The results show that high dietary fat supplied as cocoa butter (a fat source relatively high in saturated fat) and excess cholesterol

interacted to produce both the metabolic and hepatic features of NASH, whereas neither dietary factor alone was sufficient to cause significant disease. These studies provide clear evidence that the hepatic and metabolic effects induced by combined high dietary fat and cholesterol were substantially greater than the sum of the separate effects of each dietary component LY2606368 order alone. How does high dietary cholesterol synergize with high dietary fat to cause NASH? One explanation for this synergy may be the activation of the liver X receptor (LXR) pathway by cholesterol (or more specifically,

by the oxysterol metabolites of cholesterol) resulting in a gene expression program designed to detoxify and eliminate cholesterol.3, MK0683 4 The membrane disruptive effects of mildly amphipathic free cholesterol can be prevented by cholesterol esterification with fatty acids to form highly lipophilic cholesterol esters. Perhaps in an effort to preserve fatty acid availability for cholesterol esterification, LXR activation also inhibits mitochondrial β-oxidation (Fig. 1).5 This is of little consequence when the liver is not faced with a surfeit of fatty acids. However, when the liver must deal with MCE excessive fatty acids, either from de novo lipogenesis, as can occur with fructose feeding, or from excess dietary fat with spillover of fatty acids into the circulation from lipoprotein lipase-mediated hydrolysis or adipose insulin resistance, the stage is set for lipotoxic liver injury. The inability of the liver to handle fatty acids through oxidative pathways or the formation of triglyceride may predispose to the excessive formation of other fatty acid derivatives such as diacylglycerols, ceramides, and lysophosphatidyl choline that have

been proposed to cause lipotoxic liver injury manifesting itself as NASH.6 Another important observation by Savard et al. in their study of the combined effects of a high cholesterol, high-fat diet was that the mice fed this combination exhibited a much greater increase in weight than mice fed a control diet or even the high-fat diet alone. This was despite having the same daily caloric intake as the control mice and a lower daily caloric intake than the mice fed the high-fat diet. One explanation is that excess dietary cholesterol facilitates fat absorption. Increased fat absorption associated with a high cholesterol diet is a known phenomenon7 and in fact the combined diet fed mice did exhibit slightly less fecal fat loss, indicating greater absorption.