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Review
. 2022 Feb 3:8:802251.
doi: 10.3389/fmolb.2021.802251. eCollection 2021.

Immune and Metabolic Alterations in Liver Fibrosis: A Disruption of Oxygen Homeostasis?

Xinyu Li  1   2 , Quyan Zhang  1   2 , Zeyu Wang  2 , Quan Zhuang  3 , Mingyi Zhao  1
Affiliations
Review

Immune and Metabolic Alterations in Liver Fibrosis: A Disruption of Oxygen Homeostasis?

Xinyu Li et al. Front Mol Biosci. .

Abstract

According to the WHO, "cirrhosis of the liver" was the 11th leading cause of death globally in 2019. Many kinds of liver diseases can develop into liver cirrhosis, and liver fibrosis is the main pathological presentation of different aetiologies, including toxic damage, viral infection, and metabolic and genetic diseases. It is characterized by excessive synthesis and decreased decomposition of extracellular matrix (ECM). Hepatocyte cell death, hepatic stellate cell (HSC) activation, and inflammation are crucial incidences of liver fibrosis. The process of fibrosis is also closely related to metabolic and immune disorders, which are usually induced by the destruction of oxygen homeostasis, including mitochondrial dysfunction, oxidative stress, and hypoxia pathway activation. Mitochondria are important organelles in energy generation and metabolism. Hypoxia-inducible factors (HIFs) are key factors activated when hypoxia occurs. Both are considered essential factors of liver fibrosis. In this review, the authors highlight the impact of oxygen imbalance on metabolism and immunity in liver fibrosis as well as potential novel targets for antifibrotic therapies.

Keywords: hypoxia-inducible factor; immunometabolism; liver fibrosis; mitochondrial dysfunction; oxidative stress.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
HIF pathway applied in liver fibrosis. During the development of liver fibrosis, oxygen mediated metabolic reprogramming occurs in a variety of cells. Abnormal lipid metabolism and activation of HIF in hepatocytes mediate the fibrotic pathway and the activation of HSC cells. Besides, activated HSCs occur in intracellular metabolic reprogramming, and they also mediate the metabolic transformation of other parenchymal cells. (A) In hepatocytes, activated HIF-1α or HIF-2α stimulates upregulation of Cxcl12 through converting latent TGF-β to active TGF-β. Succinate accumulates in hepatocytes due to enhanced fatty acid oxidation, which stabilized and activated HIF-1α through impairing PHDs. Expression of Cxcl12 and HIF-1α is involved in activation of HSCs. (B) In LSECs, PROX1 inhibites HIF‐1α ubiquitination via a deubiquitinase called USP19. A possible loop shows that HIF-1α induces PPARγ expression as a hypoxic response, then overexpressed PPARγ will inhibit HIF-1α transcription hypoxia as a negative feedback. (C) In activated HSCs, HIF-1 upregulates the GLUT1 and PKM2 expression in exosomes. Then these exosomes are absorbed by KCs, LSECs, and quiescent HSCs, which enhanced glycolysis of these nonparenchymal cells. (D) High-fat diet and Apoe knockout are common modeling methods of NAFLD. HIF-1 is also involved in metabolic disorder in the development of NAFLD to liver fibrosis. In this process, cholesterol load increased mitochondrial dysfunction and iNOS levels, which promoted HIF-1 stabilization and transcriptional activity. Then, the abnormal activation of HIF-1 promoted the production of iNOS and formed a malignant loop for fibrosis. Furthermore, HIF-1 is also involved in the circadian locomotor-related metabolic disorders in NAFLD. In CLOCK deficiency, HIF1α binds to the Cd36 promoter, promoting CD36 expression and uptake of fatty acids in the liver. High fat feeding and AP knockout mice are common modeling methods of NAFLD.
FIGURE 2
FIGURE 2
Immune regulation in liver fibrosis. (A) Inflammation is a major process in the development of fibrosis. MtDAMPs, including mtDNA, N-formyl peptides, and ATP, are released to extracellular space in the case of ROS-driven mitochondrial membrane permeability transition. MtDNA can activate NLRP3 inflammasomes, TLR9, and cGAS-STING, which separately induce HSCs, neutrophil, and KCs activation. NFPs are released from dysfunctional mitochondrial, binding to FPRs, which leads to the migration of neutrophil cells to the injury tissue. Released ATP binds to P2X7 receptors on neutrophils, inducing NLRP3-ASC-caspase-1 inflammasome and IL-1β secretion. (B) MSCs act as a bridge to prevent inflammation and oxidative stress via extracellular vesicles, etc. MSCs suppress the proliferation of Th17 cells and decrease the expression of IL-17A and il-17RA. Meanwhile, MSCs promote the activation of M2 macrophages and inhibit M1 macrophages activation, hypoxia-preconditioning, and HIF-1 overexpression can improve MSC therapeutic. (C) HIF may play different roles in different cells. The chronic liver injury activates HIF-1α in macrophages, which may regulate the expression of PDGF-B to induce HSCs activation and fibrosis. However, liver necrotic cells can also activate HIF-1α in HSCs. HIF-1α then stimulated recruited macrophages to remove necrotic hepatocytes and alleviate fibrosis.
FIGURE 3
FIGURE 3
The regulatory mechanism for immunometabolism and oxygen homeostasis in liver fibrosis. The disorders of immunity and metabolism are cross-linked in liver fibrosis and play a central role in the pathogenesis. We reviewed the effect of the destruction of oxygen homeostasis on liver fibrosis and described how oxygen participated in this process through affecting the immune-metabolism axis.
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