The role of Microsomal Triglyceride Transfer Protein in the Brain and the Pancreas.

Abstract

Microsomal triglyceride transfer protein(MTP) is an essential chaperone forthe biosynthesis of apolipoprotein-B (apoB) containing lipoproteins mainly inthe liver and intestine. The percentage of lipids in the brain is the highestamong organs and yet very little is known about lipid metabolism within thecentral nervous system (CNS). MTP is expressed in the brain but its function isunknown. Total (whole body) loss of functional MTP leads toabetalipo proteinmeia (ABL), which is characterized by the absence ofapoB-containing lipoproteins. ABL patients suffer from neurological problemswhich are poorly studied. We hypothesized that brain MTPis involved insystemic metabolism and in energy production. To test this hypothesis first weshow that MTP expression is the highest in the cortex and both major brain celltypes, neurons and glial cells express MTP. Further, to study the role of brainMTP we acutely inhibited brain MTP by intracerebroventricular(ICV)microinjections of Lomitapide (an MTP inhibitor "MTPi") to thelateral ventricles. Brain MTP was inhibited after the injection of high dosesof MTPi. Further, we generated brain MTP specific knockout (KO) mice (B-Mttp-/-)bycrossing Mttpf/f mice with Nestin-Cretransgenic mice that expresses Crein both neurons and glial cells. B-Mttp-/-mice have significantlyreduced mRNA levels of all the MTP isoforms in the brain but not in the othertissues confirming the specific gene ablation in the brain. These mice alsohave low MTP activity in the brain compared to control mice. We challengedthese mice with obesity inducing high fat diet and found that B-Mttp-/-mice were resistant to weight gain compared to control mice. Individualindirect calorimetric analyses showed that KO mice had higher respiratoryexchange ratio and were more active than control mice. We also observed thatthe KO mice had less fat compared to control mice. These findings were thefirst in assessing brain MTP function. In short these studies show that brainMTP may play a role in energy metabolism in diet induced obesity.

Pancreas is composed of exocrine andendocrine glands are involved in thesystemic metabolism. MTP is expressed in many organs in the body but no one hasinvestigated the expression of MTP in the pancreas. We hypothesized thatpancreas expresses MTP and pancreatic MTP has a role in the systemicmetabolism. To test this hypothesis first we show that MTP activity and mRNA ismeasurable in the pancreas. Also MTP-A mRNA isoform is the predominant in thepancreas. In situ hybridization showed that MTP is expressed in the pancreaticexocrine acinar cells. Further, two different pancreatic acinar cells celllines MIA PaCa-2 and PANC-1 had measurable MTP activity. Pancreatic acinarcells are involved in metabolism by secreting the digestive enzymes to thesmall intestine to breakdown the food to nutrients. To assess the role ofpancreatic MTP we have generated pancreas specific MTP KO mice (P-Mttp -/-)by crossing Cela-CreERtransgenic mice that expresses Cre in the acinar cellsafter inducing the mice with tamoxifen with Mttpf/f mice. TheCela-CreERtransgenic mice are not C57Bl/6J background so we backcrossed theline withC57Bl/6J for 10 generations. More studies should be done on these miceby challenging them with obesity inducing diet and focus on the systemicmetabolism. These studies may provide for the first time the role of pancreaticMTP in the systemic metabolism.