Bile Acid Synthesis, Metabolism and Biological Functions.pdf

7/27/2019 Bile Acid Synthesis, Metabolism and Biological Functions.pdf

1/5


2/5

10/26/13 Bile Acid Synthesis, Metabolism and Biological Functions

themedicalbiochemistrypage.org/bileacids.php#bilereg 2/5

Following the action of HSD3B7 the bile acid intermediates can proceed via two pathways whose end products

are chenodeoxycholic acid (CDCA) and cholic acid (CA). The distribution of these two bile acids is determined by the

activity of sterol 12-hydroxylase (CYP8B1). The intermediates of the HSD3B7 reaction that are acted on by CYP8B1

become CA and those that escape the action of the enzyme will become CDCA. Therefore, the activity of the CYP8B1

gene will determine the ratio of CA to CDCA. As discussed below the CYP8B1 gene is subject to regulation by bile

acids themselves via their ability to regulate the action of the nuclear receptor FXR.

Synthesis of the 2 primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA). The reaction

catalyzed by the 7-hydroxylase (CYP7A1) is the rate limiting step in bile acid synthesis. Expression of CYP7A1

occurs only in the liver. Conversion of 7-hydroxycholesterol to the bile acids requires several steps not shown in

detail 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%). These

are referred to as the primary bile acids. Before the primary bile acids are secreted into the canalicular lumen they

are conjugated via an amide bond at the terminal carboxyl group with either of the amino acids glycine or taurine.

These conjugation reactions yield glycoconjugates and tauroconjugates, respectively. This conjugation process

increases the amphipathic nature of the bile acids making them more easily secretable as well as less cytotoxic. 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 which then

form the bile ducts. Bile acids are carried from the liver through these ducts to the gallbladder, where they are stored

for future use. In the gallbladder bile acids are concentrated up to 1000 fold. Following stimulation by food intake thegallbladder 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 process that

removes the glycine and taurine residues. The deconjugated bile acids are either excreted (only a small percentage) or

reabsorbed by the gut and returned to the liver. Anaerobic bacteria present in the colon modify the primary bile acids


3/5

10/26/13 Bile Acid Synthesis, Metabolism and Biological Functions

themedicalbiochemistrypage.org/bileacids.php#bilereg 3/5

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 intestines and delivered back to

the liver via the portal circulation. Indeed, as much as 95% of total bile acid synthesized by the liver is absorbed by the

distal ileum and returned to the liver. This process of secretion from the liver to the gallbladder, to the intestines and

finally reabsorption is termed the enterohepatic circulation.

Structure of a liver lobule. Lobules in the liver represent histologically and functionally distinct domains within the

liver. They are not to be confused with the anatomical lobes of the liver which are defined as the right and left lobes

and the median and quadrate lobes. Lobules are histologically defined as classical, portal, and acinus lobules.

Lobules contain hepatocytes, and are vascularized by the hepatic portal vein, the hepatic artery, and the central vein.

In addition, the bile cannaliculi run through the lobules allowing hepatic products such as bile acids to be delivered to

the bile ducts and ultimately to the gallbladder. Kuppfer cells are liver resident macrophages.

back to the top

Regulation of Bile Acid Homeostasis

Bile acids, in particular chenodeoxycholic acid (CDCA) and cholic acid (CA), can regulate the expression of

genes involved in their synthesis, thereby, creating a feed-back loop. The elucidation of this regulatory pathway came

about as a consequence of the isolation of a class of receptors called the farnesoid X receptors, FXRs. The FXRs

belong to the superfamily of nuclear receptorsthat includes the steroid/thyroid hormone receptor familyas well 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 havebeen identified as being derived from the FXR gene as a result of activation from different promoters and the use of

alternative splicing; FXR1, FXR2, FXR3, and FXR4. The FXR gene is also known as the NR1H4 gene (for

nuclear receptor subfamily 1, group H, member 4). The FXR genes are expressed at highest levels in the intestine and

liver.

Like all receptors of this superfamily, ligand binds the receptor in the cytoplasm and then the complex migrates to

the nucleus and forms a heterodimer with other members of the family. FXR forms a heterodimer with members of the

RXR family. Following heterodimer formation the complex binds to specific sequences in target genes called FXR

response elements (FXREs) resulting in regulated expression. One major target of FXR is the small heterodimer

partner (SHP) gene. Activation of SHP expression by FXR results in inhibition of transcription of SHP target 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 via the 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 India is that alipid 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 X receptor (PXR)

which is another member of the nuclear receptor superfamily. PXR is a recognized receptor for lithocholic acid and

other bile acid precursors. PXR activation leads to repression of bile acid synthesis due to its physical association with

hepatocyte nuclear factor 4 (HNF-4) causing this transcription factor to no longer be able to associate with the
http://themedicalbiochemistrypage.org/ppar.phphttp://themedicalbiochemistrypage.org/lxr.phphttp://themedicalbiochemistrypage.org/steroid-hormones.phphttp://themedicalbiochemistrypage.org/signal-transduction.php#insidehttp://themedicalbiochemistrypage.org/fxr.phphttp://themedicalbiochemistrypage.org/bileacids.php#top


4/5

Functions Medical Transport Amino Acids Biological
http://googleads.g.doubleclick.net/pagead/ads?client=ca-pub-0170489783089944&output=html&h=15&slotname=9660312975&adk=3872916969&w=728&lmt=1382714927&flash=11.5.31&url=http%3A%2F%2Fthemedicalbiochemistrypage.org%2Fbileacids.php&dt=1382740126355&bpp=6&bdt=582&shv=r20131022&cbv=r20130906&saldr=sa&prev_slotnames=9660312975%2C8229094811%2C8229094811%2C1175766666&correlator=1382740126942&frm=20&ga_vid=34199143.1382740126&ga_sid=1382740126&ga_hid=2010248481&ga_fc=1&u_tz=420&u_his=2&u_java=1&u_h=768&u_w=1366&u_ah=738&u_aw=1366&u_cd=32&u_nplug=14&u_nmime=61&dff=arial&dfs=16&adx=331&ady=4914&biw=1349&bih=653&oid=3&vis=1&fu=0&ifi=5&dtd=978&xpc=EbCBLpvx5k&p=http%3A//themedicalbiochemistrypage.org&rl_rc=true&adsense_enabled=true&ad_type=text&ui=rc:0&oe=utf8&height=15&width=728&format=fp_al_lp&kw_type=radlink&prev_fmts=728x15_0ads_al&rt=ChBSavCeAADlzQrinYlPAHoeEgpCaW9sb2dpY2FsGggZP5LNusuZlCDftc8gKAEwAkjftc8gSO6mmsYCUhMIs7CbsISzugIVpaLiCh22DgCC&hl=en&kw0=Functions&kw1=Medical+Transport&kw2=Amino+Acids&kw3=Biological&okw=Biologicalhttp://googleads.g.doubleclick.net/pagead/ads?client=ca-pub-0170489783089944&output=html&h=15&slotname=9660312975&adk=3872916969&w=728&lmt=1382714927&flash=11.5.31&url=http%3A%2F%2Fthemedicalbiochemistrypage.org%2Fbileacids.php&dt=1382740126355&bpp=6&bdt=582&shv=r20131022&cbv=r20130906&saldr=sa&prev_slotnames=9660312975%2C8229094811%2C8229094811%2C1175766666&correlator=1382740126942&frm=20&ga_vid=34199143.1382740126&ga_sid=1382740126&ga_hid=2010248481&ga_fc=1&u_tz=420&u_his=2&u_java=1&u_h=768&u_w=1366&u_ah=738&u_aw=1366&u_cd=32&u_nplug=14&u_nmime=61&dff=arial&dfs=16&adx=331&ady=4914&biw=1349&bih=653&oid=3&vis=1&fu=0&ifi=5&dtd=978&xpc=EbCBLpvx5k&p=http%3A//themedicalbiochemistrypage.org&rl_rc=true&adsense_enabled=true&ad_type=text&ui=rc:0&oe=utf8&height=15&width=728&format=fp_al_lp&kw_type=radlink&prev_fmts=728x15_0ads_al&rt=ChBSavCeAADlywrinYlPAHoeEgtBbWlubyBBY2lkcxoIJ_8y8qo5LRMg37XPICgBMAJI37XPIEjupprGAlITCLOwm7CEs7oCFaWi4godtg4Agg&hl=en&kw0=Functions&kw1=Medical+Transport&kw2=Amino+Acids&kw3=Biological&okw=Amino+Acidshttp://googleads.g.doubleclick.net/pagead/ads?client=ca-pub-0170489783089944&output=html&h=15&slotname=9660312975&adk=3872916969&w=728&lmt=1382714927&flash=11.5.31&url=http%3A%2F%2Fthemedicalbiochemistrypage.org%2Fbileacids.php&dt=1382740126355&bpp=6&bdt=582&shv=r20131022&cbv=r20130906&saldr=sa&prev_slotnames=9660312975%2C8229094811%2C8229094811%2C1175766666&correlator=1382740126942&frm=20&ga_vid=34199143.1382740126&ga_sid=1382740126&ga_hid=2010248481&ga_fc=1&u_tz=420&u_his=2&u_java=1&u_h=768&u_w=1366&u_ah=738&u_aw=1366&u_cd=32&u_nplug=14&u_nmime=61&dff=arial&dfs=16&adx=331&ady=4914&biw=1349&bih=653&oid=3&vis=1&fu=0&ifi=5&dtd=978&xpc=EbCBLpvx5k&p=http%3A//themedicalbiochemistrypage.org&rl_rc=true&adsense_enabled=true&ad_type=text&ui=rc:0&oe=utf8&height=15&width=728&format=fp_al_lp&kw_type=radlink&prev_fmts=728x15_0ads_al&rt=ChBSavCeAADlxwrinYlPAHoeEhFNZWRpY2FsIFRyYW5zcG9ydBoIcjEbm0CfHkwg37XPICgBMAJI37XPIEjupprGAlITCLOwm7CEs7oCFaWi4godtg4Agg&hl=en&kw0=Functions&kw1=Medical+Transport&kw2=Amino+Acids&kw3=Biological&okw=Medical+Transporthttp://googleads.g.doubleclick.net/pagead/ads?client=ca-pub-0170489783089944&output=html&h=15&slotname=9660312975&adk=3872916969&w=728&lmt=1382714927&flash=11.5.31&url=http%3A%2F%2Fthemedicalbiochemistrypage.org%2Fbileacids.php&dt=1382740126355&bpp=6&bdt=582&shv=r20131022&cbv=r20130906&saldr=sa&prev_slotnames=9660312975%2C8229094811%2C8229094811%2C1175766666&correlator=1382740126942&frm=20&ga_vid=34199143.1382740126&ga_sid=1382740126&ga_hid=2010248481&ga_fc=1&u_tz=420&u_his=2&u_java=1&u_h=768&u_w=1366&u_ah=738&u_aw=1366&u_cd=32&u_nplug=14&u_nmime=61&dff=arial&dfs=16&adx=331&ady=4914&biw=1349&bih=653&oid=3&vis=1&fu=0&ifi=5&dtd=978&xpc=EbCBLpvx5k&p=http%3A//themedicalbiochemistrypage.org&rl_rc=true&adsense_enabled=true&ad_type=text&ui=rc:0&oe=utf8&height=15&width=728&format=fp_al_lp&kw_type=radlink&prev_fmts=728x15_0ads_al&rt=ChBSavCeAADlvgrinYlPAHoeEglGdW5jdGlvbnMaCKkhJsnj4yZWIN-1zyAoATACSN-1zyBI7qaaxgJSEwizsJuwhLO6AhWlouIKHbYOAII&hl=en&kw0=Functions&kw1=Medical+Transport&kw2=Amino+Acids&kw3=Biological&okw=Functionshttp://www.google.com/url?ct=abg&q=https://www.google.com/adsense/support/bin/request.py%3Fcontact%3Dabg_afc%26url%3Dhttp://themedicalbiochemistrypage.org/bileacids.php%26gl%3DID%26hl%3Den%26client%3Dca-pub-0170489783089944&usg=AFQjCNFDw5iHc9LoJIp6J8KvpDDyquf17w


5/5

Biological Biochemistry Protein Synthesis Liver Enzyme
http://googleads.g.doubleclick.net/pagead/ads?client=ca-pub-0170489783089944&output=html&h=15&slotname=9660312975&adk=3872916969&w=728&lmt=1382714927&flash=11.5.31&url=http%3A%2F%2Fthemedicalbiochemistrypage.org%2Fbileacids.php&dt=1382740126362&bpp=7&bdt=589&shv=r20131022&cbv=r20130906&saldr=sa&prev_slotnames=9660312975%2C8229094811%2C8229094811%2C1175766666%2C9660312975&correlator=1382740126942&frm=20&ga_vid=34199143.1382740126&ga_sid=1382740126&ga_hid=2010248481&ga_fc=1&u_tz=420&u_his=2&u_java=1&u_h=768&u_w=1366&u_ah=738&u_aw=1366&u_cd=32&u_nplug=14&u_nmime=61&dff=arial&dfs=16&adx=331&ady=5815&biw=1349&bih=653&oid=3&vis=1&fu=0&ifi=6&dtd=995&xpc=cL2CDTxTtp&p=http%3A//themedicalbiochemistrypage.org&rl_rc=true&adsense_enabled=true&ad_type=text&ui=rc:0&oe=utf8&height=15&width=728&format=fp_al_lp&kw_type=radlink&prev_fmts=728x15_0ads_al&rt=ChBSavCeAAJnQgrioAlcABagEgxMaXZlciBFbnp5bWUaCP_wxdFlOo0bIN-1zyAoATADSN-1zyBI7qaaxgJSEwiruKGwhLO6AhUqpeIKHXcMAOA&hl=en&kw0=Biological&kw1=Biochemistry&kw2=Protein+Synthesis&kw3=Liver+Enzyme&okw=Liver+Enzymehttp://googleads.g.doubleclick.net/pagead/ads?client=ca-pub-0170489783089944&output=html&h=15&slotname=9660312975&adk=3872916969&w=728&lmt=1382714927&flash=11.5.31&url=http%3A%2F%2Fthemedicalbiochemistrypage.org%2Fbileacids.php&dt=1382740126362&bpp=7&bdt=589&shv=r20131022&cbv=r20130906&saldr=sa&prev_slotnames=9660312975%2C8229094811%2C8229094811%2C1175766666%2C9660312975&correlator=1382740126942&frm=20&ga_vid=34199143.1382740126&ga_sid=1382740126&ga_hid=2010248481&ga_fc=1&u_tz=420&u_his=2&u_java=1&u_h=768&u_w=1366&u_ah=738&u_aw=1366&u_cd=32&u_nplug=14&u_nmime=61&dff=arial&dfs=16&adx=331&ady=5815&biw=1349&bih=653&oid=3&vis=1&fu=0&ifi=6&dtd=995&xpc=cL2CDTxTtp&p=http%3A//themedicalbiochemistrypage.org&rl_rc=true&adsense_enabled=true&ad_type=text&ui=rc:0&oe=utf8&height=15&width=728&format=fp_al_lp&kw_type=radlink&prev_fmts=728x15_0ads_al&rt=ChBSavCeAAJnPwrioAlcABagEhFQcm90ZWluIFN5bnRoZXNpcxoIwJBmDP28WLog37XPICgBMANI37XPIEjupprGAlITCKu4obCEs7oCFSql4goddwwA4A&hl=en&kw0=Biological&kw1=Biochemistry&kw2=Protein+Synthesis&kw3=Liver+Enzyme&okw=Protein+Synthesishttp://googleads.g.doubleclick.net/pagead/ads?client=ca-pub-0170489783089944&output=html&h=15&slotname=9660312975&adk=3872916969&w=728&lmt=1382714927&flash=11.5.31&url=http%3A%2F%2Fthemedicalbiochemistrypage.org%2Fbileacids.php&dt=1382740126362&bpp=7&bdt=589&shv=r20131022&cbv=r20130906&saldr=sa&prev_slotnames=9660312975%2C8229094811%2C8229094811%2C1175766666%2C9660312975&correlator=1382740126942&frm=20&ga_vid=34199143.1382740126&ga_sid=1382740126&ga_hid=2010248481&ga_fc=1&u_tz=420&u_his=2&u_java=1&u_h=768&u_w=1366&u_ah=738&u_aw=1366&u_cd=32&u_nplug=14&u_nmime=61&dff=arial&dfs=16&adx=331&ady=5815&biw=1349&bih=653&oid=3&vis=1&fu=0&ifi=6&dtd=995&xpc=cL2CDTxTtp&p=http%3A//themedicalbiochemistrypage.org&rl_rc=true&adsense_enabled=true&ad_type=text&ui=rc:0&oe=utf8&height=15&width=728&format=fp_al_lp&kw_type=radlink&prev_fmts=728x15_0ads_al&rt=ChBSavCeAAJnPArioAlcABagEgxCaW9jaGVtaXN0cnkaCJHVXsQ2j7ocIN-1zyAoATADSN-1zyBI7qaaxgJSEwiruKGwhLO6AhUqpeIKHXcMAOA&hl=en&kw0=Biological&kw1=Biochemistry&kw2=Protein+Synthesis&kw3=Liver+Enzyme&okw=Biochemistryhttp://googleads.g.doubleclick.net/pagead/ads?client=ca-pub-0170489783089944&output=html&h=15&slotname=9660312975&adk=3872916969&w=728&lmt=1382714927&flash=11.5.31&url=http%3A%2F%2Fthemedicalbiochemistrypage.org%2Fbileacids.php&dt=1382740126362&bpp=7&bdt=589&shv=r20131022&cbv=r20130906&saldr=sa&prev_slotnames=9660312975%2C8229094811%2C8229094811%2C1175766666%2C9660312975&correlator=1382740126942&frm=20&ga_vid=34199143.1382740126&ga_sid=1382740126&ga_hid=2010248481&ga_fc=1&u_tz=420&u_his=2&u_java=1&u_h=768&u_w=1366&u_ah=738&u_aw=1366&u_cd=32&u_nplug=14&u_nmime=61&dff=arial&dfs=16&adx=331&ady=5815&biw=1349&bih=653&oid=3&vis=1&fu=0&ifi=6&dtd=995&xpc=cL2CDTxTtp&p=http%3A//themedicalbiochemistrypage.org&rl_rc=true&adsense_enabled=true&ad_type=text&ui=rc:0&oe=utf8&height=15&width=728&format=fp_al_lp&kw_type=radlink&prev_fmts=728x15_0ads_al&rt=ChBSavCeAAJnMgrioAlcABagEgpCaW9sb2dpY2FsGgjhvFvDuP8gISDftc8gKAEwA0jftc8gSO6mmsYCUhMIq7ihsISzugIVKqXiCh13DADg&hl=en&kw0=Biological&kw1=Biochemistry&kw2=Protein+Synthesis&kw3=Liver+Enzyme&okw=Biologicalhttp://www.google.com/url?ct=abg&q=https://www.google.com/adsense/support/bin/request.py%3Fcontact%3Dabg_afc%26url%3Dhttp://themedicalbiochemistrypage.org/bileacids.php%26gl%3DID%26hl%3Den%26client%3Dca-pub-0170489783089944&usg=AFQjCNFDw5iHc9LoJIp6J8KvpDDyquf17w

Bile Acid Synthesis, Metabolism and Biological Functions.pdf

Documents

Transcript of Bile Acid Synthesis, Metabolism and Biological Functions.pdf