image: (A) The classic bile acid synthesis pathway: cholesterol 7α-hydroxylase (CYP7A1) converts cholesterol to 7α-hydroxycholesterol (7α-HOC). The sterol 12α-hydroxylase (CYP8B1) converts the intermediate 7α-hydroxy-4 cholesten-3-one (C4) to 7α, 12α-dihydroxy-4-cholesten-3-one, eventually leading to synthesis of cholic acid (CA). C4 can also be eventually converted to chenodeoxycholic acid (CDCA). The mitochondrial sterol 27-hydroxylase (CYP27A1) catalyses the steroid side-chain oxidation of CA and CDCA. The alternative bile acid synthesis pathway: CYP27A1 converts cholesterol to 27-hydroxycholesterol (27-HOC), which mainly leads to the synthesis of CDCA. In mouse liver, CYP2C70 converts CDCA to α-MCA, which can be epimerized to β-MCA. In small and large intestine, bacterial bile salt hydrolase (BSH) deconjugates bile acids. Bacterial 7-dehydroxylase dehydroxylates CA to produce deoxycholic acid (DCA) and CDCA to produce lithocholic acid (LCA). Bacterial enzymes also produce secondary bile acids, including ω-muricholic acid (ω-MCA) and ursodeoxycholic acid (UDCA). (B–D) Structure of primary and secondary bile acids.
Credit: By Tiangang Li, Mohammad Nazmul Hasan, Lijie Gu.
Bile acids are essential molecules the liver produces that play a critical role in digestion. They help us absorb fat-soluble vitamins and cholesterol from our food. However, bile acids can become a double-edged sword. While they are necessary for proper digestion, high concentrations can also be toxic to the liver.
Recent research is shedding light on the complex relationship between bile acids and liver health. Scientists have identified new ways in which bile acids interact with cellular stress responses, impacting how the liver functions in diseases like cholestasis, fatty liver disease (MASLD), and alcoholic liver disease (ALD).
In cholestasis, bile flow becomes obstructed, leading to a buildup of bile acids in the liver. This can cause significant liver injury. Current treatments for cholestasis focus on reducing bile acid toxicity to protect the liver.
New evidence suggests that bile acid imbalances may also contribute to the development and progression of MASLD and ALD. Targeting bile acid signalling pathways shows promise as a potential treatment approach for these diseases. However, further research is needed to understand the underlying mechanisms.
Scientists are actively investigating how bile acids interact with cellular processes to maintain liver health. This ongoing research will pave the way for significant advancements in the field of liver disease. By unravelling the intricate mechanisms of bile acid function, researchers hope to identify the specific role of bile acids in different liver diseases, develop new diagnostic tools based on bile acid levels, and create targeted therapies that modulate bile acid signalling to promote better liver health.
Understanding the complex role of bile acids in the liver is crucial for developing new tools and treatments for a range of liver diseases.
See the article:
Li T, Hasan MN, Gu L. Bile acids regulation of cellular stress responses in liver physiology and diseases. eGastroenterology 2024;2:e100074. doi:10.1136/egastro-2024-100074
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eGastroenterology
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Bile acids regulation of cellular stress responses in liver physiology and diseases