Copper homeostasis dysregulation promoting cell damage and the association with liver diseases

Abstract

Copper plays an important role in many metabolic activities in the human body. Copper level in the human body is in a state of dynamic equilibrium. Recent research on copper metabolism has revealed that copper dyshomeostasis can cause cell damage and induce or aggravate some diseases by affecting oxidative stress, proteasome, cuprotosis, and angiogenesis. The liver plays a central role in copper metabolism in the human body. Research conducted in recent years has unraveled the relationship between copper homeostasis and liver diseases. In this paper, we review the available evidence of the mechanism by which copper dyshomeostasis promotes cell damage and the development of liver diseases, and identify the future research priorities.

Figure 1

Copper homeostasis in liver depends on the balance between absorption of copper in the duodenum and its excretion in the bile. (1) After being reduced by Cyt B or other reductases, Cu (I) is transported into the duodenum enterocytes by the non-specific DMT1 and the specific CTR1. Chaperones inside the cell transport copper to different cellular organelles or bind MT to store Cu. ATP7A either pumps copper into the TGN to assist cuproenzyme production or exports copper out of the cell. The Cu (I) in blood is oxidized Cu (II), which is then predominantly bound to albumin and α2-macroglobulin in the portal circulation and delivered to the liver. (2) After being reduced by STEAP, Cu (I) is transported into hepatocytes by CTR1 and distributed by chaperones. ATOX1 carries copper to ATP7B, which then transports copper into the TGN for integration into cuproenzymes (i.e., CP) and release by hepatocytes. It is likely that GSH and MT bind Cu for intracellular copper stores. CCS delivers Cu to SOD1. Cox17 carries Cu to CCO in the mitochondria. Excess copper is also transported across the canalicular membrane into bile for excretion by ATP7B. ATOX1: Antioxidant 1 copper chaperone; CCO: Cytochrome C oxidase; CCS: Copper chaperone for superoxide dismutase; Cox17: Cytochrome C oxidase assembly protein 17; CP: Ceruloplasmin; CU ⁺: Copper (I); CU2 ⁺: Copper (II); Cyt B: Cytochrome B; DMT1: Divalent metal transporter 1; SOD1: Copper-zinc superoxide dismutase; STEAP: Six trans membrane epithelial antigen of the prostate; TGN: Trans-Golgi network; CTR1: Copper transporter 1; MT: Metallothionein; GSH: Glutathione.

Figure 2

Schematic illustration of the mechanism by which copper deficiency or overload promotes cell damage. Copper deficiency: (1) Copper directly binds ANG to stimulate angiogenesis and binds HIF-1 to activate IL-1, 6, 8, VEGF, and bFGF, Copper deficiency inhibits angiogenesis. (2) By generating ROS and inducing oxidative stress, SOD1 activity suppression activates apoptotic proteins. Copper overload: (1) By generating ROS, oxidative stress is induced, which increases the levels of APAF-1 and procaspase 9, subsequently activating caspase 3, 7, that further leads to the induction of apoptosis. (2) Proteasome inhibition decreases the expression of anti-apoptotic proteins (e.g., Bcl2) and increases the accumulation of P53 and cyclin-dependent kinase inhibitors P21 and P27, which activates the caspase cascade and results in cell cycle arrest in G1 phase. (3) The ROS-mTOR pathway triggers autophagy, which in turn suppresses copper-induced mitochondrial malfunction and apoptosis, and promotes cellular ferroptosis by reducing GPX4 and ferritin such as FTH-1 to increase the free iron in the cytosol. (4) Copper overload encourages the production of CP and GSH synthesis, which inhibits ferroptosis. (5) Copper-XIAP inhibits XIAP activities and enhances XIAP degradation to promote apoptosis. (6) Lipoylated protein aggregation and decreased Fe-S cluster proteins cause cuproptosis. ANG: Angiopoietin; CytC:cytochrome C; APAF-1: Apoptotic protease-activating factor 1; BAX: B-cell lymphoma-2 associated X protein; Bcl2: B-cell lymphoma-2; bFGF: Basic fibroblast growth factor; CP: Ceruloplasmin; Cu: Copper; DLAT: Pyruvate dehydrogenase complex acyltransferase dihydrolipoamide transacetylase; GPX4: Glutathione peroxidase 4; GSH: Glutathione; HIF-1: Hypoxia-inducible factor-1; ROS: Reactive oxygen species; SOD1: Copper-zinc superoxide dismutase; ULK1: unc51-like autophagy activating kinase 1; VEGF: Vascular endothelial growth factor; XIAP: X-linked inhibitor of apoptosis protein; mTOR: Mammalian target of rapamycin; IL: Interleukin.