Hepatocyte Injury and Hepatic Stem Cell Niche in the Progression of Non-Alcoholic Steatohepatitis

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by lipid accumulation in hepatocytes in the absence of excessive alcohol consumption. The global prevalence of NAFLD is constantly increasing. NAFLD is a disease spectrum comprising distinct stages with different prognoses. Non-alcoholic steatohepatitis (NASH) is a progressive condition, characterized by liver inflammation and hepatocyte ballooning, with or without fibrosis. The natural history of NAFLD is negatively influenced by NASH onset and by the progression towards advanced fibrosis. Pathogenetic mechanisms and cellular interactions leading to NASH and fibrosis involve hepatocytes, liver macrophages, myofibroblast cell subpopulations, and the resident progenitor cell niche. These cells are implied in the regenerative trajectories following liver injury, and impairment or perturbation of these mechanisms could lead to NASH and fibrosis. Recent evidence underlines the contribution of extra-hepatic organs/tissues (e.g., gut, adipose tissue) in influencing NASH development by interacting with hepatic cells through various molecular pathways. The present review aims to summarize the role of hepatic parenchymal and non-parenchymal cells, their mutual influence, and the possible interactions with extra-hepatic tissues and organs in the pathogenesis of NAFLD.

Keywords: adipose tissue; atherosclerosis; disease; ductular reaction; fibrosis; lipotoxicity; liver; macrophage; progenitor cell; regeneration.

Figure 1

Histo-morphological features of non-alcoholic fatty liver disease (NAFLD). The progression from simple steatosis (non-alcoholic fatty liver—NAFL) to non-alcoholic steatohepatitis (NASH) (a) is characterized by increased hepatic steatosis (b) and inflammation, accompanied by the emergence of specific histological features, such as hepatocellular ballooning (arrows in c). As disease advances, liver fibrosis develops (d). H&E: hematoxylin and eosin; scale bars: 200 (a), 50 (b,c) and 100 μm (d). Images obtained from liver biopsies of patients affected by NAFLD.

Figure 2

Ductular reaction (DR), myofibroblasts, and portal macrophages in non-alcoholic fatty liver disease (NAFLD). (a) As NAFLD progresses from simple steatosis to non-alcoholic steatohepatitis (NASH), a prominent DR emerges (arrows in image on the left) and is associated with portal/periportal fibrosis, as evidenced in Sirius Red stains (arrows in image on the right). (b) The expansion of DR is associated with the activation of (α smooth muscle actin-positive) hepatic stellate cells and portal myofibroblasts (arrows), and the recruitment of pro-inflammatory (S100A9⁺) macrophages (arrowheads), which participate in portal/periportal fibrogenetic pathway. PT: portal tract. Scale bars: 100 μm. Images obtained from liver biopsies of patients affected by NAFLD.

Figure 3

Cellular cross-talks in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). The increase of free-fatty acid (FFA) afflux to the liver determinates hepatocyte steatosis (non-alcoholic fatty liver - NAFL); subsequently, the accumulation of abnormal lipid compounds in the hepatocytes causes lipotoxicity, leading to hepatocyte damage, apoptosis and death. Hepatocyte lipotoxicity triggers M1 macrophage recruitment and lobular inflammation (i.e., steatohepatitis: NASH) and, then, pro-fibrogenetic pathways. In pericentral zone, the activation of hepatic stellate cells (HSCs) and the M1 macrophage polarization trigger perisinusoidal fibrosis. At periportal location, ductular reaction emerges and drives the activation of local myofibroblast pools together with M1 macrophage recruitment. The main molecular factors implied in local cellular cross-talks are summarized in the scheme.

Figure 4

Interaction of liver damage with extra-hepatic organs. NAFLD is influences by interaction with other organs/tissues. Adipose tissue disarrangement (expansion/inflammation) induces increased Free Fatty Acid (FFA) afflux to the liver and insulin resistance; moreover, it releases several pro-inflammatory cytokines and modifies the adipocytokine balance. Dysbiosis in the gut results in translocation of endotoxins (i.e., lipopolysaccharides) to the liver and the subsequent activation of the Toll-like Receptor (TLR) pathway in the liver. In turn, liver with NAFLD/NASH can influence atherosclerosis (plaque formation) by several mechanisms, including, but not limited to, systemic inflammation and oxidative stress increase.