fig2

Figure 2. Hypothesis for the protective action of generated MCPC to combat hepatocellular injury induced by toxic unconjugated bile acids hitting hepatocytes via cholehepatic shunting. (A) Physiology of PC and bile acid pathways in biliary epithelium and hepatocytes connected via the portal blood flow. 1. PC in portal blood moves into the interstitial space between cholangiocytes for translocation to biliary mucus, binding to mucin 3 followed by transfer to mucin 5B to establish a bilayer shield preventing the luminal invasion of unconjugated toxic bile acids. 2. Absorbed bile acids and the hydrolyzed PC products, L-PC and fatty acids, are presented in portal blood to hepatocytes for carrier-mediated uptake. In hepatocytes, bile acids are exported into bile at the canalicular membrane, as is reconstituted PC, using different ABC transporters - BSEP and MDR3, respectively - to form micelles. In bile, only unconjugated bile acids remain in their monomeric form and are repelled by the PC bilayer shield; (B) Cholestasis due to a TJ defect impairing paracellular PC movement to the biliary mucus, resulting in mucins devoid of PC without bilayer formation. This leaky mucus layer allows unconjugated toxic bile acids to invade, pass through cholangiocytes, and recirculate to hepatocytes, followed by hepatocellular destruction (inflammation with transaminase elevation); (C) A hypothetical treatment option utilizing intrinsic MCPC, generated in hepatocytes after oral application of LCPC and MCT. The hydrolytic breakdown products of both supplements (L-PC, mono/di-glycerides and fatty acids) enter hepatocytes and reconstitute to LCPC and MCPC for excretion in bile. MCPC incorporates from the biliary lumen into empty PC binding sites to reestablish a protective phospholipid bilayer shield, protecting against the invasion of unconjugated toxic bile acids. This image was made with CorelDRAW. MCPC: Medium-chain phosphatidylcholine; PC: phosphatidylcholine; L-PC: lyso-phosphatidylcholine; ABC: ATP binding cassette; BSEP: bile salt export pump; MDR3: multidrug resistance protein 3; TJ: tight junction; LCPC: long-chain phosphatidylcholine; MCT: medium-chain triglyceride.