Skip to main content
. 2020 Jul 13;21(14):4932. doi: 10.3390/ijms21144932

Figure 4.

Figure 4

Summary of proposed steps involved in the movement of cu into bile and secreted by hepatocytes. Based mainly on the data, reviews and figures provided by Polishchuk and Polishchuk [26] and Stewart et al. [27]. Cu ions enter hepatocytes from plasma proteins via copper transporter 1 (CTR1) and at least one other as yet unidentified transporter, and are carried via the chaperone ATOX1 to ATP7B (blue triangles) in the transGolgi network (TGN). In the lumen of the TGN, Cu will be incorporated into apoceruloplasmin (apoCp) (violet circles), forming holoCp, and be released into the blood plasma by exocytosis (center right of the figure) across the “basolateral” hepatocyte membrane. In the absence of excessive Cu not otherwise incorporated into Cp and endogenous Cu-dependent proteins and mitochondria, TGN Cu in the lumen will be exported to the bile canaliculi that are formed between hepatocyte apical membranes, leading to the gall bladder and bile duct. This happens through the budding of vesicles from the TGN that contain Cu and may also contain ATP7B. These fuse with late endosomes also containing ATP7B as well as lysosomes (to form the endo-lysosomal compartment), which then fuses with the apical hepatocyte membrane at a canaliculus (left side of figure). This releases Cu that was present in the vesicular bodies and also can lead to ATP7B being part of the apical membrane. The latter is particularly important in the presence of excess Cu, which can then flow from ATOX1 directly to ATP7B that pumps it into the bile canaliculi. Small amounts of the Cu efflux “pump”, ATP7A (blue squares), are also expressed in hepatocytes (far right of the figure), and may also contribute to Cu that exits hepatocytes and enters the blood plasma, to bind to proteins like albumin in the exchangeable plasma Cu pool. Based on what is known in other cells, the much less abundant ATP7A in hepatocytes would either transfer some Cu in the TGN into secretory vesicles (for exocytosis), and/or traffic it in vesicles to the basolateral membrane to pump Cu in the cytosol (on ATOX1) into the blood plasma, following which ATP7A would recycle back to the TGN.