Metabolic inflammation as an instigator of fibrosis during non-alcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive storage of fatty acids in the form of triglycerides in hepatocytes. It is most prevalent in western countries and includes a wide range of clinical and histopathological findings, namely from simple steatosis to steatohepatitis and fibrosis, which may lead to cirrhosis and hepatocellular cancer. The key event for the transition from steatosis to fibrosis is the activation of quiescent hepatic stellate cells (qHSC) and their differentiation to myofibroblasts. Pattern recognition receptors (PRRs), expressed by a plethora of immune cells, serve as essential components of the innate immune system whose function is to stimulate phagocytosis and mediate inflammation upon binding to them of various molecules released from damaged, apoptotic and necrotic cells. The activation of PRRs on hepatocytes, Kupffer cells, the resident macrophages of the liver, and other immune cells results in the production of proinflammatory cytokines and chemokines, as well as profibrotic factors in the liver microenvironment leading to qHSC activation and subsequent fibrogenesis. Thus, elucidation of the inflammatory pathways associated with the pathogenesis and progression of NAFLD may lead to a better understanding of its pathophysiology and new therapeutic approaches.

Keywords: Hepatic stellate cells; Inflammation; Liver fibrosis; Nod-like receptors; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Toll-like receptors.

Figure 1

Innate immune pathways and mediators involved in the development of liver fibrosis during non-alcoholic fatty liver disease. Activation of the HSCs is the major event during the development of liver fibrosis. Various mediators released from parenchymal as well as non-parenchymal cells of the liver, as well as from metabolic organs (adipose tissue, gut) can promote HSCs activation. TGF-β and PDGF, mainly produced by liver macrophages, have a central role in hepatic fibrogenesis. HSCs start to produce TGF-β, PDGF and MCP-1 after their activation. Autocrine production of TGF-β and PDGF by activated HSCs induces their further proliferation. Hepatic macrophages, lymphocytes and endothelial cells secrete IL-1α and IL-1β. These molecules participate in the initial extracellular matrix degradation by induction of MMP2, MMP3 and MMP13 expression by HSCs, while are also implicated in HSC survival and proliferation. IL-1β, in particular, induces the expression of TIMP-1, PAI-1 and collagen. In addition, pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α can induce lipid accumulation in hepatocytes and in turn cause hepatocyte injury and inflammation. Apoptotic hepatocytes secrete reactive oxygen species, vascular endothelial growth factor and IGF1, which can activate hepatic macrophages. Pyroptosis can also contribute to the development of fibrosis via activation of NLRs in HSCs. Of note, TLR2, TLR4 and TLR9, expressed by liver macrophages and HSCs are the key Toll-like receptors in the pathophysiology of NASH and metabolism-related liver fibrosis by provoking the expression of pro-inflammatory and pro-fibrotic cytokines by these cells.