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Bile Acid SynthesisRegulation of Bile Acid HomeostasisBile Acids as Metabolic RegulatorsInborn Errors in Bile Acids Synthesis

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Bile Acid Synthesis and Utilization

The end products ofcholesterol utilization are the bile acids. Indeed, the synthesis of the bile acids is the majorpathway of cholesterol catabolism in mammals. Although several of the enzymes involved in bile acid synthesis areactive in many cell types, the liver is the only organ where their complete biosynthesis can occur. Synthesis of bileacids is one of the predominant mechanisms for the excretion of excess cholesterol. However, the excretion ofcholesterol in the form of bile acids is insufficient to compensate for an excess dietary intake of cholesterol.Although bile acid synthesis constitutes the route of catabolism of cholesterol, these compounds are also importantin the solubilization of dietary cholesterol, lipids, and essential nutrients thus promoting their delivery to the liver.Synthesis of a full complement of bile acids requires 17 individual enzymes and occurs in multiple intracellularcompartments that include the cytosol, endoplasmic reticulum (ER), mitochondria, and peroxisomes. The genesencoding several of the enzymes of bile acid synthesis are under tight regulatory control to ensure that thenecessary level of bile acid production is coordinated to changing metabolic conditions. Given the fact that manybile acid metabolites are cytotoxic it is understandable why their synthesis needs to be tightly controlled. Severalinborn errors in metabolism are due to defects in genes of bile acid synthesis and are associated with liver failurein early childhood to progressive neuropathies in adults.

The major pathway for the synthesis of the bile acids is initiated via hydroxylation of cholesterol at the 7position via the action of cholesterol 7!-hydroxylase (CYP7A1) which is an ER localized enzyme. CYP7A1 is amember of the cytochrome P450 family of metabolic enzymes. This pathway is depicted in highly abbreviatedfashion in the Figure below. The pathway initiated by CYP7A1 is referred to as the "classic" or "neutral" pathway ofbile acid synthesis. There is an alternative pathway that involves hydroxylation of cholesterol at the 27 position bythe mitochondrial enzyme sterol 27-hydroxylase (CYP27A1). This alternative pathway is referred to as the "acidic"pathway of bile acid synthesis. Although in rodents the acidic pathway can account for up to 25% of total bile acidsynthesis, in humans it accounts for no more than 6%. The bile acid intermediates generated via the action ofCYP27A1 are subsequently hydroxylated on the 7 position by oxysterol 7!-hydroxylase (CYP7B1). Although the

acidic pathway is not a major route for human bile acid synthesis it is an important one as demonstrated by thephenotype presenting in a newborn harboring a mutation in the CYP7B1 gene. This infant presented with severecholestasis (blockage in bile flow from liver) with cirrhosis and liver dysfunction.

The hydroxyl group on cholesterol at the 3 position is in the "-orientation and must be epimerized to the !-orientation during the synthesis of the bile acids. This epimerization is initiated by conversion of the 3"-hydroxyl to

a 3-oxo group catalyzed by 3"-hydroxy-#5-C27-steroid oxidoreductase (HSD3B7). That this reaction is critical for

bile acid synthesis and function is demonstrated in children harboring mutations in the HSD3B7 gene. Thesechildren develop progressive liver disease that is characterized by cholestatic jaundice.

Following the action of HSD3B7 the bile acid intermediates can proceed via two pathways whose end productsare chenodeoxycholic acid (CDCA) and cholic acid (CA). The distribution of these two bile acids is determined bythe activity of sterol 12!-hydroxylase (CYP8B1). The intermediates of the HSD3B7 reaction that are acted on byCYP8B1 become CA and those that escape the action of the enzyme will become CDCA. Therefore, the activity ofthe CYP8B1 gene will determine the ratio of CA to CDCA. As discussed below the CYP8B1 gene is subject toregulation by bile acids themselves via their ability to regulate the action of the nuclear receptor FXR.

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Synthesis of the 2 primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA). The reactioncatalyzed by the 7!-hydroxylase (CYP7A1) is the rate limiting step in bile acid synthesis. Expression of CYP7A1occurs only in the liver. Conversion of 7!-hydroxycholesterol to the bile acids requires several steps not shown indetail in this image. Only the relevant co-factors needed for the synthesis steps are shown. Sterol 12!-hydroxylase (CYB8B1) controls the synthesis of cholic acid and as such is under tight transcriptional control (see

text).

The most abundant bile acids in human bile are chenodeoxycholic acid (45%) and cholic acid (31%). Theseare referred to as the primary bile acids. Before the primary bile acids are secreted into the canalicular lumenthey are conjugated via an amide bond at the terminal carboxyl group with either of the amino acids glycine ortaurine. These conjugation reactions yield glycoconjugates and tauroconjugates, respectively. This conjugationprocess increases the amphipathic nature of the bile acids making them more easily secretable as well as lesscytotoxic. The conjugated bile acids are the major solutes in human bile.

Structure of the conjugated cholic acids

Following secretion by the liver the bile acids enter the bile canaliculi which join with the bile ductules whichthen form the bile ducts. Bile acids are carried from the liver through these ducts to the gallbladder, where they arestored for future use. In the gallbladder bile acids are concentrated up to 1000 fold. Following stimulation by foodintake the gallbladder releases the bile into the duodenum, via the action of the gut hormone cholecystokinin(CCK), where they aid in the emulsification of dietary lipids.

Within the intestines the primary bile acids are acted upon by bacteria and undergo a deconjugation processthat removes the glycine and taurine residues. The deconjugated bile acids are either excreted (only a smallpercentage) or reabsorbed by the gut and returned to the liver. Anaerobic bacteria present in the colon modify theprimary bile acids converting them to the secondary bile acids, identified as deoxycholate (from cholate) and

lithocholate (from chenodeoxycholate). Both primary and secondary bile acids are reabsorbed by the intestinesand delivered back to the liver via the portal circulation. Indeed, as much as 95% of total bile acid synthesized bythe liver is absorbed by the distal ileum and returned to the liver. This process of secretion from the liver to thegallbladder, to the intestines and finally reabsorption is termed the enterohepatic circulation.


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Regulation of Bile Acid Homeostasis

Bile acids, in particular chenodeoxycholic acid (CDCA) and cholic acid (CA), can regulate the expression ofgenes involved in their synthesis, thereby, creating a feed-back loop. The elucidation of this regulatory pathwaycame about as a consequence of the isolation of a class of receptors called the farnesoid X receptors, FXRs. TheFXRs belong to the superfamily of nuclear receptors that includes the steroid/thyroid hormone receptor family aswell as the liver X receptors (LXRs), retinoid X receptors (RXRs), and the peroxisome proliferator-activated

receptors (PPARs).There are two genes encoding FXRs identified as FXR! and FXR". In humans at least four FXR isoforms

have been identified as being derived from the FXR! gene as a result of activation from different promoters andthe use of alternative splicing; FXR!1, FXR!2, FXR!3, and FXR!4. The FXR gene is also known as the NR1H4gene (for nuclear receptor subfamily 1, group H, member 4). The FXR genes are expressed at highest levels in theintestine and liver.

Like all receptors of this superfamily, ligand binds the receptor in the cytoplasm and then the complex migratesto the nucleus and forms a heterodimer with other members of the family. FXR forms a heterodimer with membersof the RXR family. Following heterodimer formation the complex binds to specific sequences in target genes calledFXR response elements (FXREs) resulting in regulated expression. One major target of FXR is the smallheterodimer partner (SHP) gene. Activation of SHP expression by FXR results in inhibition of transcription of SHPtarget genes. Of significance to bile acid synthesis, SHP represses the expression of the cholesterol 7!-hydroxylase gene (CYP7A1). CYP7A1 is the rate-limiting enzyme in the synthesis of bile acids from cholesterol viathe classic pathway.

In the Ayurvedic tradition of medicine, any resin that is collected by tapping the trunk of a tree is called guggul(or guggal). The cholesterol lowering action of the guggul from the Mukul myrrh tree (Commiphora mukul) of Indiais that a lipid component of this extract called guggulsterone (also called guggul lipid) is an antagonist of FXR.However, in addition to its effects on FXR function, guggulsterone has been shown to activate the pregnane Xreceptor (PXR) which is another member of the nuclear receptor superfamily. PXR is a recognized receptor forlithocholic acid and other bile acid precursors. PXR activation leads to repression of bile acid synthesis due to itsphysical association with hepatocyte nuclear factor 4! (HNF-4!) causing this transcription factor to no longer beable to associate with the transcriptional co-activator PGC-1! (PPAR$ co-activator 1!) which ultimately leads toloss of transcription factor activation of CYP7A1.

The expression of other genes involved in bile acid synthesis is also regulated by FXR action. The action ofFXR can either be to induce or repress the expression of these genes. Genes that are repressed in addition toCYP7A1 include SREBP-1c, sterol 12!-hydroxylase (gene symbol = CYP8B1), and solute carrier family 10(sodium/bile acid cotransporter family), member 1 (gene symbol = SLC10A1). This latter gene is identified as the

Na+-taurocholate cotransporting polypeptide (NTCP). NTCP is involved in hepatic uptake of bile acids through the

sinusoidal/basolateral membrane. Thus bile acid-mediated repression of NTCP gene expression would reduceuptake of bile acids and protect the liver from the toxic effects of excess bile acid accumulation. Bile acids repressthe transcription of another bile acid transporter that is expressed in the sinusoidal/basolateral membrane. This

transporter is Na+-independent and is called the organic anion transporting polypeptide 1B1 (OATP1B1, genesymbol = SLCO1B1). OATP1B1 was formerly identified as OATP-C. The effect of bile acids on OATP1B1expression is indirect and involves SHP-mediated reduction in HNF-4! activity which in turn reduces theexpression of another liver-enriched transcription factor HNF-1! which is the major activator of the OATP1B1gene.

Genes that, in addition to SHP, are induced by FXR include liver bile salt export pump (BSEP), multidrugresistance protein 3 (MDR3), and multidrug resistance associated protein 2 (MRP2). The latter two genes areinvolved in export of organic compounds and were identified based upon their ability to transport drugs out of cellsthereby, allowing the cells to resist the intended effects of the administered drug. The normal function of MDR3,which is a member of the ATP-binding cassette (ABC) family of transporters (MDR3 is also identified as ABCB4), isthe translocation of phospholipids through the canalicular membrane of hepatocytes. Thus, it is inferred that the

bile acid-mediated increase in MDR3 expression is necessary to allow hepatocytes to respond to bile acid toxicityvia the formation of cholesterol, phospholipid, and bile acid containing micelles. BSEP is also a member of theABC family of transporters (BSEP is also identified as ABCB11) and it is involved in the process of exporting bileacids out of hepatocytes thus reducing their toxicity to these cells. Although guggulsterones antagonize the actionsof FXR, which would lead to a reduction in bile acid export, these lipids have been shown to activate theexpression of BSEP through an FXR-independent mechanism. This latter effect likely explains the cholesterollowering benefits attributed to these compounds.

Of major clinical significance is that many of the FXR target genes have been implicated in several inheritedcholestatic liver disorders. Mutations in BSEP and MDR3 are associated with familial intrahepatic cholestasis type2 and 3, respectively. Mutations in MRP2 are associated with Dubin-Johnson syndrome, a form of inheritedhyperbilirubinemia.

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Bile Acids as Metabolic RegulatorsBile acids were originally identified as being involved in four primary physiologically significant functions:


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1. their synthesis and subsequent excretion in the feces represent the only significant mechanism for theelimination of excess cholesterol.

2. bile acids and phospholipids solubilize cholesterol in the bile, thereby preventing the precipitation ofcholesterol in the gallbladder.

3. they facilitate the digestion of dietary triacylglycerols by acting as emulsifying agents that render fatsaccessible to pancreatic lipases.

4. they facilitate the intestinal absorption of fat-soluble vitamins.

However, over the past several years new insights into the biological activities of the bile acids have been

elucidated. Recent findings have demonstrated that bile acids are involved in the control of their own metabolismand transport via the enterohepatic circulation, regulate lipid metabolism, regulate glucose metabolism, controlsignaling events in liver regeneration, and the regulation of overall energy expenditure.

Following the isolation and characterization of the farnesoid X receptors (FXRs), for which the bile acids arephysiological ligands, the functions of bile acids in the regulation of lipid and glucose homeostasis has begun toemerge. As indicated above, the binding of bile acids to FXRs results in the attenuated expression of severalgenes involved in overall bile acid homeostasis. However, genes involved in bile acid metabolism are not the onlyones that are regulated by FXR action as a consequence of binding bile acid. In the liver, FXR action is known toregulate the expression of genes involved in lipid metabolism (e.g. SREBP-1c), lipoprotein metabolism (e.g. apoC-II), glucose metabolism (e.g. PEPCK), and hepatoprotection (e.g. CYP3A4, which was originally identified asnifedipine oxidase; nifedipine being a member of the calcium channel blocker drugs).

In addition to their roles in lipid emulsification in the intestine and activating FXR, the bile acids participate invarious signal transduction processes via activation of the c-JUN N-terminal kinase (JNK) as well as the mitogen-activated protein kinase (MAPK) pathways. Other members of the nuclear receptor family that are activated by bile

acids are the pregnane X receptor (PXR), the constitutive androstane receptor (CAR), and the vitamin D receptor(VDR). An additional receptor activated in response to bile acids that may have implications for control of obesity isthe transmembrane G-protein coupled bile acid receptor 1 (originally identified as TGR5 and also known asGPR131). Activation of TGR5 in brown adipose tissue results in activation of uncoupling protein 1, UCP1(thermogenin) leading to enhanced energy expenditure.

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Inborn Errors in Bile Acids Synthesis

Metabolic disorders associated with bile acid synthesis and metabolism are broadly classified as primary orsecondary disorders. Primary disorders involve inherited deficiencies in enzymes responsible for catalyzing keyreactions in the synthesis of cholic and chenodeoxycholic acids. Bile acid disorders classified as secondary refer tometabolic defects that impact primary bile acid synthesis but that are not due to defects in the enzymes

responsible for synthesis. Secondary disorders of bile acid metabolism include peroxisomal disorders such asZellweger syndrome and related peroxisomal biogenesis disorders and Smith-Lemli-Opitz syndrome which resultsfrom a deficiency of 7-dehydrocholesterol reductase (DHCR7). Shown in the Table below are six of the knownprimary disorders of bile acid metabolism.

AffectedEnzyme

GeneSymbol

Phenotype / Comments

cholesterol 7!-hydroxylase

CYP7A1

no liver dysfunction, clinical phenotype manifests with markedly elevated totalcholesterol as well as LDL, premature gallstones, premature coronary andperipheral vascular disease, elevated serum cholesterol is not responsive tostatin drug therapy

sterol 27-

hydroxylase

CYP27A1progressive neurological dysfunction, neonatal cholestasis, bilateral cataracts,

chronic diarrhea

oxysterol 7!-hydroxylase

CYP7B1

a single case was reported in 1998 of a 10-week-old boy presenting with severeprogressive cholestasis, hepatosplenomegaly, cirrhosis, and liver failure, serumALT and AST were markedly elevated; recently several individuals sufferingfrom autosomal recessive hereditary spastic paraplegia 5A (SPG5A) have beenshown to harbor mutations in the CYP7B1 gene although the number of casesonly represents around 1% of all SPG cases

3"-hydroxy-#5-C27-steroid

oxidoreductase

HSD3B7

most commonly reported defect in bile acid synthesis, heterogeneous clinicalpresentation that includes progressive jaundice, hepatomegaly, puritis,malabsorption with resultant steatorrhea (fatty diarrhea), fat soluble vitamindeficiency, rickets

#4-3-oxosteroid 5"-reductase

AKR1C4

similar clinical manifestation to HSD3B7 deficiency although with earlier

presentation afflicted infants will have a more severe liver disease with rapidprogression to cirrhosis and death if no clinical intervention is undertaken, liverfunction tests will show marked elevation in AST and ALT, serum tests show

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