Bile acids

Bile acids are a fascinating group of biochemical compounds that fall under the broader category of steroids, molecules often associated with negative health implications like cardiovascular disease or hormone imbalances. Yet, despite their controversial reputation, steroids, particularly bile acids, are crucial for cellular function. Their roles include acting as structural components, regulators, emulsifiers, and precursors to vital molecules.

As providers of fine chemicals, we aim to provide a concise introduction to bile acids, recognizing the vastness of the topic requiring deeper exploration through specialized literature.

Structure of Bile Acids

Bile acids are fundamentally steroids, characterized by their 4-ring cyclopentane-perhydrophenanthrene structure, commonly referred to as "gonane" or "sterane." This structure serves as the foundation for all bile acids.

The simplest form of this structure, sterane, highlights the basic carbon framework that defines steroids. The numbering follows IUPAC standards.

The A and B rings are typically fused in a cis-configuration, though the A ring can assume either a more stable chair or less stable ship conformation. Meanwhile, the B/C and C/D rings are fused in a trans-configuration.

Visualizing the structure, 5a-cholanic acid and 5b-cholanic acid showcase the impact of A/B cis and trans configurations on overall shape.

Functionally, bile acids often feature hydroxyl groups at key positions such as C3, C6, C7, C12, and C23, along with methyl groups at C10 and C13. The stereochemistry, especially at C19, significantly influences the arrangement of hydrogen atoms at C5, C8 (cis), and C9, C14 (trans).

Cholesterol's structure offers another perspective on these carbon skeletons, highlighting the importance of precise positioning in defining specific steroids.

Additionally, the aliphatic chain at C17 varies in length and functionality, influenced by the presence of methyl and hydroxyl groups, which, along with the stereochemistry, define each unique steroid.

Synthesis and Classification

Cholanic acid serves as the base compound from which various bile acids are derived through selective hydroxylation of the carbon skeleton. Although not commonly found in mammals, cholesterol, the precursor, plays a critical role. Liver cells transform cholesterol into primary bile acids—cholic acid and chenodeoxycholic acid—by oxidizing the aliphatic chain's end.

These acids are transported to the duodenum, where their low solubility poses challenges due to the acidic pH. To overcome this, the liver conjugates them with glycine or taurine, forming ion pairs that enhance water solubility. The intestinal microbiota further modifies these acids, creating secondary bile acids primarily through C7 dehydroxylation. Tertiary bile acids emerge through additional transformations like epimerization or N-acetylglucosamine conjugation.

Ultimately, bile acids return to the liver via enterohepatic circulation, ensuring efficient reuse.

Functions of Bile Acids

Bile acids exhibit surface-active properties in neutral or basic environments, with the carboxyl-containing aliphatic end serving as the hydrophilic region while the rest remains lipophilic. Their primary role involves emulsifying fats and non-polar substances into micelles, facilitating absorption in the small intestine and maintaining solubility in blood. This aids lipase enzymes in breaking down lipids into fatty acids and glycerol.

Beyond emulsification, bile acids act as chemical mediators, binding to cell receptors to trigger important biochemical pathways. They influence inflammation regulation, calcium mobilization, protein kinase activation, cyclic AMP synthesis, and cytokine secretion. Additionally, they participate in mitochondrial oxidative processes and insulin receptor signaling. Bile acids also help maintain cholesterol balance and remove waste products like bilirubin.

In summary, bile acids perform numerous vital functions. While cholesterol’s role might initially seem paradoxical, its proper management ensures optimal physiological function. Controlling its intake is key to avoiding adverse effects.

References:

• Kuhajda, K. et al., “Structure and origin of bile acids: an overview,” European Journal of Drug Metabolism and Pharmacokinetics, 2006, Vol. 31, No.3, pp. I3S-143.
• Chiang, J.Y.L., “Bile acids: regulation of synthesis,” Journal of Lipid Research, Volume 50, 2009, pp. 1955-66.
• Singh, J. et al., “A Review on Bile Acids: Effects of the Gut Microbiome, Interactions with Dietary Fiber, and Alterations in the Bioaccessibility of Bioactive Compounds,” J. Agric. Food Chem., Just Accepted Manuscript, DOI: 10.1021/acs.jafc.8b07306.