THE FAT BURNING PROPERTIES OF BILE ACIDS
Nature revealed that a component in bile can rev up the metabolism and increase weight loss in mice, possibly in humans as well.1 Bile is the sticky, yellow-green, fluid produced in the liver, stored in the gallbladder and secreted into the intestines during a meal. Bile emulsifies dietary fat into tiny globules so digestive enzymes (lipases) can break up triglycerides into free fatty acids and glycerol; it also aids in the absorption of fat-soluble vitamins.A 2006 study published in the journal
Bile Heats Things Up
Interestingly, bile has long been associated with health and vigor. Medieval philosophers believed that health is the balance of four vital humors, combining to determine one’s emotional and physical condition. Bile, one of the vital humors, is associated with the element fire.2 This is appropriate, as modern researchers have discovered that components of bile heat things up by increasing calorie burning and thermogenesis (heat production).1,3 Thermogenesis is an excellent way to waste calories and increase fat loss.
Bile is composed of bile acids, pigments, phospholipids and cholesterol. Bile acids are produced from cholesterol, and this process represents a major pathway of regulating cholesterol levels. Bile acid production is under the control of a negative feedback system, much like testosterone. When an excess is sensed by receptors, the enzyme that produces bile acids is shut down; if a deficiency occurs, production is increased. Two primary forms are produced in humans- cholic acid comprises about half of bile acids, while the remainder is in the form called chenodeoxycholic acid. When a chemical is closely regulated in the body, it suggests that it plays a role in regulating the metabolism. Bile acids are not wasted; when secreted during a meal into the intestines, they are mostly reabsorbed (~95%).4 The remainder travels to the colon where bacteria convert them into metabolites that have been associated with promoting colon cancer. Lithocholic acid, the metabolite of chenodeoxycholic acid, induces enzymes that clear the toxins more rapidly.5 Thus, supplementation with bile acids should be reasonably safe when used in amounts similar to that secreted during meals, perhaps 300-500 milligrams. Also, a blend containing chenodeoxycholic acid may offer protection over cholic acid alone.
Chenodeoxycholic acid, and a related isomer called ursodeoxycholic acid, are pharmaceutical drugs available by prescription used to treat gallstones and are well tolerated at a dose of 10 mg/kg/day. Further, these two bile acids have liver-protective and antioxidant properties.6 Bodybuilders may not be aware of the risk for gallstones faced when using aromatizing anabolic steroids- those that can convert to estrogens, especially orals.7 However, most are familiar with the risk of cholestasis and jaundice conditions caused by bile "backing up" in the liver. Bile pigments (not bile acids) build up in the blood and can be seen as a yellowing of the "whites of the eyes." Also, liver strain is a common side effect of orals, making bile acids an interesting consideration for liver protection for oral anabolic steroid users. A fascinating study showed bile acids can even aid in regenerating liver tissue in mice that had portions surgically removed.8
Fat-Loss Effects of Bile Acids
A slight effect on fat loss due to bile acids may occur in the gut, as they impact the type of bacteria in the colon that dominate. Gut bacteria, or microbiota, have been shown to play a role in obesity in mice and humans; bile acids influence the development of "lean" versus "fat" bacteria in the colon.9 In the liver, bile acids improve insulin sensitivity, allowing the body to better handle glucose (sugar) and fat.10 These effects occur primarily through the action of a receptor called FXR.11 Though the metabolic benefits of FXR activation are significant, bile acids appear to have fat-loss effects independent of glucose and triglyceride (fat) control. A strain of mice lacking FXR receptors avoided fat gain as they aged, remaining lean.12 This effect was associated with an increase in metabolism (calorie burning) and insulin sensitivity. As the FXR receptor was absent in these mice, bile acid production was increased, and correlated well with the increased calorie burning.
Other than FXR, bile acids interact with a number of receptors, but the most significant among them is called TGR5.10 This receptor, present in high concentration in brown fat, and skeletal muscle, triggers a cascade of effects that result in increased fatty acid oxidation (burning fat for calories), metabolic rate (how fast calories are burned) and uncoupling (wasting calories for heat instead of producing energy).1,3 Though mouse studies did not show a significant effect of bile acids on white adipose (regular storage-type of fat), TGR5 is present in human white fat to the same degree as brown fat.13 Further, white fat TGR5 levels in humans have a strong association with the resting metabolic rate. When obese people were given a very low-calorie diet, their metabolic rate dropped, along with tissue TGR5 levels! Those who have lost weight dieting recognize how the weight drops easily at first, but plateaus after a few weeks. It is possible that a downregulation of the TGR5 levels might account for this; and that bile acid supplementation may maximize the activity of the TGR5 receptors that remain and prevent the drop in metabolism. All bile acids stimulate TGR5.14
Caffeine Enhances the Fat-Burning Effect of Bile Acids
When TGR5 is stimulated, it produces a chemical called cAMP inside the cell to carry out its message. cAMP is quickly degraded, but its signal can be prolonged by the actions of caffeine. Hence, the effectiveness of bile acids may be enhanced by taking a reasonable amount of caffeine and other thermogenic fat burners at the same time. In brown fat and skeletal muscle, TGR5’s message turns on an enzyme called D2 in the cell.1,3 D2 converts the circulating form of thyroid hormone (T4), which has a modest effect on metabolism to the more potent form T3. Drug-enhanced bodybuilders and dieters may be familiar with the various forms of thyroid hormone by their brand names, Synthroid (T4) and Cytomel (T3). While T4 misuse by a healthy person often does not promote fat loss, T3 taken during pre-contest "cutting" cycles is a very potent fat-loss agent. Unfortunately, T3 misuse/abuse increases the risk of danger of cardiac arrhythmias (erratic heart rate), insomnia and tremors. Thus, the ideal would be to increase the cellular conversion of T4 to T3 in brown fat and skeletal muscle- the effect noted with cholic acid and chenodeoxycholic acid.
This pathway provides a direct connection between bile acids and fat loss. Bile acids accumulate in the blood after a meal or supplementation. They interact specifically with the TGR5 receptor on brown fat and skeletal muscle, possibly white fat as well in humans. The TGR5 receptor produces cAMP in the target cell, which turns on the D2 enzyme. Activated D2 converts the "prohormone" form of thyroid hormone (T4) to the highly active T3. T3 travels to the nucleus of the cell, as well as the mitochondria, "turning up the thermostat" and increasing the burning of fatty acids for energy. Aiding fat loss further, T3 increases "uncoupling," which wastes calories for heat instead of energy (ATP). The net result is increased thermogenesis, and fat loss.
Exercise, Cold Exposure and Clenbuterol
From the findings above, there are suggestions as to factors that may enhance or impair the fat-burning effects of bile acids. As mentioned earlier, caffeine may boost the TGR5 signal by prolonging the cAMP presence in brown fat and skeletal muscle; possibly white fat as well.15 Conditions that normally would increase thermogenesis may be enhanced by bile acid supplementation. These conditions include exercise, cold exposure and the use of beta-2 agonists (e.g., clenbuterol).15-17 Estrogens and oral contraceptives for women alter bile acid production, decreasing chenodeoxycholic acid production; cholesterol-lowering statin drugs reduce total bile acid production by as much as 30 percent.18,19 Alcohol consumption reduces bile acid production, and chronic alcoholics have markedly lower bile acid production due in part to advanced liver damage.20 Also, the effects of bile acids are not as significant in subjects consuming a low-fat diet, perhaps a possible explanation for the more rapid and effective weight loss seen in Atkins-like diets. In particular, a high-fat, high-protein diet induces an increase of 50 percent in bile acid production, and the metabolic effects may be even greater if the protein source is rich in taurine and glycine.21,22
Those who perform cardio in the fasted state to maximize the percentage of fat calories burned during exercise may note subjective benefits from supplementing with bile acids. When fasted, D2 activity is low, and serum (blood) concentrations of bile acids are at their lowest- particularly among the obese. Though it has not been studied in a metabolic chamber, it is reasonable to speculate that bile acid supplementation, along with caffeine and other fat burners (such as Thermo-Heat) may boost thermogenesis and fatty acid oxidation (calorie burning), compared to no supplementation when fasting. This may even be true in the non-fasted state.
Bile Acids: the Natural Alternative
What can a person seeking to lose fat take home from this? Bile acids are naturally produced, and can be supplemented as cholic acid or ox bile extract; ox bile extract likely will be more readily processed and well tolerated, as it represents the "natural" matrix of bile acids. Taken with a meal- they work best in meals containing fat- supplementation may aid in digestion and boost the post-meal surge in bile acids in the blood. Bile acids can also be taken while fasting, and may increase the fat-burning effect of exercise, cold exposure or certain stimulants. Doses should be moderate, as even natural levels results in a slight spillover into the colon, where bacteria convert the bile acids into more toxic metabolites. Certain bile acids are used medically at a dose of 10 mg/kg/day and are considered safe- 1,000 milligrams for a 220-pound person; side effects include diarrhea and elevated liver enzymes. Supplementation should not exceed this dose. Further, excess supplementation will reduce natural production, limiting the benefit. Bile acids can improve insulin sensitivity and reduce blood triglycerides (fat). The excitement happens in skeletal muscle and brown fat, possibly white fat. Bile acids interact with a receptor that activates a thyroid hormone in the cell, resulting in greater calorie burning, fatty acid oxidation (burning fats), and wastes many of these calories as heat.
Human studies remain to be done, but the mouse studies and "test tube" data from human muscle and fat tissue are highly supportive. Given the relatively low cost, endogenous (natural) role, clinical history of safety and novel pathway, bile acids deserve further investigation.
1. Watanabe M, Houten SM, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006;439:484-9.
2. Kagan J. Galen's prophecy. Westview Press; Boulder, CO: 1998.
3. Teodoro JS, Zouhar P, et al. Enhancement of brown fat thermogenesis using chenodeoxycholic acid in mice. Int J Obes 2013 Dec 6. [E-pub, ahead of print]
4. Shneider BL. Intestinal bile acid transport: biology, physiology, and pathophysiology. J Pediatr Gastroenterol Nutr 2001;32:407-17.
5. Hofmann AF. Detoxification of lithocholic acid, a toxic bile acid: relevance to drug hepatotoxicity. Drug Metab Rev 2004;36:703-22.
6. Komori Y, Arisawa S, et al. Ursodeoxycholic acid inhibits overexpression of P-glycoprotein induced by doxorubicin in HepG2 cells. Eur J Pharmacol. 2013 Dec 24. [E-pub, ahead of print]
7. Henriksson P, Einarsson K, et al. Estrogen-induced gallstone formation in males. Relation to changes in serum and biliary lipids during hormonal treatment of prostatic carcinoma. J Clin Invest 1989;84:811-6.
8. Huang W, Ma K, et al. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 2006;312:233-6.
9. Musso G, Gambino R, et al. Interactions between gut microbiota and host metabolism predisposing to obesity and diabetes. Annu Rev Med 2011;62:361-80.
10. Zarrinpar A, Loomba R. Review article: the emerging interplay among the gastrointestinal tract, bile acids and incretins in the pathogenesis of diabetes and non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2012;36:909-21.
11. Rizzo G, Renga B, et al. Role of FXR in regulating bile acid homeostasis and relevance for human diseases. Curr Drug Targets Immune Endocr Metabol Disord 2005;5:289-303.
12. Bjursell M, Wedin M, et al. Ageing Fxr deficient mice develop increased energy expenditure, improved glucose control and liver damage resembling NASH. PLoS One 2013;8:e64721.
13. Svensson PA, Olsson M, et al. The TGR5 gene is expressed in human subcutaneous adipose tissue and is associated with obesity, weight loss and resting metabolic rate. Biochem Biophys Res Commun 2013;433:563-6.
14. Sato H, Macchiarulo A, et al. Novel potent and selective bile acid derivatives as TGR5 agonists: biological screening, structure-activity relationships, and molecular modeling studies. J Med Chem 2008;51:1831-41.
15. Dulloo AG, Seydoux J, et al. Potentiation of the thermogenic antiobesity effects of ephedrine by dietary methylxanthines: adenosine antagonism or phosphodiesterase inhibition? Metabolism 1992;41:1233-41.
16. van den Berg SA, van Marken Lichtenbelt W, et al. Skeletal muscle mitochondrial uncoupling, adaptive thermogenesis and energy expenditure. Curr Opin Clin Nutr Metab Care 2011;14:243-9.
17. van der Lans AA, Hoeks J, et al. Cold acclimation recruits human brown fat and increases nonshivering thermogenesis. J Clin Invest 2013;123:3395-403.
18. Everson GT, Fennessey P, et al. Contraceptive steroids alter the steady-state kinetics of bile acids. J Lipid Res 1988;29:68-76.
19. Bertolotti M, Zambianchi L, et al. Influence of newly synthesized cholesterol on bile acid synthesis during chronic inhibition of bile acid absorption. Hepatology 2003;38:939-46.
20. Monroe P, Vlahcevic ZR, et al. Effects of acute and chronic ethanol intake on bile acid metabolism. Alcohol Clin Exp Res 1981;5:92-100.
21. Bortolotti M, Kreis R, et al. High protein intake reduces intrahepatocellular lipid deposition in humans. Am J Clin Nutr 2009;90:1002-10.
22. Liaset B, Hao Q, et al. Nutritional regulation of bile acid metabolism is associated with improved pathological characteristics of the metabolic syndrome. J Biol