Inflammatory signaling in NASH driven by hepatocyte mitochondrial dysfunctions

Abstract

Liver steatosis, inflammation, and variable degrees of fibrosis are the pathological manifestations of nonalcoholic steatohepatitis (NASH), an aggressive presentation of the most prevalent chronic liver disease in the Western world known as nonalcoholic fatty liver (NAFL). Mitochondrial hepatocyte dysfunction is a primary event that triggers inflammation, affecting Kupffer and hepatic stellate cell behaviour. Here, we consider the role of impaired mitochondrial function caused by lipotoxicity during oxidative stress in hepatocytes. Dysfunction in oxidative phosphorylation and mitochondrial ROS production cause the release of damage-associated molecular patterns from dying hepatocytes, leading to activation of innate immunity and trans-differentiation of hepatic stellate cells, thereby driving fibrosis in NASH.

Keywords: Hepatic stellate cells; Inflammatory process; Mitochondrial dysfunction; NASH; Ox-mtDNA.

Fig. 1

NAFL spectrum during development and progression. In healthy livers, fat accumulation in hepatocytes develops a non-alcoholic fatty liver (NAFL) that can progress from steatosis to a more severe form of steatohepatitis (NASH) characterized by inflammation and fibrosis. In most cases, but not all, NASH can be reversed to less severe disease through changes in lifestyle and diet. Continued fibrogenesis, however, drives progression of NASH to a state of irreversibility, eventually leading to cirrhosis and even hepatocellular carcinoma in some cases

Fig. 2

Liver inflammatory processes under conditions of oxidative stress in impaired mitochondria. Mitochondrial dysfunction triggers ROS production in OXPHOS. The damaged mtDNA formed under stress conditions is released into the cytosol, triggering certain inflammatory processes. NRLP3 inflammasome activation, TLR9 signaling, and activation of the cGAS-STING pathway generate inflammatory mediators, such as cytokines, including interferons, or IFNs. OXPHOS oxidative phosphorylation, OGG1 8-oxoguanine DNA glycosylase-1, FEN1 Flap Structure-Specific Endonuclease 1, VDAC voltage-dependent anion channel, IMM and OMM inner and outer mitochondrial membrane, respectively, NRLP3 NLR Family Pyrin Domain Containing 3, IL interleukin, Cas-1 caspase 1, TLR9 toll-like receptor 9, MyD88 myeloid differentiation primary response 88, cGAS cyclic GMP–AMP synthase, cGAMP cyclic guanosine monophosphate–adenosine, STING stimulator of interferon genes, IRF3 interferon regulatory factor 3. Figure created with BioRender (http://www.BioRender.com)

Fig. 3

Crosstalk between non-parenchymal and surrounding immunological cells in NASH. LSEC liver sinusoidal endothelial cells, NK natural killer, NKT natural killer T, HSC hepatic stellate cell, DAMPs damage-associated molecular pattern. Figure created with BioRender (http://www.BioRender.com)