Abstract
Bile acids control lipid homeostasis by regulating uptake from food and excretion. Additionally, bile acids are bioactive molecules acting through receptors and modulating various physiological processes. Impaired bile acid homeostasis is associated with several diseases and drug-induced liver injury. Individual bile acids may serve as disease and drug toxicity biomarkers, with a great demand for improved bile acid quantification methods. We developed, optimized, and validated an LC-MS/MS method for quantification of 36 bile acids in serum, plasma, and liver tissue samples. The simultaneous quantification of important free and taurine- and glycine-conjugated bile acids of human and rodent species has been achieved using a simple workflow. The method was applied to a mouse model of statin-induced myotoxicity to assess a possible role of bile acids. Treatment of mice for three weeks with 5, 10, and 25 mg/kg/d simvastatin, causing adverse skeletal muscle effects, did not alter plasma and liver tissue bile acid profiles, indicating that bile acids are not involved in statin-induced myotoxicity. In conclusion, the established LC-MS/MS method enables uncomplicated sample preparation and quantification of key bile acids in serum, plasma, and liver tissue of human and rodent species to facilitate future studies of disease mechanisms and drug-induced liver injury.
Highlights
Bile acids are important for the digestion and absorption of lipids and fat-soluble vitamins in the intestine and for the regulation of cholesterol homeostasis in the liver
The present study employed LC-MS/MS for the direct detection and quantification of 36 different free, taurine- and glycine-conjugated bile acids in serum, plasma, and liver tissue. These analytes include important bile acids of human and rodents and some additional bile acids found in guinea-pig (7oxoLCA and its conjugated forms) and such being relevant with regard to activities of specific enzymes (7oxoLCA, allo-bile acids, and their conjugated forms) [9,10,11,12]
In order to select the best transitions for the identification and confirmation of each bile acid included in the method, individual working standard solutions were applied to the optimizer compound software
Summary
Bile acids are important for the digestion and absorption of lipids and fat-soluble vitamins in the intestine and for the regulation of cholesterol homeostasis in the liver. They are bioactive molecules signaling through receptors such as farnesoid X receptor, pregnane X receptor, vitamin D receptor, sphingosine-1-phosphate receptor 2, and G protein-coupled bile acid receptor 1 in order to modulate lipid and glucose homeostasis, with relevance to cardio-metabolic disease and cancer [1,2]. The two primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA) are synthesized in hepatocytes by the classical and alternative pathway, respectively [6,7] (Figure 1). 7-oxolithocholic acid (7oxoLCA) is a major primary bile acid, in contrast to human, rat, and mouse where it is a secondary bile acid and only found at low levels under
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