The Function of ATPase Copper Transporter ATP7B in Intestine

Area of Science:

• Gastroenterology
• Molecular Biology
• Cell Biology

Background:

• Wilson disease is a genetic disorder characterized by copper (Cu) imbalance, primarily linked to ATP7B mutations affecting the liver.
• The role of ATP7B in intestinal copper homeostasis and its contribution to Wilson disease pathology remain largely unexplored.

Purpose of the Study:

• To investigate the function of ATP7B in the mouse intestine.
• To elucidate the mechanisms by which intestinal ATP7B regulates copper homeostasis and lipid metabolism.

Main Methods:

• Characterization of ATP7B and Cu distribution in intestinal tissues from ATP7B-knockout and control mice using immunohistochemistry and x-ray fluorescence.
• Analysis of enteroids derived from knockout and control mice, assessing effects of excess Cu or chelators on cellular fat content and ATP7B localization via fluorescent confocal microscopy.
• Histologic analyses, electron microscopy, and immunoblotting were employed to determine the impact of ATP7B loss.

Main Results:

• ATP7B establishes a Cu gradient in the duodenum and buffers intracellular Cu levels in enterocytes.
• Loss of ATP7B in mice led to reduced intestinal Cu stores, triglyceride accumulation in enterocytes, and impaired chylomicron formation.
• In vitro studies showed that excess Cu or chelators disrupted chylomicron assembly in enteroids.

Conclusions:

• Intestinal ATP7B is essential for vesicular copper storage and maintaining enterocyte copper levels within a range critical for chylomicron synthesis.
• Copper and lipid misbalance in the intestine, driven by ATP7B dysfunction, likely contributes to the gastrointestinal manifestations observed in Wilson disease.