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Oleic acid through the unfolded protein response regulate intestinal epithelial cells cholesterol transport related proteins

Author: ChenJiangYuan
Tutor: QuShen
School: Huazhong University of Science and Technology
Course: Biochemistry and Molecular Biology
Keywords: Small intestine Cholesterol Oleic acid UPR SREBP-2 NPC1L1 MTP HMGCR
CLC: Q504
Type: PhD thesis
Year: 2009
Downloads: 165
Quote: 0
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Abstract


Oleic acid is the main component of oil. Studies have shown that, in intestinal epithelial cells, as compared with other fatty acids, oleic acid, is a recognized strong induction of triglyceride-rich lipoprotein synthesis and secretion of fatty acids, which membrane cholesterol by promoting inward reticulum transportation, increases the secretion of cholesterol and its esters, in addition, in the absence of exogenous cholesterol condition, oleic acid can promote the synthesis of cholesterol. Animal experiments show that under the conditions of high cholesterol, high levels of oleic acid can reduce the absorption of cholesterol, epidemiological survey results show that oleic acid with lower plasma LDL cholesterol concentration effect, with a polyunsaturated fatty acid called \However, in intestinal epithelial cells, oleic acid affect cholesterol absorption and transport mechanism is unclear. Hypercholesterolemia is causing atherosclerosis is an important risk factor. In addition to the body's own synthesis of cholesterol, the cholesterol in food is causing hypercholesterolemia important factor in reducing the intestinal absorption of cholesterol in food and bile helps reduce blood cholesterol levels; therefore keeping the body cholesterol homeostasis in the small intestine play an important role. NPC1L1 (Niemann-Pick C1-Like 1), located in the brush border of intestinal epithelial cells in the side that is responsible for a major transporter of cholesterol absorption, NPC1L1 knockout mice were completely resistant to food-induced hypercholesterolemia, namely the use of high cholesterol feeding, it will not suffer from high cholesterol. ABCG5 / 8 heterodimer is located in the brush border of intestinal epithelial cells in the side, through the promotion of the efflux of steroids regulate cholesterol absorption. HMGCR is the rate-limiting enzyme in cholesterol synthesis. Part of the synthesis and absorption of cholesterol in the endoplasmic reticulum by acyl-coenzyme A: cholesterol acyltransferase 2 (Acy1-Coenzyme A CholesterolAcyltransferase, ACAT2) catalyze the formation of cholesterol esters. In the intestine and liver, triglyceride-rich lipoprotein assembly and secretion, MTP (Microsomal triglyceride transfer protein) is indispensable transporter. Sterol regulatory element binding protein -2 (sterol regulatoryelement-binding protein-2, SREBP-2) is a combination of transcription factors, including the endoplasmic reticulum, the activation of proteolytic cleavage, and promote absorption of cholesterol synthesis and gene expression. It has been reported that positively regulate NPC1L1, HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase) expression negatively regulates the expression of MTP. Endoplasmic reticulum protein synthesis, folding, cholesterol and fatty acid synthesis, maintaining calcium homeostasis important place. When the function of endoplasmic reticulum is disturbed, endoplasmic reticulum stress occurs through a series of endoplasmic reticulum stress-activated gene expression, increasing the unfolded protein endoplasmic reticulum processing capacity, to reduce internal pressure caused by endoplasmic reticulum stress. Has been reported in the literature, endoplasmic reticulum stress through the unfolded protein response (unfolded protein response, UPR) signaling pathways that promote or inhibit SREBP-2 maturation, thereby regulating the expression of genes whose regulation. In recent years, studies have shown that endoplasmic reticulum stress through the unfolded protein response (UPR) of different signaling pathways regulating positive or negative regulation of SREBP-2 gene expression. Have been reported in the literature, oleic acid can cause liver endoplasmic reticulum stress in cells, thus affecting the secretion of apoB100. However, the absorption of cholesterol in the intestinal epithelial cells in the process, whether oleic acid can cause endoplasmic reticulum stress, thereby affecting cholesterol transport related proteins, this is not very clear. In this paper, CaCo-2 intestinal epithelial cells as a model, using a variety of lipid micelles incubated cells, oleic acid on intestinal epithelial cells explore cholesterol absorption, transport-related protein expression, as well as oleic acid-induced UPR key on cholesterol transporter protein regulation. With sodium taurocholate (TC 5mM), TC and cholesterol (CHOL 0.2mM), TC and oleic acid (0.25mM, 0.5mM, 1.0 mM) and cholesterol (CHOL 0.2mM), and TC and oleic acid (0.25mM, 0.5mM, 1.0 mM) prepared lipid micelles CaCo-2 cells were incubated 24 hours later, with RT-PCR, NPC1L1, ABCG8, HMGCR, ACAT-2, MTP, shear XBP1, CHOP mRNA level changes, using Western Blotting Detection BIP, ATF6 (Activating transcription factor-6), SREBP2, NPC1L1, ABCG8 protein levels. And using the UPR inhibitor 4 - phenyl-butyric acid (4-phenyl-butyric acid, PBA) inhibition UPR, UPR clarify the regulation of cholesterol transporter associated protein in rats. Experimental results show that: the type of lipid micelles with CaCo-2 cells were incubated in the levels of mRNA and protein expression of ACAT-2 change; SREBP-2 protein expression levels of change; with or without the conditions of cholesterol micelles high concentrations of oleic acid (0.5mM, 1mM) increased shear XBP1 (X-box bindingprotein 1) mRNA quantity increases BIP (immunoglobulin heavy chain-bindingprotein) protein and CHOP (DNA-damage-inducible transcript 3) expression of ATF-6 promotes the maturation induced endoplasmic reticulum stress; cholesterol in a micelle condition, oleic acid in a concentration dependent manner the expression of ABCG8; reduced NPC1L1, HMGCR expression , MTP expression was significantly increased; contrast, in the absence of cholesterol micelles in the presence of oleic acid increased NPC1L1, HMGCR expression. PBA with UPR inhibitor treated cells, PBA inhibited splicing of XBP1 mature and ATF-6, eliminating the oleic acid induced upregulation of CHOP and BIP, inhibits the occurrence of endoplasmic reticulum stress. The cells were treated with PBA, a high concentration of oleic acid suppression through the endoplasmic reticulum stress-induced NPC1L1, HMGCR, MTP expression changes. However, PBA had no effect on the expression of ABCG8. In short, with or without the conditions of exogenous cholesterol, high levels of oleic acid differences in the unfolded protein response by adjusting the intestinal epithelial cells NPC1L1, HMGCR, MTP expression. In a large number of exogenous conditions, cholesterol, high levels of oleic unfolded protein response by inhibiting NPC1L1, HMGCR expression, increases the expression of MTP. In contrast, in the absence of exogenous cholesterol condition, a high concentration of oleic acid increased by the unfolded protein response NPC1L1, HMGCR expression.

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