ABSTRACT
BACKGROUND AND AIMS: Numerous studies have suggested phospholipid inhibition of dietary cholesterol absorption through the gastrointestinal tract. This study addressed the importance of luminal phospholipid hydrolysis in this process. METHODS: The effect of phospholipase inhibition on cholesterol transport from intestinal lumen to the lymphatics was evaluated in lymph fistula rats. Cholesterol and phospholipid absorption efficiency in intact animals was evaluated in control and phospholipase A(2) (PLA2) gene-targeted mice. RESULTS: The PLA2 inhibitor FPL 67047XX retarded cholesterol absorption in a lymph fistula rat model. Under basal chow-fed dietary conditions, cholesterol absorption efficiency from a single bolus meal, and plasma lipid levels, were similar among PLA2+/+, PLA2+/-, and PLA2-/- mice. Interestingly, the nonhydrolyzable phospholipid dioleoyl ether phosphatidylcholine suppressed cholesterol absorption by 10% to 18% in mice without regard to their PLA2 genotype. When 1-palmitoyl-2-[(14)C]oleoyl-phosphatidylcholine was used as the substrate, the radiolabeled phospholipid was found to be hydrolyzed and absorbed with equal efficiency in PLA2+/+, PLA2+/-, and PLA2-/- mice. CONCLUSIONS: These results suggested that although phospholipid digestion in the intestinal lumen is a prerequisite for efficient cholesterol absorption, additional enzyme(s) can compensate for pancreatic PLA2 in catalyzing phospholipid digestion and facilitating cholesterol absorption in PLA2 knockout mice.
Subject(s)
Cholesterol, Dietary/pharmacokinetics , Intestinal Absorption/physiology , Phospholipases A/genetics , Animals , Carbon Radioisotopes , Digestive System Fistula/metabolism , Female , Lymph/metabolism , Male , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Knockout , Phospholipases A/metabolism , Phospholipases A2 , Pregnancy , Rats , Rats, Sprague-Dawley , Triglycerides/pharmacokineticsABSTRACT
Pancreatic phospholipase A(2) (PLA(2)) is involved with the hydrolysis of phospholipids into lysophospholipids and unesterified fatty acids. The enzyme has been postulated to play a key role in lipid absorption by intestinal absorptive cells as well as in the regulation of secretin release from intestinal endocrine cells. This manuscript reports the genomic organization and the primary sequence of the mouse PLA(2). The results showed that the mouse PLA(2) gene contains four exons interspersed by three introns, spans over 8kb in length, and is considerably larger than the human PLA(2) gene. The mouse PLA(2) protein contains 146 amino acid residues, including the signal peptide. The mouse protein is highly homologous to the rat, dog, and human enzyme, but is two residues shorter than the human protein. Mouse PLA(2) message is synthesized predominantly in the pancreas, but the lung also contains low levels of PLA(2) mRNA.
