate hepatic fibrogenesis, through impairing the activation of hepatic stellate cells, as well as to mitigate hepatic inflammation, through impairing the activation of Kupffer cells and macrophages. Cenicriviroc (CVC) is the first in class, dual inhibitor of CCR2 and CCR5. After exhibiting favorable results in animal models, CVC was shown to be beneficial in NASH patients with more severe fibrosis at a phase 2b trial (CENTAUR) and is currently at a phase 3 clinical trial (AURORA). Apart from CVC, other CCR5 mono-antagonists, such as maraviroc, are under evaluation in clinical trials with human immunodeficiency virus patients with NAFLD. The aim of this review was to summarize existing evidence on CVC and other CCR antagonists in NASH patients, primarily focusing on their clinical efficacy and safety.

scholarly journals Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2

2012 ◽  
Vol 302 (11) ◽  
pp. G1310-G1321 ◽  
Author(s):  
Kouichi Miura ◽  
Ling Yang ◽  
Nico van Rooijen ◽  
Hirohide Ohnishi ◽  
Ekihiro Seki
Keyword(s):  
Bone Marrow ◽  
Kupffer Cells ◽  
Chemokine Receptor ◽  
Nonalcoholic Steatohepatitis ◽  
Inflammatory Cell ◽  
Therapeutic Potential ◽  
Inflammatory Cell Infiltration ◽  
Cell Infiltration ◽  
Potent Inducer ◽  
Hepatic Macrophages

Inflammatory cell infiltration in the liver is a hallmark of nonalcoholic steatohepatitis (NASH). The chemokine-chemokine receptor interaction induces inflammatory cell recruitment. CC-chemokine receptor (CCR)2 is expressed on hepatic macrophages and hepatic stellate cells. This study aims to investigate the therapeutic potential of CCR2 to NASH. Twenty-two weeks on a choline-deficient amino acid-defined (CDAA) diet induced steatosis, inflammatory cell infiltration, and liver fibrosis with increased CCR2 and monocyte chemoattractant protein (MCP)-1 expression in the wild-type livers. The infiltrated macrophages expressed CD68, CCR2, and a marker of bone marrow-derived monocytes, Ly6C. CCR2−/− mice had less steatosis, inflammatory cell infiltration, and fibrosis, and hepatic macrophages expressing CD68 and Ly6C were decreased. Toll-like receptor (TLR)4−/−, TLR9−/−, and MyD88−/− mice had reduced hepatic macrophage infiltration with decreased MCP-1 and CCR2 expression because TLR signaling is a potent inducer of MCP-1. To assess the role of Kupffer cells at the onset of NASH, Kupffer cells were depleted by liposomal clodronate. The Kupffer cell depletion ameliorated steatohepatitis with a decrease in the MCP-1 expression and recruitment of Ly6C-expressing macrophages at the onset of NASH. Finally, to test the therapeutic potential of targeting CCR2, a CCR2 inhibitor was administered to mice on a CDAA diet. The pharmaceutical inhibition of CCR2 prevented infiltration of the Ly6C-positive macrophages, resulting in an inhibition of liver inflammation and fibrosis. We concluded that CCR2 and Kupffer cells contribute to the progression of NASH by recruiting bone marrow-derived monocytes.

scholarly journals Liver X Receptors Regulate Cholesterol Metabolism and Immunity in Hepatic Nonparenchymal Cells

2019 ◽  
Vol 20 (20) ◽  
pp. 5045 ◽  
Author(s):  
Kaori Endo-Umeda ◽  
Makoto Makishima
Keyword(s):  
Kupffer Cells ◽  
Immune Cell ◽  
Cholesterol Metabolism ◽  
Dietary Cholesterol ◽  
Cell Types ◽  
Hepatic Inflammation ◽  
Cholesterol Accumulation ◽  
Transport Pathway ◽  
Nonalcoholic Fatty Liver ◽  
Nonparenchymal Cells

Excess dietary cholesterol intake and the dysregulation of cholesterol metabolism are associated with the pathogenesis and progression of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and fibrosis. Hepatic accumulation of free cholesterol induces activation of nonparenchymal cells, including Kupffer cells, macrophages, and hepatic stellate cells, which leads to persistent inflammation and fibrosis. The nuclear receptors liver X receptor α (LXRα) and LXRβ act as negative regulators of cholesterol metabolism through the induction of hepatocyte cholesterol catabolism, excretion, and the reverse cholesterol transport pathway. Additionally, LXRs exert an anti-inflammatory effect in immune cell types, such as macrophages. LXR activation suppresses acute hepatic inflammation that is mediated by Kupffer cells/macrophages. Acute liver injury, diet-induced steatohepatitis, and fibrosis are exacerbated by significant hepatic cholesterol accumulation and inflammation in LXR-deficient mice. Therefore, LXRs regulate hepatic lipid metabolism and immunity and they are potential therapeutic targets in the treatment of hepatic inflammation that is associated with cholesterol accumulation.

Nonalcoholic Fatty Liver Disease and Vitamin E - A Promising Relationship?

2019 ◽  
Vol 70 (1) ◽  
pp. 78-83
Author(s):  
Alexandra Totan ◽  
Daniela Gabriela Balan ◽  
Daniela Miricescu ◽  
Radu Radulescu ◽  
Iulia Ioana Stanescu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Vitamin E ◽  
Therapeutic Potential ◽  
Plga Nanoparticles ◽  
Diet Group ◽  
Normal Diet ◽  
Oxidative Stress Biomarkers ◽  
Promising Alternative ◽  
Nonalcoholic Fatty Liver ◽  
High Caloric Diet

Oxidative stress (OS) plays an important role in NAFLD molecular mechanism. Nanoencapsulation represents a novel strategy to enhance therapeutic potential of conventional drugs. Our study analyses the encapsulated vitamin E effect on lipid metabolism and oxidative stress biomarkers in NAFLD rats. Animals were divided into 3 groups : G1 - the normal diet group; G2- the high caloric diet group ; G3 - high-caloric diet group receiving PLGA-vit E, 50 mg / kg. Serum advanced human oxidative protein (AOPP), total antioxidant capacity (TAC) and vitamin E were analysed using ELISA technique. Our results showed significant increase of G2 GPT, ALP, GGT, TG, glucose, TC and AOPP, versus G1 ( P [ 0.05) and a significant decrease of G2 serum TAC and vitamin E versus G1 results ( p = 0.01 and 0.01). Vitamin E nanoparticles (G3) caused a significant increase of TAC and significant decrease of serum AOPP, versus G2 (p [ 0.01). Results showed a significant reduction of GPT, GGT, ALP, TG and total cholesterol ( p [0.05) in G3 versus G2. PLGA nanoparticles should be considered an attractive and promising alternative to improve the bioavailability and biological activity of vitaminE.

Pathological findings of nonalcoholic steatohepatitis and nonalcoholic fatty liver disease

2016 ◽  
Vol 67 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Michiie Sakamoto ◽  
Hanako Tsujikawa ◽  
Kathryn Effendi ◽  
Hidenori Ojima ◽  
Kenichi Harada ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Nonalcoholic Steatohepatitis ◽  
Fatty Liver Disease ◽  
Pathological Findings ◽  
Nonalcoholic Fatty Liver
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