The cellular pathways of liver fibrosis in non-alcoholic steatohepatitis

Abstract

Non-alcoholic steatohepatitis (NASH) is considered the advanced stage of non-alcoholic fatty liver disease (NAFLD). It is characterized by liver steatosis, inflammation and different degrees of fibrosis.Although the exact mechanisms by which fatty liver progresses to NASH are still not well understood, innate and adaptive immune responses seem to be essential key regulators in the establishment, progression, and chronicity of these disease. Diet-induced lipid overload of parenchymal and non-parenchymal liver cells is considered the first step for the development of fatty liver with the consequent organelle dysfunction, cellular stress and liver injury. These will generate the production of pro-inflammatory cytokines, chemokines and damage-associated molecular patterns (DAMPs) that will upregulate the activation of Kupffer cells (KCs) and monocyte-derived macrophages (MMs) favoring the polarization of the tolerogenic environment of the liver to an immunogenic phenotype with the resulting transdifferentiation of hepatic stellate cells (HSCs) into myofibroblasts developing fibrosis. In the long run, dendritic cells (DCs) will activate CD4+ T cells polarizing into the pro-inflammatory lymphocytes Th1 and Th17 worsening the liver damage and inflammation. Therefore, the objective of this review is to discuss in a systematic way the mechanisms known so far of the immune and non-proper immune liver cells in the development and progression of NASH.

Role of Oxidative Stress in Hepatic and Extrahepatic Dysfunctions during Nonalcoholic Fatty Liver Disease (NAFLD)

“…Chronic liver injury by NAFLD can progress to parenchymal scarring, cellular dysfunction, and, ultimately, to organ failure, in which OS has a crucial role [ 48 ]. The main OS-dependent alterations observed in NAFLD are liver cell abnormalities and endothelial dysfunction (ED).…”

“…Hepatic LTX produces OS, which activates Kupffer cells (KC) and hepatic stellate cells (HSC), inducing fibrosis in hepatic tissue [ 48 ]. OS-induced KC activation triggers an innate and adaptive immune response with the release of proinflammatory cytokines and chemokines, which activate natural killer T cells and HSC [ 48 , 49 ]. This response is reinforced by OS generated in hepatocytes.…”

“…This response is reinforced by OS generated in hepatocytes. Thus, OS activates the nuclear factor-kappa β (NF- κβ ) pathway, causing the production of proinflammatory cytokines favoring apoptosis of hepatocytes and fibrosis [ 41 , 48 ].…”

The Mitochondrial Citrate Carrier SLC25A1/CIC and the Fundamental Role of Citrate in Cancer, Inflammation and Beyond

“…This was later corroborated in murine models of NAFLD/NASH [ 16 ]. Inflammation is a major driver of pathology in this disease, eventually responsible for the evolution to irreversible fibrosis driven by remodeling of the extracellular matrix under the constant insults propelled by pro-inflammatory signals [ 56 ]. Macrophages and, particularly, the M1 population are at least in part responsible for these alterations [ 57 ].…”

The Role of IL-35 in the Pathophysiological Processes of Liver Disease

“…Frequently, liver diseases caused by inflammatory reaction and oxidative stress could lead to the accumulation of extracellular matrix (ECM), which then progressed to hepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC) ( Chen et al, 2020c ). Of note, liver diseases were related to imbalance between the innate immune and adaptive immune ( Mendez-Sanchez et al, 2020 ). Various immune cells (Treg cells, Th cells, CD4/CD8+ T cells, Kupffer cells, liver mononuclear cells) and inflammatory cytokines (TNF-α, interleukin, interferon) were produced in response to risk factors, such as viruses, high-fat eating habits, alcohol and drug ( Roderburg et al, 2020 ).…”