Abstract
Non-alcoholic fatty liver disease (NAFLD) and Alcoholic Liver Disease (ALD) are major causes of liver-related morbidity and mortality and constitute important causes of liver transplantation. The spectrum of the liver disease is wide and includes isolated steatosis, steatohepatitis, and cirrhosis. The treatment of NAFLD and ALD remains, however, an unmet need, and therefore it is a public health priority to develop effective treatments for these diseases. Alcoholic and non-alcoholic liver disease share common complex pathogenetic pathways that involve different organs and systems beyond the liver, including the gut, the adipose tissue, and the immune system, which cross-talk to generate damage. Myeloid-derived cells have been widely studied in the setting of NAFLD and ALD and are implicated at different levels in the onset and progression of this disease. Among these cells, monocytes and macrophages have been found to be involved in the induction of inflammation and in the progression to fibrosis, both in animal models and clinical studies and they have become interesting potential targets for the treatment of both NAFLD and ALD. The different mechanisms by which these cells can be targeted include modulation of Kupffer cell activation, monocyte recruitment in the liver and macrophage polarization and differentiation. Evidence from preclinical studies and clinical trials (some of them already in phase II and III) have shown encouraging results in ameliorating steatohepatitis, fibrosis, and the metabolic profile, individuating promising candidates for the pharmacological treatment of these diseases. The currently available results of myeloid-derived cells targeted treatments in NAFLD and ALD are covered in this review.
Highlights
Fatty liver represents a wide spectrum of disease encompassing stages ranging from isolated steatosis to steatohepatitis and it can be accompanied by different grades of fibrosis up to cirrhosis with all its complications, including hepatocellular carcinoma
The presence at liver histology of steatosis, as well as both lobular inflammation and hepatocyte ballooning identifies steatohepatitis [respectively, non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH), depending on whether or not there is an association with excessive alcohol consumption] [2] (Figure 1)
Non-alcoholic fatty liver disease (NAFLD) can be associated to metabolic impairment and to cardiovascular disease and is considered the hepatic expression of the metabolic syndrome [3, 4] (Table 1)
Summary
Fatty liver represents a wide spectrum of disease encompassing stages ranging from isolated steatosis to steatohepatitis and it can be accompanied by different grades of fibrosis up to cirrhosis with all its complications, including hepatocellular carcinoma. A phase-2 double-blind, placebocontrolled trial of OCA in patients with moderate to severe AH is currently ongoing to evaluate a possible reduction in Model For End-Stage Liver Disease (MELD) score as a measure of effectiveness, as well as the incidence of serious adverse events during treatment This cytokine is a potent stimulus of neutrophil function and is able to mobilize hematopoietic stem cells and induce liver regeneration. DUR-928 is an endogenous, orally bio-available small molecule that modulates the activity of various nuclear receptors that play an important regulatory role in lipid homeostasis, inflammation and cell survival It has been demonstrated in mice models of NASH that this molecule exerts anti-fibrotic and antiinflammatory effects and is able to reduce hepatic transcripts of TNF-α and MCP-1 in a dose-dependent manner [72]. DUR928 is currently being investigated in a phase-2, open-label, dose-escalation study in AH
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