Thus, while HF diets produce a range of the components of the metabolic syndrome, fructose consumption would appear necessary to move the process from Angiogenesis chemical liver fat deposition alone to fibrogenesis. ROS has been thought to be an important trigger for hepatic stellate cell activation and for promoting expression of fibrogenic molecules such as α-SMA, TGF-β1, and collagen 1.15, 28, 42, 43 Recently, fructose-fed rats have been reported

to develop hepatocyte damage with a decrease in the mitochondrial membrane potential similar to that induced by low noncytotoxic doses of exogenous ROS.44 In vitro studies have also shown that the cytotoxic mechanism involving fructose-driven ROS formation precedes hepatocytotoxicity, and that this cell

injury could be prevented by ROS scavengers.44 We therefore investigated this as a potential process in our model and demonstrated that HFHC mice had significantly higher ROS levels compared with both HF and chow-fed mice (Fig. 5). Previous studies performed with fructose diets have reported insulin resistance and severe necroinflammatory NAFLD but not NASH with fibrosis.18, 19 In contrast to the ALIOS diet, which provided fructose water in gelatin form and long chain–saturated trans fats in their RAD001 clinical trial solid diet, our HF diet provided 58% of calories from medium chain–saturated trans fats and fructose and sucrose in their regular drinking water. This diet resulted in 50% of MCE the mice in the HFHC group having fibrosis with a minority having stage 2 fibrosis (Table 2). Karlmark et al.7 highlighted the role of CD11+F4/80+Gr1+ monocytes in perpetuating hepatic stellate cell–driven TGF-β1–dependent fibrosis. More recently, Niedermeier et al.36 reported that Gr1+ monocytes may be essential in the production of murine fibrocytes. In our experiment, intrahepatic CD11+F4/80+Gr1+ monocyte-derived

macrophages were 10-fold higher than either HF or chow-fed mice, with 50% of the macrophages in HFHC livers being Gr1+ (Fig. 4). We propose that the conversion of CD11b+F4/80+Gr1+ monocytes into fibrocytes maybe responsible for the increased collagen 1 deposition through ROS-driven TGF-β signaling and stellate cell activation. In humans, studies have shown extensive mitochondrial damage including paracrystalline inclusion bodies, megamitochondria, damaged respiratory chain and low adenosine triphosphate production with NASH.24 We have previously reported that increased ROS released from damaged mitochondrial respiratory chain is important in NAFLD development.