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ZIP8, encoded by the SLC39A8 gene, is a divalent metal ion transporter highly expressed in hepatocytes and critical for the uptake and homeostatic regulation of manganese. It is localized to canalicular (apical) membranes in hepatocytes, enabling the reclamation of manganese from bile and controlling systemic manganese availability. Loss-of-function mutations in ZIP8 cause profound manganese deficiency, protein glycosylation disorders, and broad metabolic disturbances. Hepatic ZIP8 plays central roles in the activity of manganese-dependent enzymes (notably arginase and glycosyltransferases) that impact numerous physiological functions. Secondary transporters, such as ZIP14 and ZnT10, also contribute to hepatic Mn uptake and efflux, but ZIP8 has a key regulatory role in hepatocyte manganese import, especially during enterohepatic circulation. The term "Hepatocyte manganese uptake transport" should be replaced by the name of a defined transporter, most notably ZIP8/SLC39A8, for structured data representation.
Restoration or inhibition of ZIP8 function alters cellular and systemic manganese (and zinc) levels, impacting the activity of Mn-dependent enzymes and global metabolic/physiological functions.
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