Bile Metabolism

The liver synthesizes bile acids and is chiefly responsible for excreting sterols from the body. Roughly 600 to 800 mL of bile is produced each day. Bile contains lipids, electrolytes, organic anions, and most importantly the bile acids (also called bile salts), which account for 85% of biliary solids.^[110] The body works to conserve bile acids; the enterohepatic circulation recycles them 20 to 30 times a day, relying on specific transmembrane transporters (on apical and basolateral hepatocellular surfaces) and binding proteins in hepatocytes and enterocytes. Also, a unique sodium-dependent bile acid transporter prevents loss of bile acids in the stool.

Bile acids are natural ionic detergents and play key roles in absorbing, transporting, solubilizing, and secreting lipids.^{[111] [112]} They activate lipases (bile acid-dependent) and enable fat micelles to form in the gut; these micelles are needed for the intestinal absorption of cholesterol, fat-soluble vitamins, and other lipids. The liver relies on bile acids for excreting most endogenous (e.g., bilirubin, cholesterol, amphipathic steroid hormonal derivatives) and exogenous (e.g., drugs, xenobiotics) substances. Bile acids regulate the expression of specific genes by binding to, or activating, members of the sterol nuclear receptor family, such as the farnesoid X receptor (FXR). They are the chief regulators of pathways for metabolizing and excreting sterols, including cholesterol. Bile acids also regulate lipoprotein receptors, which control the uptake of lipoprotein cholesterol by hepatocytes^{[110] [113]} and directly influence 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting step in cholesterol biosynthesis.

Unlike the kidney, which secretes small, hydrophilic molecules, the liver secretes a wide range of organic anions with higher molecular weights. Because the hydrostatic pressure within bile ducts exceeds that within the sinusoidal space, hydrostatic pressure cannot drive bile formation. Instead, the energy is from an osmotic pressure gradient, caused by the active secretion of solutes across apical hepatocellular membranes and bile duct epithelium. Primary active transporters, powered by the hydrolysis of ATP, create bile by pumping solutes against their concentration gradients into the canalicular space. This canalicular bile is alkalinized and diluted as it courses through the ductular collecting system.^[110] Opioids (μ-agonists) may interfere with biliary flow by

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