Abstract
Intestinal cells control delivery of lipids to the body by adsorption, storage and secretion. Copper (Cu) is an important trace element and has been shown to modulate lipid metabolism. Mutation of the liver Cu exporter ATP7B is the cause of Wilson disease and is associated with Cu accumulation in different tissues. To determine the relationship of Cu and lipid homeostasis in intestinal cells, a CRISPR/Cas9 knockout of ATP7B (KO) was introduced in Caco-2 cells. KO cells showed increased sensitivity to Cu, elevated intracellular Cu storage, and induction of genes regulating oxidative stress. Chylomicron structural protein ApoB48 was significantly downregulated in KO cells by Cu. Apolipoproteins ApoA1, ApoC3 and ApoE were constitutively induced by loss of ATP7B. Formation of small sized lipid droplets (LDs) was enhanced by Cu, whereas large sized LDs were reduced. Cu reduced triglyceride (TG) storage and secretion. Exposure of KO cells to oleic acid (OA) resulted in enhanced TG storage. The findings suggest that Cu represses intestinal TG lipogenesis, while loss of ATP7B results in OA-induced TG storage.
Highlights
The absorption of lipids and essential trace elements, including copper (Cu), is predominantly mediated by specific cells of the small intestine
An ATP7B knockout cell line was generated in human intestinal Caco-2 cells to study the impact of ATP7B on Cu and lipid metabolism
The availability of Cu was recently linked to lipid metabolism and implicated in the pathogenesis of epidemic nutritional disorders, e.g. nonalcoholic fatty liver disease (NAFLD) and obesity [16, 29, 30]
Summary
The absorption of lipids and essential trace elements, including copper (Cu), is predominantly mediated by specific cells of the small intestine. Dietary intake and processing of lipids has to be considered in metabolic diseases of Cu homeostasis, like Wilson disease (WD) and Menke disease (MD) [1, 2]. The molecular mechanism that governs uptake and intracellular metabolism of Cu and lipids by intestinal cells is not fully understood. MD patients suffer from Cu deficiency, caused by mutation of Cu transporter ATP7A, a ubiquitously expressed Cu exporter, resulting in deficiency of Cu in the body due to Cu accumulation in the enterocyte. WD patients are characterized by Cu overload of various tissues, prominently liver and brain, due to mutation of Cu transporter ATP7B [4]
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