John Bumler's List: Bile Acid Biosynthesis

• taurine can influence (and possibly reverse) defects in nerve blood flow, motor nerve conduction velocity, and nerve sensory thresholds in experimental diabetic neuropathic rats.^[38][39]
• taurine may exert a beneficial effect in preventing diabetes-associated microangiopathy and tubulointerstitial injury in diabetic nephropathy.^[43][44]
• Taurine acts as a glycation inhibitor.
• Studies have shown that taurine treated diabetic rats had a decrease in the formation of advanced glycation end products (AGEs) and AGEs content.^[45][46]
• shown to be effective in removing fatty liver deposits in humans

3 more annotations...

• Bile salts are bile acids conjugated to glycine or taurine.
• The main function of bile acid is to facilitate the formation of micelles, which promotes processing of dietary fat.
• Bile acids are made in the liver by the cytochrome P450-mediated oxidation of cholesterol.
• They are conjugated with taurine or the amino acid glycine, or with a sulfate or a glucuronide, and are then stored in the gallbladder.
• the rate limiting step is the addition of a hydroxyl group on position 7 of the steroid nucleus by the enzyme cholesterol 7 alpha-hydroxylase.
• Bile acids serve other functions, including eliminating cholesterol from the body, driving the flow of bile to eliminate catabolites from the liver, emulsifying lipids and fat soluble vitamins in the intestine, and aiding in the reduction of the bacteria flora found in the small intestine and biliary tract.
• bile acids serve the purpose of emulsifying dietary fats
• The body produces about 800 mg of cholesterol per day and about half of that is used for bile acid synthesis.
• In total about 20-30 grams of bile acids are secreted into the intestine daily.
• about 90% of excreted bile acids are reabsorbed by active transport in the ileum and recycled in what is referred to as the enterohepatic circulation.
• Bile is also used to break down fat globules into tiny droplets.
• Bile acids formed by synthesis in the liver are termed "primary" bile acids, and those made by bacteria are termed "secondary" bile acids.
• In humans, the most important bile acids are cholic acid, deoxycholic acid, and chenodeoxycholic acid. Prior to secretion by the liver, they are conjugated with either the amino acid glycine or taurine.
• Conjugation increases water solubility, preventing passive re-absorption once secreted into the small intestine.
• As a result, the concentration of bile acids in the small intestine can stay high enough to form micelles and solubilize lipids.
• "Critical micellar concentration" refers to both an intrinsic property of the bile acid itself and amount of bile acid necessary to function in the spontaneous and dynamic formation of micelles.
• As surfactants or detergents, bile acids are potentially toxic to cells, and their concentrations are tightly regulated. They function as a signaling molecule in the liver and the intestines by activating a nuclear hormone receptor, FXR, also known by its gene name NR1H4. Such activation inhibits synthesis of bile acid in the liver when bile acid levels are too high. Emerging evidence associates FXR activation with alterations in triglyceride metabolism, glucose metabolism, and liver growth.
• Since bile acids are made from endogenous cholesterol, the enterohepatic circulation of bile acids may be disrupted to lower cholesterol. Bile acid sequestrants bind bile acids in the gut, preventing reabsorption. In so doing, more endogenous cholesterol is shunted into the production of bile acids, thereby lowering cholesterol levels. The sequestered bile acids are then excreted in the feces.

16 more annotations...

• Cholesterol 7 alpha-hydroxylase (CYP7A1) is the rate-limiting enzyme in the synthesis of bile acid from cholesterol, catalyzing the formation of 7-alpha-hydroxycholesterol.
• CYP7A1 is a cytochrome P450 heme enzyme that oxidizes cholesterol using molecular oxygen.
• It is downregulated by Sterol regulatory element binding proteins (SREBP) when plasma cholesterol levels are low. It is upregulated by the nuclear receptor LXR (liver X receptor) when cholesterol (specifically - oxysterol) levels are high.^[1] The effect of this upregulation is to increase the production of bile acids and reduce the level of cholesterol in hepatocytes.

1 more annotation...

• The bile acid sequestrants are a group of medications used to bind certain components of bile in the gastrointestinal tract. They disrupt the enterohepatic circulation of bile acids by sequestering them and preventing their reabsorption from the gut. They are generally classified as hypolipidemic agents, although they may be used for purposes other than lowering cholesterol.

• Bile acid sequestrants are polymeric compounds which serve as ion exchange resins. Bile acid sequestrants exchange anions such as chloride ions for bile acids. By doing so, they bind bile acids and sequester them from enterohepatic circulation.

   

  Since bile acid sequestrants are large polymeric structures, they are not well-absorbed from the gut into the bloodstream. Thus, bile acid sequestrants, along with any bile acids bound to the drug, are excreted via the feces after passage through the gastrointestinal tract.^[1]
• Since bile acids are biosynthesized from cholesterol, the disruption of bile acid reabsorption will decrease cholesterol levels, particularly low density lipoprotein (commonly known as "bad cholesterol"). Therefore, they may be used for the treatment of hypercholesterolemia and dyslipidemia.
• In chronic liver diseases such as cirrhosis, bile acids may deposit in the skin, causing pruritus (itching). Hence, bile acid sequenstrants may be used for the prevention of pruritus in patients with chronic liver disease.
• diarrhea may be caused by excess bile salts entering the colon rather than being absorbed at the end of the small intestine, typically shortly after eating.
• Bile salt diarrhea is a possible side-effect of gallbladder removal. Bile acid sequestrants may reduce diarrhea in these patients.
• Bile acid sequetrants may also be used to treat hyperthyroidism as an adjunct therapy. By inhibiting the enterohepatic circulation, more L-thyroxine will be lost through defecation and thus lowers body thyroxine levels.
• Since bile acid sequestrants are designed to stay in the gut, they generally do not have systemic side effects. However, they may cause problems in the gastrointestinal tract (GI tract), such as constipation, diarrhea, and flatulence. Some patients complain of the bad taste.
• In addition to bile acids, bile acid sequestrants may also bind drugs in the GI tract, preventing their absorption into the bloodstream. For this reason, it is generally advised that bile acid sequestrants be spaced several hours apart from other drugs.
• They may also bind fat-soluble vitamins, such as vitamin A, vitamin D, vitamin E, and vitamin K. This effect may result in a vitamin deficiency. Hence, vitamin supplementation may be warranted.

8 more annotations...

• Bile acid metabolism in ascorbic acid-deficient guinea pigs

  WS Harris, BA Kottke and MT Subbiah
  

  Sterol balance techniques have been used to determine the effect of short-term ascorbic acid (AA) deprivation on bile acid excretion in the guinea pig. The effects of a brief (2-week) AA deficiency on bile acid pool sizes and the activity of the rate controlling enzyme in bile acid biosynthesis have been determined. It was found that, while food intake and body weight were not affected by the short-term AA deficiency, liver AA levels had fallen to 25% of control levels. At the same time, the rate of excretion of bile acids and the size of the bile acid pool were both reduced by about 50% in guinea pigs deficient in AA. These results were supported by a decrease in the activity of cholesterol 7 alpha-hydroxylase in the deficient animals. It is concluded that an AA deficiency will significantly impair bile acid metabolism independent of any side effects of clinical scurvy.

• Chrysanthemum morifolium – A water extract which activates an enzyme called 7-alpha hydroxylase which takes cholesterol out of the system and converts it to bile acids

• Stop and Smell the Chrysanthemums

   

  Unicity Research and Development discovered that a water extract of chrysanthemum morifolium energizes an enzyme called 7-alpha hydroxylase. 7-alpha hydroxylase takes cholesterol out of your system and converts it to cholic acid-a form of bile acid.

   

  Chrysanthemum morifolium extract is like giving the 7-alpha hydroxylase enzymes an energy drink that makes them work twice as hard. As a result, more cholesterol is taken from your body’s storage and converted into cholic acid-thus reducing the total amount of cholesterol in your body.

   

  Chrysanthemum morifolium extract is The Fourth Mechanism of Bios Life ™.

• Some hypothesize that vitamin C may even have  a hypocholesterolemic effect. This has been suggested because  the enzyme needed for the first step in bile acid synthesis,  cholesterol 7-alpha hydroxylase, is dependent upon the presence  of vitamin C.

• At 10 AM, the time of lowest mRNA expression and gene transcription rate, only four to five hepatocytes, located close to the hepatic venules ("perivenular"), contained the CYP7A mRNA. At 10 PM, the time of highest mRNA expression and fastest in vitro transcription rate, approximately one half of the hepatocytes (still in a "perivenular" location) contained the cholesterol 7 alpha-hydroxylase mRNA.

• We conclude that physiological concentrations of insulin suppress bile acid synthesis by downregulation of cholesterol 7-hydroxylase and sterol 27-hydroxylase gene transcription, and that this effect is mediated through a direct action of the hormone on the hepatocyte.

• Thus, human cholesterol 7 alpha-hydroxylase gene promoter is  strongly repressed by insulin, PMA, and steroid/thyroid hormones and  results in the low level of cholesterol 7 alpha-hydroxylase expression in  the human liver.

• Cholesterol 7 alpha-hydroxylase (P-450 Ch7 alpha) catalyzes the first and  rate-limiting step in the hepatic conversion of cholesterol to bile acids.  P-450 Ch7 alpha activity in rat liver is regulated at three independent  levels: (a) feedback inhibition by bile acids (long term regulation); (b)  midterm regulation through the diurnal cycle; (c) short term modulation by  hormones and dietary factors.

• Bile acid synthesis in humans has a diurnal rhythm, with 2 peaks during the daytime, that is opposite from the circadian rhythm of cholesterol synthesis. This is completely different from the pattern in rodents and indicates the presence of an important species variation in the regulation of cholesterol homeostasis.