Chronic liver disease is characterized by hepatocyte injury and inflammation that lead to the development of cirrhosis and liver cancer, accounting for approximately 2 million deaths every year worldwide (1). Multiple etiologies include chronic HBV and HCV infection, nonalcoholic steatohepatitis (NASH), alcoholic liver disease, and autoimmune liver disease cause the global burden of liver disease. Hepatocytes comprise the majority (~85%) of the liver mass, and play a role in various biochemical and metabolic functions (2). Traditional concepts viewed hepatocytes as targets of immune or insults mediated injury, resulting in hepatocyte death which identified as a typical pathological feature in liver disease. However, recent studies have emphasized a role for hepatocyte as active drivers in liver inflammation and fibrosis through intercellular communication (3). Organelle damage, including mitochondria, lysosome, endoplasmic reticulum may determine the severity of hepatocyte injury (4). It is widely accepted that sterile hepatocyte death leads to the release of damage-associated molecular patterns (DAMPs), which are recognized by the innate immune system through pattern recognition receptors, and exaggerate inflammatory response in liver (5). What’s more, stressed hepatocytes engage in liver inflammation as well, for they can change their phenotype, make an adaptation to the microenvironment and alter their surrounding cell populations (2). Substantial evidence show that hepatocytes constitutively produce and secrete a variety of mediators that play important roles in immune regulation and fibrosis (6, 7). In this review, we will provide current literature investigating the adaptive and maladaptive alterations of hepatocytes during the initiation of liver injury, and how the stressed hepatocytes interact with the surrounding cells to trigger a proinflammatory microenvironment in chronic liver disease.

Endoplasmic reticulum (ER) is the major site of secretory and transmembrane protein folding, calcium homeostasis and lipid synthesis. Upon the accumulation of misfolded proteins in the ER, unfolded protein response (UPR) is activated by three ER-transmembrane sensors, namely PKR like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol requiring enzyme 1 (IRE1), coordinately through downstream factors including X-box binding protein 1 (XBP1), α-subunit of eukaryotic initiation factor 2 (eIF2α), C/EBP homologous protein (CHOP), activating Transcription Factor 4 (ATF4), to resolve the protein folding defect (8). Sustained or massive ER stress leads to hepatocyte steatosis and apoptosis (9) ( Figure 1 ).

ER stress is observed in many chronic liver diseases. Chronic ER stress plays a causative role in NAFLD progression by promoting lipogenesis, disturbing mitochondrial function and modulating insulin signaling (10). ER stress markers are shown to decline in livers of obese patients following weight loss after bariatric surgery (11). It has confirmed that impaired autophagic flux is associated with increased ER stress in livers from patients with biopsy-proven NASH during the development of NAFLD (12). Various HBV and HCV proteins localize inside the ER lumen and are undergo envelopment. HBV infection can cause ER stress, which enhance HBV viral replication by initiating autophagy (13). Moreover, chronic HCV infection induce ER stress and the minimal expression of UPR target genes, which confers hepatocytes adaptation and resistance to liver injury (14–16). Hepatic PHLDA3 regulates ER stress-induced hepatocyte death through Akt inhibition in HCV hepatitis (17). Besides, it is reported that interferon regulatory factor 3 (IRF3) is activated by ER stress and induce hepatocyte apoptosis in early alcoholic liver disease (18).

Under chronic ER stress, UPR is linked to the activation of several inflammatory response pathways including NFκB, JNK, ROS, IL-6, TNF-α (8, 19). Activated IRE1α induces JNKs activation, and subsequent implicates in cell pro-inflammatory and pro-apoptotic pathways. Knockdown of JNK1 gene protects mice from the development of obesity and insulin resistance (20). Enhanced ER stress can trigger NFκB activation through IRE1α and PERK pathway, followed by the secretion of inflammatory and chemotactic cytokines in hepatocytes (21, 22). Some HCV and HBV protein accumulate at the ER membranes which cause a deregulation of Ca2+ flux, generation of reactive oxygen and nitrogen species, and the resulting ER stress could induce IL-8 transcription (10, 23, 24). ER stress also induces CHOP-dependent NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome activation in hepatocytes, potentially causing pyroptotic death and hepatic inflammation in patients with HBV-associated liver failure and NAFLD (25, 26). Recent study shows that activation of IRE1A in hepatocytes promotes the release of inflammatory extracellular vesicles (EVs), which recruit macrophages to liver, resulting in liver inflammation and injury in steatohepatitis (27). Therefore, chronic ER stress cause inflammation and the deregulation of lipid metabolism, that further exacerbate liver diseases.

Autophagy is a catabolic lysosomal process responsible for clearing damaged proteins, dysfunction organelles and lipid droplets. It is considered as a cellular response to maintain energy balance and in reaction to multiple of cellular stress, such as starvation, hypoxia, and viral infection (28).

Autophagy generally plays a protective role in hepatocytes, since they can protect against steatosis and hepatocyte death. It is reported autophagy can selectively degrades lipid droplets, termed lipophagy, as evidenced by the increase in lipid accumulation upon inhibition of autophagy in hepatocytes (29). Recent studies with specific genetic inhibition of autophagy have established that hepatocytes are more susceptible to various liver injury, such as alcohol, toxic agents, lipotoxic metabolites, and pro-inflammatory factors. Autophagy may promote cell survival by clearing misfolded proteins, lipids and damaged mitochondria (30–33).

Studies show that regulation of autophagy links to the progression of chronic liver diseases. Impaired autophagic flux links to steatosis and progression to NASH in NAFLD patients and mouse models by genetic or phamacological inhibition of autophagy (12). Shen et al. have uncovered pathogenesis of IL-1β-induced liver injury in steatohepatitis by finding that IL-1β becomes cytotoxic and pro-inflammatory to hepatocytes when inhibition of autophagy, leading to cell necrosis and liver inflammation (34). Although autophagy can alleviate hepatocyte apoptosis and steatosis in acute alcohol liver disease (35), decrease autophagic flux in hepatocyte is observed in models of chronic alcohol exposure (36, 37). A significant decrease in UQCRC2 protein expression cause impaired mitophagy, which may aggravate MLKL-mediated hepatocyte necroptosis and inflammation in alcoholic liver disease (38, 39). Furthermore, early autophagy enhance HBV infection and envelopment (40). Inhibition of autophagy by liver-specific knockout of Atg5 in HBV transgenic mice can obviously reduce HBV DNA level (41). Additionally, autophagy plays an important role in HBV-mediated immune response (40). GAL9, a type I IFN-stimulated gene, exerts effect on direct autophagic degradation of HBc in HBV-infected hepatocytes (42). ATG12 is required for HBV replication and impediment of the IFN signaling pathway, as evidence by decreased levels of IFN-α, IFN-β in ATG12-knockdown hepatocytes (43). Autophagy inhibition also abrogates HBx-induced activation of nuclear factor-κB (NF-κB) and production of interleukin-6 (IL-6), IL-8, and CXCL2 (44). Similarly, autophagy is required to promote HCV replication, partly through suppression of innate immunity (45, 46). HCV-induced autophagy can suppress host innate immune response through autophagic degradation of TRAF6, which is an important signaling molecule that mediates the activation of NF-kB and expression of cytokines and interferons (47). Meanwhile, loss of autophagy signaling upregulates HCV-induced cytoplasmic RIG-I signaling and IFN-β–mediated antiviral responses (48). Interference of HCV-induced mitophagy by Drp1 silencing enhances innate immune signaling (49). The correlation between AIH and autophagy in hepatocyte is not clear. It has been observed increased LC3 and p62 expression in hepatocytes of AIH patients, and p62 level is strongly correlated with necroinflammatory grade, which indicates that decreasing autophagic activity may be linked to severity of inflammation in AIH (50).

Mitochondria are abundant in the liver and required for lipid metabolism and energy production. They can directly or indirectly influence other cellular components such as the lysosomes, the endoplasmic reticulum (ER), and cytosolic pathway, to meet the cellular demands and alleviate mitochondrial dysfunction (51). Generally, mitochondria maintain normal morphology and homeostasis by the way of mitochondrial quality control, including the regulation of mitochondrial fusion, fission, biogenesis, and mitophagy (52). When they fail to adapt to various stress, they can release mitochondrial DNA (mtDNA) in the cytosol or circulation, which could induce cGAS-STING-dependent type I interferon (IFN) response. Furthermore, mtDNA synthesis can activate the NLRP3 inflammasome which initiates inflammation (53). In addition, mitochondrial dysfunction can generate excessive reactive oxygen species (ROS), which stimulate synthesis of cytokines to amplify the inflammatory cascade reaction and cause apoptosis and necrosis of hepatocytes (52) ( Figure 2 ).

Emerging evidence shows that mitochondria dysfunction, especially mitochondria-derived immunogenic components (including its DNA) have profound impacts on the development of various chronic liver diseases. It is reported that NASH patients produce high mitochondrial levels of ROS and ROS-mediated mtDNA damage (54). Moreover, mtDNA is elevated in the serum of NASH patients and in association with histological degree of hepatic fibrosis. The mtDNA released from injured hepatocyte mitochondria could directly activate hepatic stellate cells (HSCs) and promote inflammation through binding to endosomal TLR9 of Kupffer cells (55, 56). Besides, Mitochondrial protein mitofusion 2 (Mfn2) plays an important role in connecting ER membranes to mitochondria and mitochondrial fusion, studies show that hepatic mfn2 deficiency impairs ER-mitochondrial phosphatidylserine transfer and mitochondrial function, leading to ER stress and liver inflammation in NAFLD (57, 58). Mitochondrial dysregulation is also observed in hepatocytes of patients with AIH and experimental mouse model with immune-mediated liver injury. Blockade of dynamin-related protein 1(Drp1)-mediated mitochondrial fission protects mice from concanavalin A (ConA)-induced liver injury (59). In addition, hepatic ATF4 plays a pathological role in alcohol-induced mitochondrial dysfunction and liver injury by repressing TFAM expression, while AMPK protects against alcohol-induced liver injury through up-regulating mitophagy (39, 60). Apart from the above, chronic HBV and HCV infection could induce mitochondrial oxidative stress and mitochondrial antiviral signaling-mediated innate immune signaling as well (61, 62).

During chronic liver injury, stressed hepatocytes can release mediators that involved in crosstalk between hepatocytes and surrounding cell populations. Besides, hepatocytes serve as liver-resident nonprofessional antigen presenting cells (APCs), resulting in a bias toward immune tolerance.

A growing number of evidences have demonstrated stressed hepatocytes exert a pivotal role on the development of inflammation and fibrosis via cell-cell interactions during liver injury. In this review, we summarize the role of hepatic organelle disorders in the pathogenesis of chronic liver diseases, especially, their links to liver inflammation. Furthermore, we introduce a wide variety of pro-inflammatory signals carried by hepatocyte derived-EVs that can deliver the message to neighbor target cells and in the circulation to modulate immune response. Besides, we conclude several cytokines and chemokines of hepatocyte origin which engage in chronic liver diseases. Finally, we address briefly antigen-presentation properties of hepatocytes in immune regulation. Understanding of the molecular mechanisms involved in the regulation of hepatic organelle damage, as well as role of hepatocyte in immune regulation may provide us novel insights of dysregulated inflammation during liver injury and identify new therapeutic targets for various liver diseases.

JG and JL contributed to select the topic of the manuscript. WT collected relevant literature. JG wrote the manuscript. JL and DT reviewed and edited the final version of manuscript. All authors contributed to the article and approved the submitted version.