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The functional relationship between peroxisomes, bile salts and lipid rafts in the liver

Rembacz, K., 2013, [S.n.]. 128 p.

Research output: ThesisThesis fully internal (DIV)Academic

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The liver is a central organ in regulating body homeostasis. It controls body temperature, protein, glucose and fat metabolism as well as the removal of toxic (waste) products. It plays an integrative function in the whole organism by
cooperation with the circular and digestive system. This feature of the liver allows for the effective exchange of nutrients between every cell in the body coupled to the neutralization and elimination of metabolic waste products.
A main function of the liver is the production of bile, which is a mixture of water, phospholipids, cholesterol and bile salts. Bile salts are synthesized from cholesterol in the parenchymal cells of the liver, the hepatocytes. Together with phospholipids, bile acids form mixed micelles that are the fat-solubilizing particles that keep dietary fats in solution for absorption in the intestine. At the same time they are
crucial for excretion of cholesterol and toxic waste products via the feces.
Peroxisomes are single membrane-bound organelles present in cells of all eukaryotes. In mammals, they are particularly abundant in the liver. They are responsible for a great variety of metabolic processes, including breakdown of very-long chain acids, D-amino acids, and polyamines and the biosynthesis of plasmalogens and bile salts. Peroxisomes are essential organelles containing a wide range of enzymes located inside this organelle to perform the diverse metabolic
activities. In addition, specific substrate transporters are located in the peroxisomal membrane to fuel the metabolic processes and remove their products (ATP, fatty acids and bile salts).
Bile salts biosynthesis involves at least 13 different enzymes located to various organelles in liver hepatocytes. The bile salt biosynthesis pathway consists of two main routes and starts either in the ER (the “classical pathway” involving CYP7A1) or in the mitochondria (the so-called “acidic pathway” involving CYP27A1). Both routes yield CoA-activated C-27 bile acid biosynthesis intermediates and converge in peroxisomes where the primary C-24 bile salts cholic acid (CA) and chenodeoxycholic acid (CDCA) are formed. The final step of bile salt synthesis is the conjugation of CA and CDCA to either taurine or glycine. The sole enzyme responsible for bile acid conjugation in humans is bile acid-amino acid Nacytransferase (BAAT), which resides (most probably exclusively) in liver peroxisomes. After export from peroxisomes, bile salts are then transported by the Bile Salt Export Pump (BSEP) from the hepatocytes to the bile. This way, bile salts enter the enterohepatic circulation, where over 95% will be reabsorbed in the intestine, specifically at the terminal ileum, and return back to the liver via the portal vein for recycling. Bile salts returning from the intestine are imported into hepatocytes via the sodium-taurocholate cotransporting polypeptide (NTCP). The amount of bile salts that is lost via the feces is compensated for by de novo bile salt synthesis in the liver.
Original languageEnglish
Supervisors/Advisors
Award date11-Feb-2013
Publisher
Print ISBNs9789036760454
Electronic ISBNs9789036760485
Publication statusPublished - 2013

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