Cholic Acid: Metabolic Health and Therapeutic Applications

General Description

Cholic acid, a primary bile acid derived from cholesterol, plays a crucial role in fat digestion, cholesterol regulation, and metabolic health. It facilitates dietary fat absorption by forming micelles in the intestines and regulates hepatic cholesterol synthesis through nuclear receptors like FXR. Recent research indicates its involvement in glucose metabolism and insulin sensitivity, highlighting its potential protective role against metabolic disorders such as type 2 diabetes. Additionally, cholic acid's effects on gut microbiota and liver health suggest its therapeutic applications for metabolic diseases and liver dysfunction, emphasizing its significance in maintaining overall metabolic and hepatic health.

Figure 1. Cholic acid

Overview

Structure

Cholic acid is a primary bile acid synthesized in the liver from cholesterol through a complex enzymatic process. As one of the principal bile acids, it plays a vital role in the emulsification of dietary fats, promoting their absorption in the intestines. Structurally, cholic acid consists of a steroid nucleus with a hydrophobic core and several hydroxyl groups, making it amphipathic. This unique structure allows cholic acid to interact with lipids and aqueous environments effectively. Upon secretion into the bile, it forms micelles with dietary lipids, facilitating their breakdown by pancreatic lipase. The absorption of fatty acids and monoglycerides in the intestines is crucial for maintaining energy balance and providing essential fatty acids that are necessary for various physiological functions. ¹

Function

Cholic acid not only aids in fat digestion but also plays a significant role in regulating cholesterol homeostasis. It exerts feedback inhibition on hepatic cholesterol synthesis, ensuring that cholesterol levels remain within a physiological range. This regulatory function is primarily mediated through the activation of nuclear receptors, such as the farnesoid X receptor (FXR). Upon binding to cholic acid, FXR regulates the expression of genes involved in cholesterol metabolism and bile acid synthesis. This interplay between bile acids and cholesterol underscores the importance of cholic acid in maintaining lipid homeostasis, which is vital for overall metabolic health. Furthermore, the conversion of cholic acid into secondary bile acids by gut microbiota introduces additional complexity to its biological significance, as these metabolites can influence gut health and systemic metabolism. ¹

Metabolic Health

Many metabolic enzymes and transport proteins bind to corresponding substrates, such as different drugs. They are responsible for the metabolism and transport of BAs(such as Cholic Acid) through cell membranes in both directions. It is important to note that nuclear receptors and other ligand–dependent transcription factors have the role of sensor that detects the presence of drugs or BAs, and regulates the expression of metabolic enzymes and transport proteins in order to maintain homeostasis. Molecular mechanisms regulate the inducible expression of the gene by drugs and BAs, where key mediators in these processes are nuclear subfamily 1 receptors [pregnane X receptor (PXR), constitutive androstane receptor (CAR), FXR, and vitamin D receptor (VDR)]. Membrane transport proteins regulate the transport of substrates and, for this reason, they represent the essential regulators of absorption, distribution, metabolism, excretion, and toxicity (ADMET) of any substrate in body, both natural ligands and metabolites and medicaments. Also, many xenobiotics are involved in the transport roads common to physiological intermediates. Many physiological transporters are not monospecific, but have a wide range of specific substrate. Interactions of substrate (endogenous metabolite or drug / xenobiotics) with transport proteins have a very significant effect on both the efficacy and safety profile of the drug. The most important bile acid transport proteins with a wide range of substrate specificities of great importance for drug action and disposition are the influx transporters from the group of organic anion transporters that belong to the solute carrier (SLCO) gene family as well as an efflux ABC transporter protein. For some transporter proteins from the above–metioned groups, BAs represent physiological substrates with proven effects on absorption, distribution, metabolism, excretion, and toxicity features of many medicaments (substrates for said membrane transporters). Transport proteins for the substrate acquisition have developed evolutionarily for the purpose of facilitating not only the takeover of cell nutrients and vitamins, but also resorption of endogenous products such as glucose and other carbohydrates, amino acids, and small peptide or BAs. Many of these transporters use an electrochemical gradient of ions such as Na+ for transport versus a concentration gradient.²

Therapeutic Applications

The diverse biological roles of cholic acid have prompted research into its potential therapeutic applications. One area of interest is the use of bile acids, including cholic acid, as treatment options for metabolic disorders. The development of FXR agonists, which mimic the actions of cholic acid, has shown promise in clinical trials for managing conditions such as type 2 diabetes and NAFLD. These compounds leverage the beneficial effects of cholic acid on glucose and lipid metabolism while minimizing the adverse effects associated with cholesterol derivatives. ²

Moreover, the role of cholic acid in modulating the gut microbiome offers exciting prospects for therapeutic interventions. Since alterations in gut microbiota composition are linked to various diseases, cholic acid and its derivatives could be utilized to restore gut health and improve metabolic outcomes. Additionally, the potential for cholic acid to act as a cholagogue, promoting bile flow and liver function, makes it a candidate for treating liver diseases associated with bile acid dysregulation. Overall, the exploration of cholic acid in therapeutic contexts underscores its multifaceted biological significance, paving the way for innovative treatment strategies aimed at improving metabolic health and liver function. ²

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