A Pathogenic Role of Non-Parenchymal Liver Cells in Alcohol-Associated Liver Disease of Infectious and Non-Infectious Origin

Abstract

Now, much is known regarding the impact of chronic and heavy alcohol consumption on the disruption of physiological liver functions and the induction of structural distortions in the hepatic tissues in alcohol-associated liver disease (ALD). This review deliberates the effects of alcohol on the activity and properties of liver non-parenchymal cells (NPCs), which are either residential or infiltrated into the liver from the general circulation. NPCs play a pivotal role in the regulation of organ inflammation and fibrosis, both in the context of hepatotropic infections and in non-infectious settings. Here, we overview how NPC functions in ALD are regulated by second hits, such as gender and the exposure to bacterial or viral infections. As an example of the virus-mediated trigger of liver injury, we focused on HIV infections potentiated by alcohol exposure, since this combination was only limitedly studied in relation to the role of hepatic stellate cells (HSCs) in the development of liver fibrosis. The review specifically focusses on liver macrophages, HSC, and T-lymphocytes and their regulation of ALD pathogenesis and outcomes. It also illustrates the activation of NPCs by the engulfment of apoptotic bodies, a frequent event observed when hepatocytes are exposed to ethanol metabolites and infections. As an example of such a double-hit-induced apoptotic hepatocyte death, we deliberate on the hepatotoxic accumulation of HIV proteins, which in combination with ethanol metabolites, causes intensive hepatic cell death and pro-fibrotic activation of HSCs engulfing these HIV- and malondialdehyde-expressing apoptotic hepatocytes.

An update on animal models of liver fibrosis

“…The most common signs of fibrosis in NASH are mainly caused by excessive consumption of high-fat components, where patients absorb nutrients The HFD-induced liver fibrosis model overcomes the shortcomings of the MCD-induced liver fibrosis model, in which animals with increased body weight and peripheral insulin resistance develop and mimic the etiology of the disease by Top three animal models used in articles in the field of liver fibrosis treatment: Among the collected articles, the details of the top three animal models used in articles in each field of treatment are as follows: gene therapy: CCl 4 (109), HFD (41), BDL (31); natural substance therapy: CCl 4 (192), HFD (55), TAA (48); herbal therapy. CCl 4 (128), MCD (19), BDL (18), HFD (18); stem cell therapy: CCl 4 (130), BDL (18), TAA (16); drug therapy: CCl 4 (129), HFD (98), BDL (89); biomaterial therapy: CCl 4 (42), TAA (10), BDL (7); microbiological treatment: CCl 4 (13), BDL (7), HFD (6); surgical treatment: TAA (3), DEN (2), CCl 4 (2), HFD (2); general treatment: HFD (15), WD (10), CCl 4 (10); molecular level treatment: CCl 4 (95), BDL (46), HFD (40); combination therapy: CCl 4 (33), TAA (12), HFD (10). replicating poor dietary habits, with phenotypic features similar to those of human nonalcoholic steatohepatitis.…”

“…Moreover, alcohol-stimulated liver fibrosis is the result of strong immune response involving many types of hepatocyte and different signal transduction pathways ( 17 ). Alcohol-induced liver injury significantly increases the production of cytokines, chemokines, other soluble mediators and components of the innate immune system, this pro-inflammatory environment leads to the activation of HSC and myofibroblast, increases the production of extracellular matrix (ECM) proteins, which can subsequently induce fibrosis in the liver ( 18 ).…”

A microvascularizedin vitroliver model for disease modeling and drug discovery

“…Whereas the first suffers from interspecies translational limitations, the latter lacks the complexity of human physiology. In many cases homeostasis and diseases occur in the interplay between hepatocytes, non-parenchymal cells (NPCs), such as stellate cells, endothelial cells and resident macrophages (3)(4)(5)(6)(7)(8). Hence, researchers have developed various advanced in vitro liver models following a more comprehensive approach where hepatocytes and several NPCs are combined.…”