fax: 314-577-8125. Copyright © 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
Excess cholesterol and fat in the diet: A dangerous liaison for energy expenditure and the liver†
Article first published online: 7 JAN 2013
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 57, Issue 1, pages 7–9, January 2013
How to Cite
Neuschwander-Tetri, B. A. and Wang, D. Q.-H. (2013), Excess cholesterol and fat in the diet: A dangerous liaison for energy expenditure and the liver. Hepatology, 57: 7–9. doi: 10.1002/hep.25953
Potential conflict of interest: Nothing to report.
- Issue published online: 7 JAN 2013
- Article first published online: 7 JAN 2013
- Accepted manuscript online: 14 JUL 2012 03:11AM EST
- Manuscript Accepted: 25 JUN 2012
- Manuscript Revised: 22 JUN 2012
- Manuscript Received: 1 JUN 2012
See Article on Page 81
Cholesterol 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),1 now arguably the most common liver disease afflicting modern society.
In this issue of Hepatology, Savard et al.2 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.3, 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 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. 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.7 This is thought to occur mostly through the inhibition of a putative cholesterol transporter, awkwardly named Niemann-Pick C1-like 1 protein (NPC1L1), on the apical membrane of enterocytes. A similar benefit has been demonstrated in NPC1L1 knockout mice on a high-fat and high-cholesterol diet. However, as pointed out by the authors, the relatively trivial increase in fat absorption facilitated by dietary cholesterol is unlikely to explain the excessive weight gain in mice fed both cholesterol and fat.
An alternative explanation suggested by the authors was that, together, a high cholesterol and high-fat diet leads to reductions in energy expenditure. Although this could be due to something as simple as diminished activity level, a more plausible explanation is that the combined diet could actually increase energy efficiency. A cause of this improved energy efficiency can be hypothesized based on the newly recognized role of bile acids in energy consumption and thermogenesis. Although bile acids are primarily known for their major roles in bile formation and intestinal fat digestion, recent data indicate that circulating bile acids play an important role in thermogenesis. A newly discovered bile acid activated receptor, TGR5, has been identified in rodent brown adipose tissue and human muscle that facilitates local thyroid hormone activation, mitochondrial uncoupling, energy “wasting,” and heat generation.8, 9 Thus, factors that change the partitioning of hepatic cholesterol between biliary secretion versus conversion to bile acids could alter energy efficiency. In the results reported by Savard et al. the high-fat, high-cholesterol diet strongly up-regulated the pathways responsible for decreasing intracellular cholesterol levels through diminished uptake and increased secretion but having no effect on the competing pathway of converting cholesterol to bile acids. Others have shown that LXR activation increases CYP7a1 expression and thus increases conversion of cholesterol to bile acids, so this is somewhat surprising.10 Nonetheless, it is possible that the induction of the LXR pathway by a high-cholesterol diet diminishes circulating bile acids through preferential disposal of cholesterol through other pathways. The impact of this may only be seen when the animals are also fed excessive calories in the form of a high-fat diet. Supporting this hypothesis is the observation that the LXR null mouse is resistant to diet-induced obesity and was shown to have unexplained excessive energy wasting, especially when fed a high-cholesterol diet, an observation made before the role of bile acids in thermoregulation was discovered.5 In light of the newer data on bile acids and thermogenesis, the LXR null mouse might be expected to have increased disposal of cholesterol through the bile acid synthesis pathway, especially when fed a high-cholesterol diet, and thus increased circulating bile acids and increased activation of the TGR5 pathway of thermogenesis and energy expenditure.
In summary, the crosstalk between metabolic signaling pathways that receive input from a high-fat and high-cholesterol diet may result in inappropriate suppression of β-oxidation that promotes NASH and diminished circulating bile acids, resulting in inappropriately improved energy efficiency leading to weight gain. These are testable hypotheses with major implications for human health that could be exploited pharmacologically to prevent NASH and improve energy disposal and weight management.
- 7Ezetimibe: its novel effects on the prevention and the treatment of cholesterol gallstones and nonalcoholic fatty liver disease. J Lipids 2012; 2012: 302847., , , , .