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 4α (hnf-4α) causing this transcription factor to no longer be able to associate with the transcriptional co-activator pgc-1α (pparγ co-activator 1α) which ultimately leads to loss. The expression of other genes involved in bile acid synthesis is also regulated by fxr action. The action of fxr can either be to induce or repress the expression of these genes. Genes that are repressed in addition to cyp7A1 include srebp-1c, sterol 12α-hydroxylase (gene symbol: cyp8B1 and solute carrier family 10 (sodium/bile acid cotransporter family member 1 (gene symbol: slc10A1).
Dna and rna in, protein, synthesis?
The fxr genes david are expressed at highest levels essay 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 7α-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 a lipid component of this extract called guggulsterone (also called guggul lipid) is an antagonist of fxr.
Kuppfer cells are liver resident macrophages. Back to the top 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 task a consequence of the isolation of a class of receptors called the farnesoid X receptors, fxrs. The fxrs belong to the superfamily of nuclear receptors that includes the steroid/thyroid hormone receptor family as 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 fxrα and fxrβ. In humans at least four fxr isoforms have been identified as being derived from the fxrα gene as a result of activation from different promoters and the use of alternative splicing; fxrα1, fxrα2, fxrα3, and fxrα4. The fxr gene is also known as the nr1H4 gene (for nuclear receptor subfamily 1, group h, member 4).
The bile acid pool contains about 24 gm of bile acids and this pool is recycled via the water enterohepatic circulation on the assignments order of six to ten times each day. Of the total bile salt pool, around.20.6 gm are excreted in the feces each day. This lost fraction of bile salts is replenished via de novo hepatic bile acid synthesis from cholesterol. 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.
Once bile salts reach the basolateral membrane they are transported (effluxed) into the blood by the heterodimeric transporter ostα/ostβ (organic solute transporters). A small percentage of the bile salts are not reabsorbed and undergo deconjugation by intestinal microbiota before either being absorbed or converted into secondary bile acids. Anaerobic bacteria present in the colon modify the primary bile acids converting them to the secondary bile acids, identified as deoxycholate and ursodeoxycholate (dca and udca, from cholate) and lithocholate (lca, from chenodeoxycholate). These secondary bile acids are either passively absorbed from the colon or they are excreted in the feces. The absorbed primary and secondary bile acids and salts are transported back to the liver where most, but not all, are actively transported into hepatocytes by sodium sodium (Na)-taurocholate cotransporting polypeptide (ntcp/SLC10A1) and organic anion transporters (oatp) such as oat1B2) that mediate the uptake. Once in the liver the bile acids are reconjugated and then re-secreted together with newly synthesized bile salts. This overall process constitutes one cycle of what is called the enterohepatic circulation. When lca is returned to the liver it undergoes a sulfation reaction and is subsequently excreted in the feces.
Protein, synthesis, protein, synthesis
In addition, bile contains electrolytes, minerals, minor levels of proteins, plus bilirubin and biliverdin pigments. The bilirubin and biliverdin are what impart the health yellow-green or even orange hue resume to bile. The primary role of bile salt in the bile contained in the gall bladder is to solubilize cholesterol, thereby preventing cholesterol crystallization and the formation of cholesterol calculi (gallstones). Following the consumption of lipid in the diet, enteroendocrine i cells in the duodenum secrete the hormone cholecystokinin (CCK) into the circulation. The release of cck, and its subsequent binding to receptors on the gall bladder, promotes contraction of smooth muscle cells of the gall bladder and relaxation of the sphincter of Oddi, resulting in the pulsatile secretion of bile into the duodenum.
Within the lumen of the duodenum the bile salt-containing mixed micelles facilitate absorption of the fat-soluble vitamins a, d, k, and e and the digestion of dietary lipids by pancreatic enzymes. Although the gall bladder stores bile, as an organ it is not essential since patients who have undergone a cholecystectomy (gall bladder removal are still able to absorb lipids from the diet as a result of direct secretion of bile into the duodenum. Once bile salts are secreted into the duodenum and carry out their emulsification role, around 95 are reabsorbed into the distal ileum. Bile salt reabsorption occurs via the apical sodium-dependent bile transporter (asbt) present in the brush border membrane of the enterocyte. Ileal bile acid-binding protein (ibabp; also known as fatty acid-binding protein subclass 6: fabp6) is thought to be involved in the transport of bile salts across the enterocyte cytosol to the basolateral membrane.
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 Bile salts are secreted from hepatocytes, into the bile canaliculi, via the action of the bile salt export protein (bsep; atp-binding cassette B11, abcb11). Transport of phospholipids into the canaliculi requires the transporter abcb4.
Abcb4 is also known as multi-drug resistance protein 3 (MDR3, a member of the p-glycoprotein family of transporters). Some free cholesterol is also transported out of hepatocytes into the canaliculi via the action of the obligate heterodimeric transporter abcg5/abcg8. The transport of cholesterol via this complex also requires abcb4. The abcb4 requirement is consistent with the known actions of phospholipids in the bile canaliculi functioning as a sink to accept cholesterol tranported out by abcg5/abcg8. Each of these hepatic lipid transporters is critical for normal hepato-biliary function since mutations in any of the genes encoding the transporters have been shown to be associated with cholestatic liver diseases. These transport defects result in the accumulation of toxic levels of bile salts within the hepatocytes resulting in liver failure. The mixture of bile salts, phospholipids and cholesterol is then transported, via the canaliculi, into the gall bladder, where they are concentrated to form bile. The composition of bile is 85 water, 67 bile salts, 22 phospholipids, and 4 cholesterol.
Role of, ribosomes in, protein, synthesis (With diagram)
Expression of cyp7A1 occurs only in the liver. Conversion of 7α-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 12α-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 reviews 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.
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 12α-hydroxylase (CYP8B1). The intermediates of the hsd3B7 reaction that are acted on by cyp8B1 become ca and those report 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 7α-hydroxylase (CYP7A1) is the rate limiting step in bile acid synthesis.
bile acid intermediates generated via the action. Cyp27A1 are subsequently hydroxylated on the 7 position by oxysterol 7α-hydroxylase (CYP7B1). Although the acidic pathway is not a major route for human bile acid synthesis it is an important one as demonstrated by the phenotype presenting in a newborn harboring a mutation in the cyp7B1 gene. This infant presented with severe cholestasis (blockage in bile flow from liver) with cirrhosis and liver dysfunction. The hydroxyl group on cholesterol at the 3 position is in the β-orientation and must be epimerized to the α-orientation during the synthesis of the bile acids. This epimerization is initiated by conversion of the 3β-hydroxyl to a 3-oxo group catalyzed by 3β-hydroxy-Δ5-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. These children develop progressive liver disease that is characterized by cholestatic jaundice.
Given the fact that global many bile acid metabolites are cytotoxic it is understandable why their synthesis needs to be tightly controlled. Several inborn errors in metabolism are due to defects in genes of bile acid synthesis and are associated with liver failure in 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 7 position via the action of cholesterol 7α-hydroxylase (CYP7A1) which is an er localized enzyme. Cyp7A1 is a member of the cytochrome. P450 family of metabolic enzymes. This pathway is depicted in highly abbreviated fashion in the figure below. The pathway initiated by cyp7A1 is referred to as the "classic" or "neutral" pathway of bile acid synthesis. There is an alternative pathway that involves hydroxylation of cholesterol at the 27 position by the mitochondrial enzyme sterol 27-hydroxylase (CYP27A1).
Roles of, rna in, protein, synthesis - molecular
Return to The medical biochemistry page llc info @ the end products of cholesterol utilization are the bile acids. Indeed, the synthesis of the bile acids is the major pathway of cholesterol catabolism in mammals. Although several of the enzymes involved in bile acid synthesis are active in many cell types, the liver is the only organ where their complete biosynthesis can occur. Synthesis of bile acids is one of the predominant mechanisms for the excretion of excess cholesterol. However, the excretion of cholesterol 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 important in the solubilization of dietary cholesterol, lipids, fat xmas soluble vitamins, and other 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 intracellular compartments that include the cytosol, endoplasmic reticulum (er mitochondria, and peroxisomes. The genes encoding several of the enzymes of bile acid synthesis are under tight regulatory control to ensure that the necessary level of bile acid production is coordinated to changing metabolic conditions.