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      Very low-density lipoprotein receptor increases in a liver-specific manner due to protein deficiency but does not affect fatty liver in mice

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          Abstract

          Very low-density lipoprotein receptor (VLDLR) is a member of the LDL receptor family that is involved in the uptake of VLDL into cells. Increased hepatic VLDLR under endoplasmic reticulum (ER) stress has been shown to cause fatty liver. In this study, the effect of dietary protein restriction on hepatic VLDLR and the role of VLDLR in fatty liver were investigated using Vldlr knockout (KO) mice. Growing wild-type (WT) and KO mice were fed a control diet containing 20% ​​protein or a low protein diet containing 3% protein for 11 days. In WT mice, the amount of hepatic Vldlr mRNA and VLDLR protein increased by approximately 8- and 7-fold, respectively, due to protein restriction. Vldlr mRNA and protein levels increased in both type 1 and type 2 VLDLR. However, neither Vldlr mRNA nor protein levels were significantly increased in heart, muscle, and adipose tissue, demonstrating that VLDLR increase due to protein restriction occurred in a liver-specific manner. Increased liver triglyceride levels during protein restriction occurred in KO mice to the same extent as in WT mice, indicating that increased VLDLR during protein restriction was not the main cause of fatty liver, which was different from the case of ER stress.

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          A RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATION

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            Low-Density Lipoprotein Receptor (LDLR) Family Orchestrates Cholesterol Homeostasis

            The LDLR family of proteins is involved in lipoproteins trafficking. While the role of LDLR in cardiovascular disease has been widely studied, only recently the role of other members of the LDLR proteins in lipoprotein homeostasis and atherosclerosis has emerged. LDLR, VLDLR, and LRPs bind and internalize apoE- and apoB-containing lipoprotein, including LDL and VLDL, and regulate their cellular uptake. LRP6 is a unique member of this family for its function as a co-receptor for Wnt signal transduction. The work in our laboratory has shown that LRP6 also plays a key role in lipoprotein and TG clearance, glucose homoeostasis, and atherosclerosis. The role of these receptor proteins in pathogenesis of diverse metabolic risk factors is emerging, rendering them targets of novel therapeutics for metabolic syndrome and atherosclerosis. This manuscript reviews the physiological role of the LDLR family of proteins and describes its involvement in pathogenesis of hyperlipidemia and atherosclerosis.
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              ATF4-dependent transcription mediates signaling of amino acid limitation.

              Mammals respond to dietary nutrient fluctuations; for example, deficiency of dietary protein or an imbalance of essential amino acids activates an amino acid response (AAR) signal transduction pathway, consisting of detection of uncharged tRNA by the GCN2 kinase, eIF2alpha phosphorylation and ATF4 expression. In concert with heterodimerization partners, ATF4 activates specific genes via a CCAAT-enhancer binding protein-activating transcription factor response element (CARE). This review outlines the ATF4-dependent transcriptional mechanisms associated with the AAR, focusing on progress during the past 5 years. Recent evidence suggests that maternal nutrient deprivation not only has immediate metabolic effects on the fetus, but also triggers gene expression changes in adulthood, possibly through epigenetic mechanisms. Therefore, understanding the transcriptional programs initiated by amino acid limitation is crucial and timely.
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                Author and article information

                Contributors
                takenaka@meiji.ac.jp
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                13 April 2021
                13 April 2021
                2021
                : 11
                : 8003
                Affiliations
                [1 ]GRID grid.411764.1, ISNI 0000 0001 2106 7990, Department of Agricultural Chemistry, School of Agriculture, , Meiji University, ; Kawasaki, Kanagawa 214-8571 Japan
                [2 ]GRID grid.260969.2, ISNI 0000 0001 2149 8846, Department of Chemistry and Life Science, College of Bioresource Sciences, , Nihon University, ; Kameino, Fujisawa, Kanagawa Japan
                Article
                87568
                10.1038/s41598-021-87568-2
                8044231
                33850206
                cd2ebf26-75a1-4028-a426-f5db99e91106
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 1 December 2020
                : 15 March 2021
                Funding
                Funded by: Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research (B)
                Award ID: 19H02916
                Award Recipient :
                Funded by: Advanced Research Networks from JSPS and R&D matching funds in the field for Knowledge, Integration, and Innovation from the Bio-oriented Technology Research Advancement Institution, NARO
                Categories
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                © The Author(s) 2021

                Uncategorized
                biochemistry,physiology
                Uncategorized
                biochemistry, physiology

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