Archives

  • 2018-07
  • 2019-04
  • Bile acids are cholesterol derivatives

    2019-04-15

    Bile acids are cholesterol derivatives produced only in the hepatocytes of the liver. Hepatic bile acid synthesis represents the only quantitatively significant route for cholesterol elimination. Bile acids are amphipathic physiological detergents that facilitate dietary cholesterol, lipid and fat-soluble vitamin procyanidin b2 in the small intestine. Studies over the past couple decades have demonstrated that bile acids act as signaling molecules that regulate intracellular signaling pathways. Many of these pathways are critically involved in the regulation of lipid, glucose and energy metabolism. In addition, bile acid synthesis and plasma bile acid concentrations are sensitive to circadian and nutrient regulation, which suggests that bile acid signaling integrates nutrient sensing to the maintenance of metabolic homeostasis. Drugs targeting bile acid metabolism and signaling have been used clinically to treat patients with hypercholesterolemia and hyperglycemia. New therapies targeting bile acid signaling pathways are currently being developed to treat fatty liver diseases. In this review, we will summarize the current knowledge of bile acid synthesis regulation and the mechanisms underlying bile acid signaling regulation of metabolic homeostasis. These comprise the molecular basis for the development of bile acid-based therapies for fatty liver disease.
    A brief introduction on bile acid metabolism Cholesterol conversion into bile acids involves several enzymatic and non-enzymatic reactions (Fig. 1A). Hepatocytes are the only cell type that expresses all the required bile acid synthetic enzymes, which are located in different intracellular compartments, including the endothelium reticulum (ER), cytosol, mitochondria and peroxisomes. Cholesterol 7α-hydroxylase (CYP7A1), which is a cytochrome P450 (CYP) enzyme residing in the ER, catalyzes the first and rate-limiting step in the classic bile acid synthesis pathway to convert cholesterol to 7α-hydroxycholesterol. 7α-hydroxycholesterol is subsequently converted to two primary bile acids, chenodeoxycholic acid (CDCA) and cholic acid (CA) (Fig. 1A). CA synthesis involves the C-12 hydroxylation of 7α-hydroxy-4-choesten-3-one to 7α, 12α-dihydroxy-4-cholesten-3-one, which is catalyzed by another cytochrome p450 enzyme sterol 12α-hydroxylase (CYP8B1) that is located in the ER (Fig. 1B). As displayed in Fig. 1A, CDCA can also be produced via the alternative bile acid biosynthesis pathway, in which cholesterol is first converted to 27-hydroxycholesterol by the mitochondrial sterol 27-hydroxylase (CYP27A1). Newly synthesized bile acids are conjugated to the amino acids glycine or taurine on the side chain to form N-acyl amidates, a process that is catalyzed sequentially by two enzymes, bile acid-CoA ligase and bile acid-CoA:amino acid N-acyltransferase. Conjugation of bile acids increases bile acid water-solubility under physiological pH and decreases bile acid toxicity. The bile of human patients with defective bile acid-conjugating enzymes contains high levels of unconjugated bile acids, which causes fat-soluble vitamin malabsorption, growth retardation and liver injury. Human bile contains glycine- and taurine- conjugated bile acids in a roughly 3:1 ratio, while mouse bile contains predominantly taurine-conjugated bile acids. In this review, the terms CDCA, CA and other bile acid species mentioned later will be used to refer to both the conjugated and unconjugated forms unless specified. Bile acids circulate between the liver and the intestine in a process called enterohepatic circulation of the bile, which is stimulated by nutrient intake and occurs a few times a day in humans (Fig. 2). Bile acids are secreted across the apical membrane of hepatocytes and stored in the gallbladder. Bile acid secretion into the bile against the concentration gradient is mediated by ATP binding cassette transporter B11 (also called the bile salt export pump [BSEP]). Cholesterol and phospholipids are two other major constituents in the bile, and their efflux is mediated by ATP-binding cassette (ABC) transporters, the ABCG5/ABCG8 heterodimer and canalicular phospholipid floppase multi-drug resistance 3, respectively. Some bile acids can be absorbed by cholangiocytes after they are secreted by hepatocytes. Cholangiocytes take up unconjugated bile acids via passive diffusion and conjugated bile acids via the apical sodium-dependent bile salt transporter (ASBT). Bile acids in cholangiocytes are then secreted into the peribiliary plexus via organic solute transporter (OST) α and OSTβ, which form a heterodimer, and subsequently taken up by hepatocytes. Meal intake stimulates the release of bile acids into the intestinal tract where bile acids help emulsify dietary lipids and thus facilitate dietary lipid and fat-soluble vitamin absorption. In the small intestine, some colonized bacteria express bile salt hydrolases, which convert some of the conjugated bile acids to unconjugated bile acids. These unconjugated bile acids can then serve as substrates for bacterial 7α-dehydroxylase, which mediates the C-7 dehydroxylation reaction of primary bile acids to produce secondary bile acids deoxycholic acid (DCA) from CA and lithocholic acid (LCA) from CDCA. The majority of bile acids are efficiently reabsorbed in the ileum and transported back to the liver via portal circulation. The daily fecal loss of bile acids is approximately 5%, which is replenished by de novo bile acid biosynthesis in the hepatocytes to maintain a relatively constant bile acid pool. The ileum has high expression of bile acid transporters. ASBT mediates bile acid uptake into enterocytes, and OSTα/OSTβ heterodimers at the basolateral membrane of the enterocyte mediate bile acid efflux into the portal circulation. Conjugated bile acids in the portal circulation are taken up primarily by the sodium-dependent taurocholate transporter. Because the first pass extraction rate of portal bile acids by the liver is approximately 90%, bile acid concentrations in the systemic circulation are significantly lower than those of the portal blood under normal physiology. Under normal conditions, bile acid excretion through the kidney is minimal. However, in cholestasis, where bile acid excretion via the biliary route is impaired, more bile acids are secreted across the basolateral side of hepatocytes into the systemic circulation. Basolateral bile acid efflux from the hepatocyte can be mediated by multidrug resistance-related protein (MRP) 3, MRP4 and OSTα/OSTβ heterodimer. Increased systemic bile acid concentrations lead to renal bile acid excretion.