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Cholic acid, a crucial bile acid, features a steroid backbone with a hydroxyl group at the 3-position, a carboxyl group at the 24-position, and a side chain at the 17-position [1]. It is synthesized in the liver from cholesterol and plays a vital role in bile formation, essential for emulsifying lipids in the small intestine. The discovery of cholic acid is credited to pioneering work in the early to mid-20th century, notably highlighted by the 1928 isolation of cholic acid from ox bile by scientists William L. Hughes and David W. Wooley. This milestone significantly advanced our understanding of bile acid composition [2].
Cholic acid biosynthesis is a complex process that involves multiple steps and enzymes. It primarily occurs in the liver, where cholesterol is transformed into cholic acid. The biosynthesis can be divided into several key steps [3,4]:
Cholesterol is taken up by liver cells (hepatocytes) through receptor-mediated endocytosis.
The rate-limiting step is the conversion of cholesterol to 7α-hydroxycholesterol, catalyzed by the enzyme cholesterol 7α-hydroxylase (CYP7A1). This reaction occurs in the endoplasmic reticulum of hepatocytes.
The 7α-hydroxycholesterol is then converted to 7α-hydroxy-4-cholesten-3-one through the action of 3β-hydroxy-Δ5-C27-steroid oxidoreductase (HSD3B7).
The final step involves several enzymatic transformations leading to the formation of cholic acid. Key enzymes include 3-oxo-Δ4-steroid 5β-reductase (AKR1D1) and 12α-hydroxylase (CYP8B1).
![Bile_acid_biosynthetic_pathways [4]](/uploads/image/20240201/Bile_acid_biosynthetic_pathways.png "Bile_acid_biosynthetic_pathways [4]")
The rate of cholic acid biosynthesis is tightly regulated by feedback mechanisms involving bile acid-activated nuclear receptors, particularly the farnesoid X receptor (FXR) and the liver X receptor (LXR). These receptors control the expression of key enzymes such as CYP7A1, maintaining bile acid homeostasis.
Cholic acid biosynthesis is interconnected with other pathways, such as the mevalonate pathway, which produces cholesterol as a precursor. Additionally, intermediates like chenodeoxycholic acid may be formed in alternative bile acid biosynthetic pathways.
Cholic acid metabolism involves a series of intricate processes that regulate its synthesis, conversion, and elimination from the body. The metabolism of cholic acid is tightly regulated to maintain bile acid homeostasis. Here is an overview of the key steps and elements involved in cholic acid metabolism [3,5]:
Cholic acid is conjugated with the amino acids glycine or taurine to form bile salts, which are then secreted into bile. This process enhances the solubility of bile acids in water and aids in their emulsification of dietary fats.
Bile, containing cholic acid and other bile salts, is stored in the gallbladder. Upon food intake, the gallbladder contracts, releasing bile into the small intestine to aid in the digestion and absorption of fats.
In the small intestine, cholic acid is partially reabsorbed. The reabsorbed cholic acid, along with newly synthesized bile acids, enters the portal circulation and is transported back to the liver. This enterohepatic circulation is crucial for the efficient utilization of bile acids.
Cholic acid is intricately involved in various diseases, with its functions extending beyond digestion and lipid metabolism. Here are some insights into its roles in specific diseases, highlighting key findings and mechanisms:
Elevated levels of cholic acid are often associated with cholestatic liver diseases, such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). In these conditions, impaired bile flow leads to the accumulation of bile acids, including cholic acid, in the liver. Mechanistic insights into the impact of elevated cholic acid reveal its involvement in hepatocyte injury, oxidative stress, apoptosis, and inflammation. Excess cholic acid induces hepatocyte injury through mechanisms involving mitochondrial dysfunction and endoplasmic reticulum stress [6]. Furthermore, cholic acid, among other bile acids, promotes oxidative stress by increasing reactive oxygen species (ROS) production [7]. This oxidative damage exacerbates liver injury. Cholic acid is also implicated in activating apoptotic pathways, involving caspase activation and programmed cell death [8]. Additionally, its accumulation triggers inflammatory responses, activating immune cells and promoting the release of pro-inflammatory cytokines.
Imbalances in bile acid composition, particularly an increased ratio of cholic acid to chenodeoxycholic acid, have been implicated in the formation of gallstones. Mechanistic insights into gallstone formation reveal that an elevated cholic acid to chenodeoxycholic acid ratio actively promotes the nucleation of cholesterol in bile, creating an environment conducive to cholesterol aggregation, a pivotal step in initiating gallstone formation [9]. Additionally, excess cholic acid has been shown to facilitate the crystallization of cholesterol in bile, altering its physical properties and promoting the formation of cholesterol crystals—the cornerstone of gallstone development [10].
Bile acids, notably cholic acid, play pivotal roles in the pathogenesis of inflammatory bowel diseases (IBD) like Crohn's disease and ulcerative colitis. Altered bile acid metabolism and transport within the intestines contribute to the inflammatory processes observed in these disorders.
Elevated cholic acid levels are implicated in disrupting the intestinal barrier by downregulating tight junction proteins, including occludin and zonula occludens-1 (ZO-1) [11]. This disruption compromises the integrity of the intestinal epithelial barrier, facilitating the translocation of luminal antigens and triggering inflammatory responses. Cholic acid achieves immune modulation by interacting with nuclear receptors like farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (GPBAR1), influencing immune cell activation and pro-inflammatory cytokine release [12]. Additionally, cholic acid alterations impact the gut microbiota composition, with bile salt hydrolases (BSH) produced by certain bacteria playing a role in bile acid deconjugation and potentially affecting the inflammatory milieu [13].
Dysregulation of bile acid homeostasis, marked by elevated cholic acid levels, is intricately linked to colorectal cancer (CRC) development. Bile acids, including cholic acid, act as signaling molecules through nuclear receptors, notably the farnesoid X receptor (FXR), exerting profound effects on cell proliferation, apoptosis, and inflammation within the colon.
Cholic acid, specifically, demonstrates the ability to activate FXR, a pivotal regulator in CRC pathogenesis. FXR activation modulates the expression of genes crucial for cell cycle regulation and apoptosis in colorectal cancer cells [14]. Notably, the FXR-mediated regulation of cell cycle-related genes, such as cyclin D1 and cyclin-dependent kinase 4 (CDK4), contributes to the control of cell proliferation [14]. Additionally, the activation of FXR by cholic acid influences apoptosis in CRC cells by regulating the expression of anti-apoptotic B-cell lymphoma 2 (Bcl-2) and pro-apoptotic Bcl-2-associated X protein (Bax) [16].
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