The importance of membrane microdomains for bile salt-dependent biliary lipid secretion

J Cell Sci. 2018 Mar 1;131(5):jcs211524. doi: 10.1242/jcs.211524.

Abstract

Alternative models explaining the biliary lipid secretion at the canalicular membrane of hepatocytes exist: successive lipid extraction by preformed bile salt micelles, or budding of membrane fragments with formation of mixed micelles. To test the feasibility of the latter mechanism, we developed a mathematical model that describes the formation of lipid microdomains in the canalicular membrane. Bile salt monomers intercalate into the external hemileaflet of the canalicular membrane, to form a rim to liquid disordered domain patches that then pinch off to form nanometer-scale mixed micelles. Model simulations perfectly recapitulate the measured dependence of bile salt-dependent biliary lipid extraction rates upon modulation of the membrane cholesterol (lack or overexpression of the cholesterol transporter Abcg5-Abcg8) and phosphatidylcholine (lack of Mdr2, also known as Abcb4) content. The model reveals a strong dependence of the biliary secretion rate on the protein density of the membrane. Taken together, the proposed model is consistent with crucial experimental findings in the field and provides a consistent explanation of the central molecular processes involved in bile formation.

Keywords: Bile formation; Bile salts; Mathematical modeling; Membrane lipid; Microdomain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 5 / genetics
  • ATP Binding Cassette Transporter, Subfamily G, Member 8 / genetics
  • Animals
  • Bile Acids and Salts / metabolism*
  • Bile Canaliculi / growth & development
  • Bile Canaliculi / metabolism
  • Biliary Tract / growth & development
  • Biliary Tract / metabolism*
  • Cholesterol / metabolism
  • Hepatocytes / metabolism
  • Lipids / biosynthesis
  • Lipids / genetics*
  • Membrane Lipids / genetics
  • Membrane Lipids / metabolism
  • Mice
  • Models, Theoretical*
  • Phosphatidylcholines / genetics
  • Phosphatidylcholines / metabolism

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily G, Member 5
  • ATP Binding Cassette Transporter, Subfamily G, Member 8
  • Bile Acids and Salts
  • Lipids
  • Membrane Lipids
  • P-glycoprotein 2
  • Phosphatidylcholines
  • Cholesterol