Excess cholesterol and fat in the diet: A dangerous liaison for energy expenditure and the liver

C holesterol is essential for life, both as a regulator of membrane structure and as a precursor for the synthesis of essential molecules such as steroid hormones and bile acids. However, excess circulating cholesterol predisposes to cardiovascular disease and premature death. Thus, much of the attention on the role of cholesterol in human disease has focused on processes responsible for its deposition in the vascular endothelium and promoting its clearance from the vasculature. Comparatively little attention has been given to its role in the pathogenesis of nonalcoholic steatohepatitis (NASH), now arguably the most common liver disease afflicting modern society. In this issue of HEPATOLOGY, Savard et al. methodically investigated the individual and synergistic contributions of high dietary fat and cholesterol content in the development of NASH and the associated metabolic abnormalities in normal mice. Male C57BL/6 mice were fed a diet containing either 33% of calories as fat, or 1% cholesterol by weight, or a combination of both for up to 30 weeks to determine the individual and synergistic effects of these common dietary abnormalities. 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 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. 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 b-oxidation (Fig. 1). This is of little consequence when the liver is not faced with a surfeit of fatty acids. However, when the liver must deal with 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. 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 phenomenon and in fact the combined diet fed mice did exhibit slightly less fecal fat loss, indicating greater absorption. Other studies have shown that the potent intestinal cholesterol absorption inhibitor ezetimibe can prevent the development of hepatic steatosis in rodents fed a high-fat and high-cholesterol diet. This is thought to occur mostly through the inhibition of a putative cholesterol Abbreviations: ER, endoplasmic reticulum; HMG-CoA, 3-hydroxy-3methylglutaryl-CoA; LXR, liver X receptor; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NPC1L1, Niemann-Pick C1-like 1 protein. Address reprint requests to: Brent A. Neuschwander-Tetri, M.D., Saint Louis University School of Medicine, Division of Gastroenterology and Hepatology, Department of Internal Medicine, 3635 Vista Ave., St. Louis, MO 63110. E-mail: tetriba@slu.edu; fax: 314-577-8125. CopyrightVC 2012 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.25953 Potential conflict of interest: Nothing to report.