Abstract
Glicksman et al. 1 in this edition report a decreased postprandial bile acid response in obese individuals. Obesity is known to be associated with an increased incidence of gallstones and increased biliary cholesterol secretion. Jejunoileal bypass, which is sometimes used as a bariatric surgical procedure to treat morbid obesity, decreases pool sizes of bile salts, by increasing their turnover rates, while the rate of bile salt synthesis increases. 2
Four main bile acids are produced in humans. Two of these, cholic acid and chenodeoxycholic acid (CDCA), are synthesized from cholesterol in the liver. They are secreted in bile as sodium salts, conjugated with the amino acids glycine or taurine although some are conjugated with sulphate (primary bile salts). These in turn are converted by bacteria within the intestinal lumen to the secondary bile salts deoxycholate and lithocholate, respectively. Secondary bile salts are absorbed from the terminal ileum and colon and are re-excreted by the liver (enterohepatic circulation of bile salts). In the normal fasting state, serum CDCA predominates. The biliary canalicular secretion of bile salts is mediated mainly by the bile salt export pump.
Serum total bile salt concentrations increase about 2–5-fold after meals, with a peak at about 60–90 min postprandially. Concentrations return to fasting levels over several hours. Hepatic extraction of these is highly efficient, meaning that bile salts are present at very low concentrations in the systemic circulation where they are highly protein-bound. Currently, the main clinical indication to measure serum bile salts is in the investigation of cholestasis of pregnancy. 3
Bile salts are far more than simply gastrointestinal detergents. They are also involved in cholesterol and fat soluble vitamin absorption as well as conferring resistance to intestinal bacterial overgrowth and regulation of the small intestine enzyme enteropeptidase. 4,5 Bile salts have more recently been shown to be important biochemical modulators and activate certain nuclear receptors such as preganane X, farnesoid X (FXR), vitamin D and also G protein coupled TGR5. The latter regulates in vivo glucagon-like peptide-1 and peptide YY secretion which enhance glucose tolerance and also energy expenditure in adipose tissue. Administration of bile salts to mice increased energy expenditure in brown adipose tissue and reduced insulin resistance and obesity. 6–9
Bile salts are also implicated in cell signalling pathways, e.g. extracellular signal regulated kinases. Indeed, relevant to obesity is the observation that bile salts act as ‘nutrient signalling molecules’ in a feed/fast cycle controlling the flow of absorbed molecules after meals. This could be of considerable interest if there was a postprandial reduced bile response in obese individuals as reported by Glicksman et al. 1 FXR is essential in the feed/fast cycle and inhibition of glycolysis and may lower triglycerides by enhanced very-low-density lipoprotein production turnover and lipoprotein lipase activation. FXR also is implicated in the downregulation of hepatic fatty acid and triglyceride biosynthesis mediated by sterol-regulatory-element-binding protein 1c. 10–12 Indeed, this may help to explain the ‘paradoxical’ hypertriglyceridaemia sometimes associated with the use of cholesterol lowering bile acid sequestering agents such as cholestyramine, colestipol and colesevelam. 13
The work of Glicksman and co-workers is interesting but has some areas of opacity. For example, it is a cross-sectional study with a small sample size and no age- or gender-control. Whether the reduced bile salt response is due to obesity per se or a mechanism involved in the aetiology of obesity is currently unresolved. The study did not report high-density lipoprotein (HDL) cholesterol concentrations that may be expected to be lower in the obese and yet HDL particles are thought to bind bile salts. It is also unclear from their work whether bile salt turnover is increased in the obese regardless of the type or amount of food consumed. If there was an increased bile acid turnover rate in the obese then does this mean the absorption of fat could be more efficient in these individuals? Moreover, does a decreased postprandial bile acid response in obese individuals mean that the nutrient signalling mechanisms described above are impaired helping to evoke adipose tissue deposition? Further understanding of the actions of bile salts in obesity may open up translational research opportunities for therapy in such patients.
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