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Di Li, Weiqing Long, Rong Huang, Ying Chen, Min Xia
OBJECTIVE: Although 27-hydroxycholesterol (27-HC) has been reported as a potent regulator of lipid homeostasis, its role in hepatic lipogenesis remains obscure. The present study was designed to investigate the impact of 27-HC on sterol regulatory element-binding protein 1 (SREBP-1) and hepatic steatosis. METHODS: In this study, the 27-HC level in mice was upregulated by overexpressing CYP27A1 or treating primary hepatocytes with 27-HC, and then the hepatic lipid accumulation was detected...
February 24, 2018: Obesity
Lu-Yi Jiang, Wei Jiang, Na Tian, Yan-Ni Xiong, Jie Liu, Jian Wei, Kai-Yue Wu, Jie Luo, Xiong-Jie Shi, Bao-Liang Song
Cholesterol biosynthesis is tightly regulated in the cell. For example, high sterol concentrations can stimulate the degradation of the rate-limiting cholesterol biosynthesis enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase, HMGCR). HMGCR is broken down by endoplasmic reticulum (ER) membrane-associated protein complexes consisting of insulin-induced genes (Insigs) and the E3 ubiquitin ligase gp78. Here, we found that HMGCR degradation is partially blunted in Chinese hamster ovary (CHO) cells lacking gp78 (gp78-KO)...
January 26, 2018: Journal of Biological Chemistry
Jinyan Li, Guanhua Qian, Xiaocui Zhong, Tinghe Yu
Gestational diabetes mellitus (GDM) has a higher incidence of neonatal respiratory distress syndrome, and lipogenesis is required for the synthesis of pulmonary surfactants. The aim of this study was to determine the effect of insulin treatment in GDM on the production of lipids in the lungs of fetal rats. GDM was induced by streptozotocin, and insulin was used to manage diabetes. Type II alveolar epithelial cells (AEC II), bronchoalveolar lavage fluid (BALF), and lung tissues of the neonatal rats were sampled for analyses...
January 22, 2018: DNA and Cell Biology
Rituraj Khound, Jing Shen, Yongyan Song, Dipak Santra, Qiaozhu Su
SCOPE: This study aims to characterize the effect of fenugreek (Trigonella foenum-graecum) seed and its phytoceutical trigonelline in antimetabolic inflammation and ameliorating overproduction of very low density lipoprotein (VLDL) in insulin resistance. METHODS AND RESULTS: Two groups of genetic hyperlipidemic mice generated by depletion of cAMP responsive element binding protein H (CREBH) are fed either a chow containing 2% fenugreek seed or vehicle for 7 weeks...
March 2018: Molecular Nutrition & Food Research
Juliana Mikaelly Dias Soares, Ana Ediléia Barbosa Pereira Leal, Juliane Cabral Silva, Jackson R G S Almeida, Helinando Pequeno de Oliveira
Background: The development of alternatives for insulin secretion control in vivo or in vitro represents an important aspect to be investigated. In this direction, natural products have been progressively explored with this aim. In particular, flavonoids are potential candidates to act as insulin secretagogue. Objective: To study the influence of flavonoid on overall modulation mechanisms of insulin secretion. Methods: The research was conducted in the following databases and platforms: PubMed, Scopus, ISI Web of Knowledge, SciELO, LILACS, and ScienceDirect, and the MeSH terms used for the search were flavonoids, flavones, islets of Langerhans, and insulin-secreting cells...
October 2017: Pharmacognosy Magazine
Brittany M Johnson, Russell A DeBose-Boyd
Accelerated ubiquitination and subsequent endoplasmic reticulum (ER)-associated degradation (ERAD) constitute one of several mechanisms for feedback control of HMG CoA reductase, the rate-limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids. This ERAD is initiated by the accumulation of certain sterols in ER membranes, which trigger binding of reductase to ER membrane proteins called Insigs. Insig-associated ubiquitin ligases facilitate ubiquitination of reductase, marking the enzyme for extraction across the ER membrane through a reaction that is augmented by nonsterol isoprenoids...
October 28, 2017: Seminars in Cell & Developmental Biology
Chien-Chih Chen, Li-Wen Hsu, Kuang-Tzu Huang, Shigeru Goto, Chao-Long Chen, Toshiaki Nakano
Atypical antipsychotics (AAPs) are considered to possess superior efficacy for treating both the positive and negative symptoms of schizophrenia; however, AAP use often causes excessive weight gain and metabolic abnormalities. Recently, several reports have demonstrated that AAPs activate sterol regulatory element-binding protein (SREBP). SREBP, SREBP cleavage-activating protein (SCAP) and insulin-induced gene (Insig) regulate downstream cholesterol and fatty acid biosynthesis. In this study, we explored the effects of clozapine, olanzapine and risperidone on SREBP signaling and downstream lipid biosynthesis genes in the early events of adipogenic differentiation in adipose-derived stem cells (ASCs)...
September 7, 2017: Scientific Reports
Jae-Ho Lee, Hye Suk Kang, Hyeon Young Park, Young-Ah Moon, Yu Na Kang, Byung-Chul Oh, Dae-Kyu Song, Jae-Hoon Bae, Seung-Soon Im
Peroxisome-proliferator-activated receptor alpha (PPARα) and sterol regulatory element-binding protein (SREBP) play a role in regulating cellular fatty acid and cholesterol homeostasis via fatty acid oxidation and lipogenesis. The control of SREBP processing is regulated by the insulin induced gene (INSIG)2a protein, which binds SREBP to prevent SREBP translocation to the Golgi apparatus during nutrient starvation in the liver. However, the regulation of SREBP-1c processing by INSIGs during fasting and the regulatory mechanisms of the mouse Insig2a gene expression have not been clearly addressed...
August 30, 2017: Scientific Reports
Luke J Engelking, Mary Jo Cantoria, Yanchao Xu, Guosheng Liang
Sterol regulatory element-binding proteins (SREBPs), master transcriptional regulators of cholesterol and fatty acid synthesis, have been found to contribute to a diverse array of cellular processes. In this review, we focus on genetically engineered mice in which the activities of six components of the SREBP gene pathway, namely SREBP-1, SREBP-2, Scap, Insig-1, Insig-2, or Site-1 protease have been altered through gene knockout or transgenic approaches. In addition to the expected impacts on lipid metabolism, manipulation of these genes in mice is found to affect a wide array of developmental and physiologic processes ranging from interferon signaling in macrophages to synaptic transmission in the brain...
July 20, 2017: Seminars in Cell & Developmental Biology
Hui Cheng, Na Xu, Wenxia Zhao, Jingjing Su, Mengru Liang, Zhongwen Xie, Xianli Wu, Qinglin Li
SCOPE: (-)-Epicatechin (EC) is a natural flavanol monomer found in cocoa, green tea, and a variety of other plant foods. In this study, effects of EC on blood lipids and hepatic steatosis, and the underlying mechanisms were investigated. METHODS AND RESULTS: A hyperlipidemic rat model was induced by high-fat, high-cholesterol diet. EC was then administrated to the animals by gavage at doses of 10, 20, 40 mg/kg body weight (BW) for 12 weeks. Simvastatin was included as a positive control...
July 21, 2017: Molecular Nutrition & Food Research
Yong-Jian Wang, Yan Bian, Jie Luo, Ming Lu, Ying Xiong, Shu-Yuan Guo, Hui-Yong Yin, Xu Lin, Qin Li, Catherine C Y Chang, Ta-Yuan Chang, Bo-Liang Li, Bao-Liang Song
Ubiquitin linkage to cysteine is an unconventional modification targeting protein for degradation. However, the physiological regulation of cysteine ubiquitylation is still mysterious. Here we found that ACAT2, a cellular enzyme converting cholesterol and fatty acid to cholesteryl esters, was ubiquitylated on Cys277 for degradation when the lipid level was low. gp78-Insigs catalysed Lys48-linked polyubiquitylation on this Cys277. A high concentration of cholesterol and fatty acid, however, induced cellular reactive oxygen species (ROS) that oxidized Cys277, resulting in ACAT2 stabilization and subsequently elevated cholesteryl esters...
July 2017: Nature Cell Biology
Hoang Thi Minh Hien, Nguyen Cam Ha, Le Thi Thom, Dang Diem Hong
OBJECTIVE: To examine the effect of squalene on liver X receptors (LXRs) that regulate target genes associated with reverse cholesterol transport and thus control whole-body cholesterol homeostasis. RESULTS: To examine the effect of squalene on liver X receptors (LXRs) that regulate target genes associated with reverse cholesterol transport and thus control whole-body cholesterol homeostasis. Squalene significantly stimulated the transactivation of liver X receptor modulator LXRα and LXRβ...
May 10, 2017: Biotechnology Letters
Ying Zhang, Pan Ren, Qunfu Kang, Weihong Liu, Sinai Li, Ping Li, Hongxu Liu, Juju Shang, Lei Zhang, Yanbing Gong, Mingxue Zhou
Lipid metabolism dysregulation plays a crucial role in the occurrence of atherosclerosis (As). SCAP/SREBP signaling is the main pathway for regulating lipid metabolism. Tetramethylpyrazine (TMP), a Traditional Chinese Medicine (TCM) for treating angina pectoris, has antiatherosclerotic effects and ameliorates blood lipids disturbance. However, its precise mechanism remains unclear. This study investigated the mechanism of TMP in ameliorating As in mice model. After six weeks of high-fat diet, 30 ApoE(-/-) mice were randomized (n = 10) and treated with Lipitor, TMP, or distilled water for six weeks...
2017: Evidence-based Complementary and Alternative Medicine: ECAM
Seonghwan Hwang, Andrew D Nguyen, Youngah Jo, Luke J Engelking, James Brugarolas, Russell A DeBose-Boyd
Cholesterol synthesis is a highly oxygen-consuming process. As such, oxygen deprivation (hypoxia) limits cholesterol synthesis through incompletely understood mechanisms mediated by the oxygen-sensitive transcription factor hypoxia-inducible factor 1α (HIF-1α). We show here that HIF-1α links pathways for oxygen sensing and feedback control of cholesterol synthesis in human fibroblasts by directly activating transcription of the INSIG-2 gene. Insig-2 is one of two endoplasmic reticulum membrane proteins that inhibit cholesterol synthesis by mediating sterol-induced ubiquitination and subsequent endoplasmic reticulum-associated degradation of the rate-limiting enzyme in the pathway, HMG-CoA reductase (HMGCR)...
June 2, 2017: Journal of Biological Chemistry
Neetu Sud, Hanyuan Zhang, Kaichao Pan, Xiao Cheng, Juan Cui, Qiaozhu Su
Fructose is a highly lipogenic sugar that can alter energy metabolism and trigger metabolic disorders. In the current study, microRNAs (miRNAs) altered by a high-fructose diet were comprehensively explored to elucidate their significance in the pathogenesis of chronic metabolic disorders. miRNA expression profiling using small noncoding RNA sequencing revealed that 19 miRNAs were significantly upregulated and 26 were downregulated in the livers of high-fructose-fed mice compared to chow-fed mice. Computational prediction and functional analysis identified 10 miRNAs, miR-19b-3p, miR-101a-3p, miR-30a-5p, miR-223-3p, miR-378a-3p, miR-33-5p, miR-145a-3p, miR-128-3p, miR-125b-5p and miR-582-3p, assembled as a regulatory network to potentially target key genes in lipid and lipoprotein metabolism and insulin signaling at multiple levels...
May 2017: Journal of Nutritional Biochemistry
Lisa Asano, Mizuki Watanabe, Yuta Ryoden, Kousuke Usuda, Takuya Yamaguchi, Bilon Khambu, Megumi Takashima, Shin-Ichi Sato, Juro Sakai, Kazuo Nagasawa, Motonari Uesugi
Sterol regulatory element-binding proteins (SREBPs) are transcription factors that control lipid homeostasis. SREBP activation is regulated by a negative feedback loop in which sterols bind to SREBP cleavage-activating protein (SCAP), an escort protein essential for SREBP activation, or to insulin-induced genes (Insigs) (endoplasmic reticulum [ER] anchor proteins), sequestering the SREBP-SCAP-Insig complex in the ER. We screened a chemical library of endogenous molecules and identified 25-hydroxyvitamin D (25OHD) as an inhibitor of SREBP activation...
February 16, 2017: Cell Chemical Biology
T Komprda, V Rozíková, N Zamazalová, O Škultéty, M Vícenová, M Trčková, M Faldyna
The objective of the present study was to compare hepatic fatty acid deposition, plasma lipid level and expression of cholesterol homeostasis controlling genes in the liver of rats (Wistar Albino; n = 32) and pigs (Large White × Landrace; n = 32) randomly assigned into two groups of 16 animals each and fed 10 weeks the diet with either 2.5% of fish oil (F; source of eicosapentaenoic and docosahexaenoic acid, EPA+DHA) or 2.5% of palm oil (P; high content of saturated fatty acids; control). F-rats deposited in the liver three times less EPA, but 1...
October 16, 2016: Journal of Animal Physiology and Animal Nutrition
Jamie N Connarn, Ruijuan Luo, Jim Windak, Xinyuan Zhang, Andrew Babiskin, Marisa Kelly, Gloria Harrington, Vicki L Ellingrod, Masoud Kamali, Melvin McInnis, Duxin Sun
Bupropion and its three active metabolites exhibit clinical efficacy in the treatment of major depression, seasonal depression and smoking cessation. The pharmacokinetics of bupropion in humans is highly variable. It is not known if there are any non-reported metabolites formed in humans in addition to the three known active metabolites. This paper reports newly identified and non-reported metabolites of bupropion in human plasma samples. Human subjects were dosed with a single oral dose of 75 mg of an immediate release bupropion HCl tablet...
December 2016: Biopharmaceutics & Drug Disposition
Tingxian Deng, Chunying Pang, Xiaoya Ma, Xingrong Lu, Anqin Duan, Peng Zhu, Xianwei Liang
Insulin-induced genes (INSIGs), including INSIG1 and INSIG2, are important mediators that play a pivotal role in the lipid metabolism and could cause the retention of the SCAP/SREBP complex. Therefore, the objective of this study is to detect the single nucleotide polymorphisms (SNPs) of buffalo INSIG2 gene and evaluate their associations with milk production traits in Chinese buffaloes. A total of four SNPs (g.621272A > G, g.621364A > C, g.632543G > A, and g.632684C > T) were identified using DNA pooled sequencing, and the SNP genotyping for the identified SNPs was performed by using Matrix-assisted laser desorption/ionization time of flight mass spectrometry method from 264 individuals...
October 2016: Molecular and Cellular Probes
Mohammed Kaplan, Cecilia Pinto, Klaartje Houben, Marc Baldus
Increasing evidence suggests that most proteins occur and function in complexes rather than as isolated entities when embedded in cellular membranes. Nuclear magnetic resonance (NMR) provides increasing possibilities to study structure, dynamics and assembly of such systems. In our review, we discuss recent methodological progress to study membrane-protein complexes (MPCs) by NMR, starting with expression, isotope-labeling and reconstitution protocols. We review approaches to deal with spectral complexity and limited spectral spectroscopic sensitivity that are usually encountered in NMR-based studies of MPCs...
January 2016: Quarterly Reviews of Biophysics
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