Non-Parenchymal Cells and the Extracellular Matrix in Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease

Abstract

Hepatocellular carcinoma (HCC) in the setting of non-alcoholic fatty liver disease (NAFLD)-related cirrhosis and even in the pre-cirrhotic state is increasing in incidence. NAFLD-related HCC has a poor clinical outcome as it is often advanced at diagnosis due to late diagnosis and systemic treatment response is poor due to reduced immune surveillance. Much of the focus of molecular research has been on the pathological changes in hepatocytes; however, immune cells, hepatic stellate cells, liver sinusoidal endothelial cells and the extracellular matrix may play important roles in the pathogenesis of NAFLD-related HCC as well. Here, we review the role of non-parenchymal cells in the liver in the pathogenesis of HCC in the context of NAFLD-NASH, with a particular focus on the innate and the adaptive immune system, fibrogenesis and angiogenesis. We review the key roles of macrophages, hepatic stellate cells (HSCs), T cells, natural killer (NK) cells, NKT cells and liver sinusoidal endothelial cells (LSECs) and the role of the extracellular matrix in hepatocarcinogenesis within the steatotic milieu.

Diagnostic value of triglyceride–glucose index and related parameters in metabolism-associated fatty liver disease in a Chinese population: a cross-sectional study

“…Activated hepatic gluconeogenesis also increases blood glucose levels. 36 High intrahepatic TGs and fasting blood glucose are the distinguishing features of diagnostic MAFLD pairs. Therefore, using the TyG index as a valid diagnostic indicator of MAFLD is logical.…”

Recent Insights into the Biomarkers, Molecular Targets and Mechanisms of Non-Alcoholic Steatohepatitis-Driven Hepatocarcinogenesis

“…It has been shown that stress-related signaling pathways, like c-Jun N-terminal kinase (JNK) and NF-κB, are activated by pro-inflammatory cytokines, such as TNF-α, IL-1, IL-6, STAT3, and ERK. This activation leads to increased hepatocyte proliferation and ultimately promotes the development of hepatocarcinogenesis [ 61 ]. HSCs that are not strongly activated generate growth factors and cytokines, including hepatocyte growth factor (HGF), which can help prevent hepatocyte death and the development of HCC [ 62 ].…”

“…In addition, integrins, which act as cell surface mechanoreceptors, can interfere with TGF-β1 and PDGF and modulate the proliferation and survival of hepatocytes and HSC [ 65 ]. The regenerative repair pathways, such as the Hedgehog signaling pathway, are induced during the process of fibrogenesis in NASH and predict the induction of hepatocarcinogenesis [ 61 ].…”

“…The influence of gut bacterial dysbiosis and microbial metabolites in the promotion of NASH hepatocarcinogenesis, worsening liver disease through enterohepatic circulation, has been recently reported [ 70 , 71 ]. It is known that the liver carries out immunological functions and participates in the physiological connection between gut-derived molecules and the systemic circulation, in which liver macrophages, Kupffer cells (KCs) producing pro-inflammatory and pro-fibrogenic cytokines and chemokines, liver resident cells, and monocytes play a very important role [ 61 ]. M1 macrophages promote inflammation, whereas M2 macrophages exert inhibitory effects and induce tissue repair.…”

“…M1 macrophages promote inflammation, whereas M2 macrophages exert inhibitory effects and induce tissue repair. Moreover, pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, IL-12, C-C chemokine ligand 2 (CCL2) and 5 (CCL5) are secreted by M1 macrophages and exhibit increased amounts of nitric oxide species (NOS) and ROS [ 61 ]. Obesity, whether caused by diet or genetics, can affect the gut microbiota and increase the levels of deoxycholic acid (DCA), a metabolite produced by gut bacteria.…”