Copper - Fructose interaction and NAFLD 1 Kupffer cell

24 High fructose feeding impairs copper status and leads to low copper availability, which is 25 a novel mechanism in obesity related fatty liver. Copper deficiency associated hepatic 26 iron overload likely plays an important role in fructose-induced liver injury. Excess iron 27 in the liver is distributed throughout hepatocytes and Kupffer cells (KCs). The aim of this 28 study was to examine the role of KCs in the pathogenesis of nonalcoholic fatty liver 29 disease (NAFLD) induced by a marginal copper high fructose diet (CuMF). Male 30 weanling Sprague-Dawley rats were fed either a copper adequate or a marginally copper 31 deficient diet for 4 weeks. Deionized water or deionized water containing 30% fructose 32 (w/v) was also given ad lib. KCs were depleted by intravenous administration of 33 gadolinium chloride (GdCl3) before and/or in the middle of the experimental period. 34 Hepatic triglyceride accumulation was completely eliminated with KC depletion in 35 CuMF consumption rats, which was associated with the normalization of elevated plasma 36 monocyte chemoattractant protein-1(MCP-1) and increased hepatic sterol regulatory 37 element binding protein-1 (SREBP-1) expression. However, hepatic copper and iron 38 content were not significantly affected by KC depletion. In addition, KC depletion 39 reduced body weight and epididymal fat weight as well as adipocyte size. Plasma 40 endotoxin and gut permeability were markedly increased in CuMF rats. Moreover, MCP41 1 was robustly increased in the culture medium when isolated KCs from CuMF rats were 42 treated with LPS. Our data suggest that KCs play a critical role in the development of 43 hepatic steatosis induced by marginal copper high fructose diet. 44 45