negative regulation of bile acid secretion

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of the controlled release of bile acid from a cell or a tissue. [GOC:BHF, GOC:BHF_miRNA, GOC:rph, PMID:22767443]

Negative regulation of bile acid secretion is a complex process involving multiple cellular mechanisms and signaling pathways to control the flow of bile acids from the liver into the bile duct. This intricate regulation ensures that bile acids are available for their critical roles in lipid digestion and absorption, but also prevents excessive levels that could lead to liver damage.

**1. Regulation at the Hepatocyte Level:**

* **Bile Acid Synthesis and Transport:** Bile acids are synthesized in the liver from cholesterol. Their secretion is primarily controlled by the enzyme **cholestasis-induced liver enzyme (CILE)**. This enzyme regulates the formation of bile acids, which then are transported into the bile canaliculi, the tiny spaces between hepatocytes where bile flow begins.
* **Bile Salt Export Pump (BSEP):** BSEP is a protein embedded in the hepatocyte membrane that actively transports bile salts, the conjugated forms of bile acids, from the liver into the bile canaliculi. This is a key step in bile acid secretion and is regulated by several factors, including **hormones (e.g., glucagon and insulin), bile acids themselves (feedback mechanism), and signaling pathways (e.g., PPAR alpha)**.
* **Intracellular Signaling Pathways:** Several intracellular signaling pathways contribute to the regulation of bile acid secretion.
* **cAMP signaling:** This pathway, activated by glucagon, stimulates bile acid secretion by promoting BSEP activity.
* **PPAR alpha signaling:** This pathway, activated by bile acids themselves, promotes bile acid synthesis and secretion, but also increases the expression of BSEP and other transporters.

**2. Regulation at the Bile Duct Level:**

* **Sphincter of Oddi:** This muscular valve at the junction of the common bile duct and the duodenum regulates the flow of bile into the small intestine. The sphincter is normally contracted, preventing bile flow. When food enters the duodenum, hormones like **cholecystokinin (CCK)** are released, leading to sphincter relaxation and bile release.
* **Bile Duct Epithelial Cells:** These cells contribute to bile acid secretion by actively transporting bile acids into the bile duct lumen and by reabsorbing bile acids from the duct. They also participate in the production of bicarbonate, which neutralizes the acidic bile and helps maintain its flow.

**3. Feedback Mechanisms:**

* **Bile Acid Feedback:** Bile acids themselves regulate their own secretion. High levels of bile acids in the intestine trigger the release of hormones like **fibroblast growth factor 19 (FGF19)**, which signals the liver to decrease bile acid synthesis and secretion.
* **Hormonal Regulation:** Hormones like **glucagon and insulin** play a role in bile acid secretion, with glucagon stimulating secretion and insulin inhibiting it.

**4. Other Factors Influencing Bile Acid Secretion:**

* **Liver Diseases:** Liver diseases like **cholestasis** and **cirrhosis** can disrupt bile acid secretion, leading to bile acid accumulation in the liver and potentially causing damage.
* **Drugs:** Some medications, such as **fibrates** and **statins**, can affect bile acid secretion by influencing the expression of key transport proteins.
* **Dietary Factors:** Dietary intake of fat, cholesterol, and certain medications can also influence bile acid secretion.

In summary, negative regulation of bile acid secretion is a complex process involving multiple levels of regulation, from intracellular signaling pathways to hormonal and dietary factors. This precise control ensures that bile acids are available for their essential roles in digestion and absorption, while preventing harmful consequences of excessive levels.
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