scholarly journals 17β-Estradiol-Induced Conformational Changes of Human Microsomal Triglyceride Transfer Protein: A Computational Molecular Modelling Study

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1566
Author(s):  
Yongxiao Yang ◽  
Peng Li ◽  
Pan Wang ◽  
Baoting Zhu
Keyword(s):  
Molecular Dynamics ◽  
Lipid Metabolism ◽  
Conformational Changes ◽  
Liver Lipid ◽  
Microsomal Triglyceride Transfer Protein ◽  
Blood Levels ◽  
Transfer Protein ◽  
17Β Estradiol ◽  
Dynamics Analyses

Human microsomal triglyceride transfer protein (hMTP) plays an essential role in the assembly of apoB-containing lipoproteins, and has become an important drug target for the treatment of several disease states, such as abetalipoproteinemia, fat malabsorption and familial hypercholesterolemia. hMTP is a heterodimer composed of a larger hMTPα subunit and a smaller hMTPβ subunit (namely, protein disulfide isomerase, hPDI). hPDI can interact with 17β-estradiol (E2), an endogenous female sex hormone. It has been reported that E2 can significantly reduce the blood levels of low-density lipoprotein, cholesterol and triglyceride, and modulate liver lipid metabolism in vivo. However, some of the estrogen’s actions on lipid metabolism are not associated with estrogen receptors (ER), and the exact mechanism underlying estrogen’s ER-independent lipid-modulating action is still not clear at present. In this study, the potential influence of E2 on the stability of the hMTP complex is investigated by jointly using multiple molecular dynamics analyses based on available experimental structures. The molecular dynamics analyses indicate that the hMTP complex in the presence of E2 has reduced interface contacts and surface areas. A steered molecular dynamics analysis shows that the forces required to separate the two subunits (namely, hPDI and hMTPα subunit) of the hMTP complex in the absence of E2 are significantly higher than the forces required to separate the complex in which its hPDI is already bound with E2. E2 makes the interface between hMTPα and hPDI subunits more flexible and less stable. The results of this study suggest that E2-induced conformational changes of the hMTP complex might be a novel mechanism partly accounting for the ER-independent lipid-modulating effect of E2.

scholarly journals miR-130b is a potent stimulator of hepatic very-low-density lipoprotein assembly and secretion via marked induction of microsomal triglyceride transfer protein

2020 ◽  
Vol 318 (2) ◽  
pp. E262-E275 ◽  
Author(s):  
Jing Zhang ◽  
Ferdous Rastgar Jazii ◽  
Mahdi Montazer Haghighi ◽  
Danielle Alvares ◽  
Lipei Liu ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Hepg2 Cells ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Microsomal Triglyceride Transfer Protein ◽  
Luciferase Reporter ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Transfer Protein ◽  
Stimulation Of

miR-130b is a microRNA whose expression is particularly elevated within adipose tissue and in the circulation in diabetic states. Hepatic miR-130b expression has been linked to hepatocellular carcinoma and changes in lipid metabolism. Here, we investigated the role of miR-130b in hepatic lipid homeostasis and lipoprotein export. We observed that overexpression of miR-130b-3p or -5p in HepG2 cells markedly enhanced the secretion of very-low-density lipoprotein (VLDL) particles, enhanced the secretion of [3H]glycerol metabolically labeled triglyceride (TG), and significantly increased the number or the average size of lipid droplets (LDs), respectively. Overexpression of miR-130b also altered the expression of key genes involved in lipid metabolism and in particular markedly increased both mRNA and protein expression levels of microsomal triglyceride transfer protein (MTP). Conversely, the miR-130b inhibitor decreased mRNA levels of MTP and fatty acid synthase ( FAS) in HepG2 cells. However, dual-luciferase reporter assays indicated that MTP is not a direct target of miR-130b-3p. miR-130b overexpression did not alter de novo synthesized TG or the stability and secretion of apolipoprotein B 100. Interestingly, knockdown of phosphatase and tensin homolog ( PTEN) blocked the upregulation of MTP mRNA induced by miR-130b. Finally, miR-130b-induced stimulation of VLDL secretion was also observed in a second hepatocyte cell culture model, immortalized human hepatocytes, confirming the effects observed in HepG2 cells. Overall, these data suggest a potential role for miR-130b in promoting hepatic VLDL assembly and secretion mediated by marked stimulation of MTP expression and TG mobilization. Thus miR-130b overexpression corrects the defect in VLDL production in HepG2 cells.

Metformin improves lipid metabolism disorders through reducing the expression of microsomal triglyceride transfer protein in OLETF rats

2016 ◽  
Vol 122 ◽  
pp. 170-178 ◽  
Author(s):  
Nianhong Wang ◽  
Junqing Zhang ◽  
Yiming Wu ◽  
Jia Liu ◽  
Lin Liu ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Microsomal Triglyceride Transfer Protein ◽  
Transfer Protein ◽  
Oletf Rats ◽  
Lipid Metabolism Disorders

scholarly journals Combination Therapy of an Intestine-Specific Inhibitor of Microsomal Triglyceride Transfer Protein and Peroxisome Proliferator-Activated ReceptorγAgonist in Diabetic Rat

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Shohei Sakata ◽  
Yasuko Mera ◽  
Yukiharu Kuroki ◽  
Reiko Nashida ◽  
Makoto Kakutani ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Treatment Group ◽  
Glycemic Control ◽  
Combination Therapy ◽  
Microsomal Triglyceride Transfer Protein ◽  
Combination Group ◽  
Peroxisome Proliferator ◽  
Transfer Protein ◽  
Glucose And Lipid Metabolism ◽  
Zucker Diabetic Fatty Rats

We investigated effects on glucose and lipid metabolism in combination of JTT-130, a novel intestine-specific microsomal triglyceride transfer protein (MTP) inhibitor, and pioglitazone, peroxisome proliferator-activated receptor (PPAR)γagonist. Male Zucker diabetic fatty rats were divided into 4 groups: control group, JTT-130 treatment group, pioglitazone treatment group, and combination group. The Zucker diabetic fatty rats were fed a regular powdered diet with JTT-130 and/or pioglitazone as a food admixture for 6 weeks. Effects on glucose and lipid metabolism were compared mainly between JTT-130 treatment group and combination group. JTT-130 treatment showed good glycemic control, while the plasma glucose and glycated hemoglobin levels in combination group were significantly decreased as compared with those JTT-130 treatment group. The reduction in the plasma triglyceride and free fatty acid levels in combination group was higher than that in JTT-130 treatment group, and glucose utilization was significantly elevated in adipose tissues. In Zucker diabetic fatty rats, combination treatment of JTT-130 and pioglitazone showed better glycemic control and a strong hypolipidemic action with an enhancement of insulin sensitivity. Combination therapy of MTP inhibitor and PPARγagonist might be more useful in the treatment of type 2 diabetes accompanied with obesity and insulin resistance.

scholarly journals HNF1α Controls Liver Lipid Metabolism and Insulin Resistance via Negatively Regulating the SOCS-3-STAT3 Signaling Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Jiaorong Tan ◽  
Jiahong Xu ◽  
Guohua Wei ◽  
Lijuan Zhang ◽  
Long’e Sun ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
Liver Lipid ◽  
Fatty Degeneration ◽  
Glycolipid Metabolism ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

This study is aimed at evaluating the effects, functions, and mechanism of HNF1α on hepatic glycolipid metabolism. In this study, free fatty acid- (FFA-) induced steatosis of hepatocyte liver cell LO2 was used as an in vitro model. The methods of Oil Red O staining, RT-qPCR, western blot, and immunofluorescence staining were used to detect LO2-regulated HNF1α expression and its effects on FFA-induced LO2 cell steatosis, the insulin signaling and SOCS-3-STAT3 signaling pathways, the expression of lipid metabolism-related regulators, and phosphorylation. With increased FFA induction time, the expression of HNF1α in the LO2 fatty degeneration hepatic cells gradually decreased. Downregulation of HNF1α expression aggravated FFA-induced steatosis of LO2 hepatocytes. HNF1α promotes activation of the insulin pathway and oxidative breakdown of fat and inhibits lipid anabolism. Inhibitors of STAT3 can reverse the regulation of decreased HNF1α expression on the insulin signaling pathway and fat metabolism. We also confirmed this pathway using HNF1α-/- mice combining treatment with STAT3 inhibitor NSC 74859 in vivo. HNF1α regulates hepatic lipid metabolism by promoting the expression of SOCS-3 and negatively regulating the STAT3 signaling pathway.

scholarly journals The Vitamin D Receptor Regulates Glycerolipid and Phospholipid Metabolism in Human Hepatocytes

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 493 ◽  
Author(s):  
Teresa Martínez-Sena ◽  
Polina Soluyanova ◽  
Carla Guzmán ◽  
José Manuel Valdivielso ◽  
José Vicente Castell ◽  
...  
Keyword(s):  
Vitamin D ◽  
Lipid Metabolism ◽  
Vitamin D Receptor ◽  
Lithocholic Acid ◽  
Liver Lipid ◽  
Ultra Performance Liquid Chromatography ◽  
Phospholipid Metabolism ◽  
Human Hepatocytes ◽  
Liquid Chromatography Tandem Mass

The vitamin D receptor (VDR) must be relevant to liver lipid metabolism because VDR deficient mice are protected from hepatosteatosis. Therefore, our objective was to define the role of VDR on the overall lipid metabolism in human hepatocytes. We developed an adenoviral vector for human VDR and performed transcriptomic and metabolomic analyses of cultured human hepatocytes upon VDR activation by vitamin D (VitD). Twenty percent of the VDR responsive genes were related to lipid metabolism, including MOGAT1, LPGAT1, AGPAT2, and DGAT1 (glycerolipid metabolism); CDS1, PCTP, and MAT1A (phospholipid metabolism); and FATP2, SLC6A12, and AQP3 (uptake of fatty acids, betaine, and glycerol, respectively). They were rapidly induced (4–6 h) upon VDR activation by 10 nM VitD or 100 µM lithocholic acid (LCA). Most of these genes were also upregulated by VDR/VitD in mouse livers in vivo. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) metabolomics demonstrated intracellular accumulation of triglycerides, with concomitant decreases in diglycerides and phosphatidates, at 8 and 24 h upon VDR activation. Significant alterations in phosphatidylcholines, increases in lyso-phosphatidylcholines and decreases in phosphatidylethanolamines and phosphatidylethanolamine plasmalogens were also observed. In conclusion, active VitD/VDR signaling in hepatocytes triggers an unanticipated coordinated gene response leading to triglyceride synthesis and to important perturbations in glycerolipids and phospholipids.

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