Loading...
Journal Title
Keywords
Readers/Advisors
Jiang, Xian-Cheng
Journal Title
Term and Year
Fall 2016
Publication Date
2016-12-12
Book Title
Publication Volume
Publication Issue
Publication Begin
Publication End
Number of pages
Files
Loading...
KabirInamul.pdf
Adobe PDF, 7.76 MB
Research Projects
Organizational Units
Journal Issue
Abstract
Cellular plasma membrane is composed of phospholipid bilayer. Our understanding about the plasma membrane has been reshaped during the last two decades. According to the recent model, lipids and proteins are heterogeneously distributed in the plasma membrane forming the membrane microdomains. Microdomains serve as the cellular signaling platform in the plasma membrane. Phosphatidylcholine (PC) and sphingomyelin (SM) are the two major lipids in the microdomains of cellular plasma membrane. Phosphatidylcholine and sphingomyelin compositions within the microdomains determine the bio-physical properties of the plasma membrane. Here, we have evaluated the effect of Lysophosphatidylcholine acyltransferase (LPCAT), which is involved in phosphatidylcholine (PC) remodeling, and serine palmitoyltransferase (SPT), which is the key enzyme in sphingolipid biosynthesis, in the intestinal plasma membrane.
Lysophosphatidylcholine acyltransferase 3 (Lpcat3) is involved in phosphatidylcholine (PC) remodeling in the small intestine and liver. We investigated lipid metabolism in inducible intestine-specific and liver-specific Lpcat3 gene knockout mice. We produced Lpcat3-Flox/villinCre-ERT2 mice, which were treated with tamoxifen (at day 1, 3, 5, and 7) to delete Lpcat3 specifically in the intestine. At day 9 after the treatment, we found that Lpcat3 deficiency in enterocytes significantly reduced polyunsaturated PCs in the enterocyte plasma membrane and reduced Niemann-Pick C1-like 1 (NPC1L1), CD36, ATP-binding cassette transporter 1 (ABCA1), and ABCG8 levels on the membrane, thus significantly reduced lipid absorption, cholesterol secretion through apoB-dependent and apoB-independent pathways, and plasma triglyceride, cholesterol, and phospholipid levels, as well as body weight. Moreover, Lpcat3 deficiency does not cause significant lipid accumulation in the small intestine. We also utilized adeno-associated virus (AAV)-Cre to deplete Lpcat3 in the liver. We found that the liver deficiency only reduces plasma triglyceride but not other lipid levels. Furthermore, there is no significant lipid accumulation in the liver. Importantly, small intestine Lpcat3 deficiency has much bigger effect on plasma lipid levels than that of the liver deficiency. Thus, inhibition of small intestine Lpcat3 might constitute a novel approach for treating hyperlipidemia.
Serine palmitoyltransferase (SPT) is the first and rate-limiting enzyme of the de novo biosynthetic pathway of sphingolipids. It has been demonstrated that bioactive sphingolipids are implicated in proliferation, differentiation, cellular growth and apoptosis. Here, we have investigated the role of SPT subunit 2 (Sptlc2) on intestinal functions, again using intestinespecific gene knock out approach. We have generated Sptlc2-Flox/villin-Cre-ERT2 mice which were treated with tamoxifen (at day 1, 3, and 5) to ablate Sptlc2 specifically in the intestine. At day 6 after the tamoxifen treatment, we found that Sptlc2 deficiency in intestine significantly decreased the body weight. The number of Paneth and goblet cells were greatly reduced in both small intestine and colon of Sptlc2 deficient mice compared to the controls. We found that Sptlc2 deficiency significantly reduced sphingolipid levels in the plasma membrane of the small intestine and colon. The Sptlc2 ablation dramatically suppressed mucin 2 (Muc2) expression in the colon and significantly increased plasma lipopolysaccharides (LPS) levels. All intestinal Sptlc2 deficient mice died at 7-10 days interval after tamoxifen treatment; however, multiple low absorbable antibiotics and dexamethasone supplementation rescued around 70% of the lethality. This study has evaluated the relationship between intestinal sphingolipids and the maintenance of the intestinal barrier functions. The Sptlc2 deficient mice could be used as a model for human inflammatory bowel diseases. This study will shed light on the development of new modality for the therapeutic interventions for intestinal inflammatory diseases.
Citation
Khabir, I. (2016). Impact of Cellular Lipid Composition Changes on Intestine Functions. [Doctoral dissertation, SUNY Downstate Health Sciences University]. SUNY Open Access Repository. https://soar.suny.edu/handle/20.500.12648/15964
DOI
Description
Doctoral Dissertation