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Hiroki Otsuka, Hideo Sasai, Mina Nakama, Yuka Aoyama, Elsayed Abdelkreem, Hidenori Ohnishi, Vassiliki Konstantopoulou, Jörn Oliver Sass, Toshiyuki Fukao
Beta-ketothiolase deficiency, also known as mitochondrial acetoacetyl-CoA thiolase (T2) deficiency, is an autosomal recessive disease caused by mutations in the acetyl‑CoA acetyltransferase 1 (ACAT1) gene. A German T2‑deficient patient that developed a severe ketoacidotic episode at the age of 11 months, was revealed to be a compound heterozygote of a previously reported null mutation, c.472A>G (p.N158D) and a novel mutation, c.949G>A (p.D317N), in ACAT1. The c.949G>A mutation was suspected to cause aberrant splicing as it is located within an exonic splicing enhancer sequence (c...
October 10, 2016: Molecular Medicine Reports
Fen Liu, Yi Wang, Jing Xu, Fangqiang Liu, Rongdang Hu, Hui Deng
INTRODUCTION: Cardiovascular diseases are positively correlated with periodontal disease. However, the molecular mechanisms linking atherosclerosis and periodontal infection are not clear. This study aimed to determine whether Porphyromonas gingivalis lipopolysaccharide (Pg-LPS) altered the expression of genes regulating cholesterol metabolism in macrophages in the presence of low-density lipoprotein (LDL). MATERIAL AND METHODS: THP-1-derived macrophages were exposed to different concentrations (0...
October 1, 2016: Archives of Medical Science: AMS
Bo Wang, Ping-Ping He, Gao-Feng Zeng, Tao Zhang, Xin-Ping Ou Yang
Previous studies have shown that miR-467b plays a central role in the progression of atherosclerosis via regulating LPL expression. However, the regulatory mechanism of miR-467b in regulateing the CE and FC formation is still unclear. Interestingly, computational analysis demonstrated that ACAT1 which converts intracellular FC into the storage form of CE, and ABCA1 which promotes cellular FC efflux may be target gene of miR-467b. Here, we examined whether miR-467b could target ACAT1 and ABCA1, thereby affecting the CE and FC formation in oxLDL-treatment RAW 264...
September 24, 2016: Biochimie
Yimin Jia, Mingfa Ling, Luchu Zhang, Shuxia Jiang, Yusheng Sha, Ruqian Zhao
Excess 2-hydroxy-(4-methylthio)butanoic acid (HMB) supplementation induces hyperhomocysteinemia, which contributes to hepatic cholesterol accumulation. However, it is unclear whether and how high levels of HMB break hepatic cholesterol homeostasis in nursery piglets. In this study, HMB oversupplementation suppressed food intake and decreased body weight in nursery piglets. Hyperhomocysteinemia and higher hepatic cholesterol accumulation were observed in HMB groups. Accordingly, HMB significantly increased the protein content of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and glycine N-methyltransferase (GNMT) but decreased that of acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT1)...
October 12, 2016: Journal of Agricultural and Food Chemistry
Wakako Takabe, Yasuomi Urano, Diep-Khanh Ho Vo, Kimiyuki Shibuya, Masaaki Tanno, Hiroaki Kitagishi, Toyoshi Fujimoto, Noriko Noguchi
24(S)-hydroxycholesterol (24S-OHC), which plays an important role in maintaining brain cholesterol homeostasis, has been shown to possess neurotoxicity. We have previously reported that 24S-OHC esterification by acyl-CoA:cholesterol acyltransferase 1 (ACAT1) and the resulting lipid droplet (LD) formation are responsible for 24S-OHC-induced cell death. In the present study, we investigate the functional roles of 24S-OHC esters and LD formation in 24S-OHC-induced cell death, and we identify four long-chain unsaturated fatty acids (oleic acid, linoleic acid, arachidonic acid, and docosahexaenoic acid) with which 24S-OHC is esterified in human neuroblastoma SH-SY5Y cells treated with 24S-OHC...
September 19, 2016: Journal of Lipid Research
Lei Xu, Yi-Ru Wang, Pei-Cheng Li, Bo Feng
BACKGROUND: Previous reports have suggested that advanced glycation end products (AGEs) participate in the pathogenesis of diabetic macroangiopathy. Our previous study have found that AGEs can increase the lipid droplets accumulation in aortas of diabetic rats, but the current understanding of the mechanisms remains incomplete by which AGEs affect lipids accumulation in macrophages and accelerate atherosclerosis. In this study, we investigated the role of AGEs on lipids accumulation in macrophages and the possible molecular mechanisms including cholesterol influx, esterification and efflux of macrophages...
2016: Lipids in Health and Disease
R J Kern, C M Zarek, A K Lindholm-Perry, L A Kuehn, W M Snelling, H C Freetly, H C Cunningham, A M Meyer
Ruminal genes differentially expressed in crossbred beef steers from USMARC with variation in gain and feed intake were identified in a previous study. Several of the genes identified with expression patterns differing between animals with high gain-low feed intake and low gain-high feed intake were evaluated in a separate, unrelated population of Angus × Hereford beef steers from the University of Wyoming that was classified to differ in residual feed intake (RFI). Of the 17 genes tested, two were differentially expressed by RFI class in the Angus × Hereford animals...
September 9, 2016: Animal Genetics
Sabiha S Chowdhury, Virginie Lecomte, Jonathan H Erlich, Christopher A Maloney, Margaret J Morris
Along with diabetes and obesity, chronic kidney disease (CKD) is increasing across the globe. Although some data support an effect of maternal obesity on offspring kidney, the impact of paternal obesity is unknown; thus, we have studied the effect of paternal obesity prior to conception. Male Sprague Dawley rats were fed chow diet or high fat diet (HFD) for 13-14 weeks before mating with chow-fed females. Male offspring were weaned onto chow and killed at 27 weeks for renal gene expression and histology. Fathers on HFD were 30% heavier than Controls at mating...
2016: Nutrients
Aicha Saadane, Natalia Mast, Tung Dao, Baseer Ahmad, Irina A Pikuleva
The process of vision is impossible without the photoreceptor cells, which have a unique structure and specific maintenance of cholesterol. Herein we report on the previously unrecognized cholesterol-related pathway in the retina discovered during follow-up characterizations of Cyp27a1(-/-)Cyp46a1(-/-) mice. These animals have retinal hypercholesterolemia and convert excess retinal cholesterol into cholesterol esters, normally present in the retina in very small amounts. We established that in the Cyp27a1(-/-)Cyp46a1(-/-) retina, cholesterol esters are generated by and accumulate in the photoreceptor outer segments (OS), which is the retinal layer with the lowest cholesterol content...
September 23, 2016: Journal of Biological Chemistry
Keigo Yamamoto, Yukie Tajima, Akinori Hasegawa, Yui Takahashi, Miho Kojima, Rena Watanabe, Kengo Sato, Masayoshi Shichiri, Takuya Watanabe
Stanniocalcin (STC) is a calcium- and phosphate-regulating hormone secreted by the corpuscles of Stannius, an endocrine gland of bony fish. Its human homologues, STC1 and STC2 showing 34% amino acid identity each other, are expressed in a variety of human tissues. To clarify their roles in atherosclerosis, we investigated the effects of their full-length proteins, STC1(18-247) and STC2(25-302), and STC2-derived fragment peptides, STC2(80-100) and STC2(85-99), on inflammatory responses in human umbilical vein endothelial cells (HUVECs), human macrophage foam cell formation, the migration and proliferation of human aortic smooth muscle cells (HASMCs) and the extracellular matrix expression...
August 2016: Peptides
Pengqiang Wen, Zhanling Chen, Guobing Wang, Zhe Su, Xiuwei Zhang, Gen Tang, Dong Cui, Xiaohong Liu, Chengrong Li
OBJECTIVE: To investigate the clinical phenotype and ACAT1 gene mutation in a family affected with beta-ketothiolase deficiency (BKTD). METHODS: Clinical features and laboratory test data were collected. The probands were monozygotic twin brothers. Genomic DNA was isolated from peripheral blood leukocytes obtained from the probands and their family members. Molecular genetic testing of the ACAT1 gene was carried out. RESULTS: The probands have presented with fever, vomiting and severe ketoacidosis...
June 2016: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
Jing Ge, Bei Cheng, Benling Qi, Wen Peng, Hui Wen, Lijuan Bai, Yun Liu, Wei Zhai
Acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1) catalyzes the conversion of free cholesterol (FC) to cholesterol ester. The human ACAT1 gene P1 promoter has been cloned. However, the activity and specificity of the ACAT1 gene P1 promoter in diverse cell types remains unclear. The P1 promoter fragment was digested with KpnI/XhoI from a P1 promoter cloning vector, and was subcloned into the multiple cloning site of the Firefly luciferase vector pGL3‑Enhancer to obtain the construct P1E‑1. According to the analysis of biological information, the P1E‑1 plasmid was used to generate deletions of the ACAT1 gene P1 promoter with varying 5' ends and an identical 3' end at +65 by polymerase chain reaction (PCR)...
July 2016: Molecular Medicine Reports
Kai Ye, Yiyang Wu, Yafeng Sun, Jian'an Lin, Jianhua Xu
AIMS: Toll-like receptor 4 (TLR4) is involved in tumor development. Numerous studies have confirmed that TLR4 mediates processes in tumorigenesis, for example, inflammation, proliferation and invasion. However, the effects of TLR4 on colorectal cancer development have not been fully elucidated. The present study aimed to evaluate the effects and mechanisms of TLR4 on colorectal cancer development. MAIN METHODS: The expression of TLR4 and Acyl coenzyme A cholesterol acyltransferase 1 (ACAT1) in colorectal cancer tissues and cell lines was detected using RT-PCR and Western blot...
June 15, 2016: Life Sciences
Sheng-Chao Ma, Hui-Ping Zhang, Fan-Qi Kong, Hui Zhang, Cheng Yang, Yang-Yang He, Yan-Hua Wang, An-Ning Yang, Ju Tian, Xiao-Ling Yang, Ming-Hao Zhang, Hua Xu, Yi-Deng Jiang, Zheng Yu
The aim of the present study was to identify an effective method for detecting early‑phase atherosclerosis (AS), as well as to provide useful DNA methylation profiles to serve as biomarkers for the detection of AS. A total of 300 individuals (150 AS patients and 150 healthy subjects) were recruited for peripheral blood DNA methylation analyses at 12 gene promoter loci using nested methylation‑specific polymerase chain reaction in a test set. Based on the test set, the promoter methylation of TIMP metallopeptidase inhibitor 1 (TIMP1), ATP binding cassette subfamily A member 1 (ABCA1), and acetyl-CoA acetyltransferase 1 (ACAT1) were determined to be candidate biomarkers; demonstrating the highest sensitivity (88%) and specificity (90%)...
June 2016: Molecular Medicine Reports
Christopher R LaPensee, Jacqueline E Mann, William E Rainey, Valentina Crudo, Stephen W Hunt, Gary D Hammer
ATR-101 is a novel, oral drug candidate currently in development for the treatment of adrenocortical cancer. ATR-101 is a selective and potent inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase 1 (ACAT1), an enzyme located in the endoplasmic reticulum (ER) membrane that catalyzes esterification of intracellular free cholesterol (FC). We aimed to identify mechanisms by which ATR-101 induces adrenocortical cell death. In H295R human adrenocortical carcinoma cells, ATR-101 decreases the formation of cholesteryl esters and increases FC levels, demonstrating potent inhibition of ACAT1 activity...
May 2016: Endocrinology
Wei Yang, Yibing Bai, Ying Xiong, Jin Zhang, Shuokai Chen, Xiaojun Zheng, Xiangbo Meng, Lunyi Li, Jing Wang, Chenguang Xu, Chengsong Yan, Lijuan Wang, Catharine C Y Chang, Ta-Yuan Chang, Ti Zhang, Penghui Zhou, Bao-Liang Song, Wanli Liu, Shao-cong Sun, Xiaolong Liu, Bo-liang Li, Chenqi Xu
CD8(+) T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment. Reactivating the cytotoxicity of CD8(+) T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8(+) T cells can be potentiated by modulating cholesterol metabolism. Inhibiting cholesterol esterification in T cells by genetic ablation or pharmacological inhibition of ACAT1, a key cholesterol esterification enzyme, led to potentiated effector function and enhanced proliferation of CD8(+) but not CD4(+) T cells...
March 31, 2016: Nature
Li-Hao Huang, Elaina M Melton, Haibo Li, Paul Sohn, Maximillian A Rogers, Mary Jo Mulligan-Kehoe, Steven N Fiering, William F Hickey, Catherine C Y Chang, Ta-Yuan Chang
Acyl-CoA:cholesterol acyltransferase 1 (Acat1) converts cellular cholesterol to cholesteryl esters and is considered a drug target for treating atherosclerosis. However, in mouse models for atherosclerosis, global Acat1 knockout (Acat1(-/-)) did not prevent lesion development. Acat1(-/-) increased apoptosis within lesions and led to several additional undesirable phenotypes, including hair loss, dry eye, leukocytosis, xanthomatosis, and a reduced life span. To determine the roles of Acat1 in monocytes/macrophages in atherosclerosis, we produced a myeloid-specific Acat1 knockout (Acat1(-M/-M)) mouse and showed that, in the Apoe knockout (Apoe(-/-)) mouse model for atherosclerosis, Acat1(-M/-M) decreased the plaque area and reduced lesion size without causing leukocytosis, dry eye, hair loss, or a reduced life span...
March 18, 2016: Journal of Biological Chemistry
Yohei Shibuya, Catherine Cy Chang, Ta-Yuan Chang
Alzheimer's disease (AD) is the most common cause of dementia with no cure at present. Cholesterol metabolism is closely associated with AD at several stages. ACAT1 converts free cholesterol to cholesteryl esters, and plays important roles in cellular cholesterol homeostasis. Recent studies show that in a mouse model, blocking ACAT1 provides multiple beneficial effects on AD. Here we review the current evidence that implicates ACAT1 as a therapeutic target for AD. We also discuss the potential usage of various ACAT inhibitors currently available to treat AD...
2015: Future Medicinal Chemistry
Yang Zhan, Xiao-Wei Zhang, Ying Xiong, Bo-Liang Li, Fa-Jun Nan
A series of pyripyropene A-based compounds were designed and synthesized by opening the upper section of the A-ring, which significantly simplifies the structure and synthesis from commercially available starting materials. Representative compound (-)-3 exhibited potent activity against ACAT2 and greater selectivity for ACAT2 than for ACAT1.
January 14, 2016: Organic & Biomolecular Chemistry
Dimitry A Chistiakov, Yuri V Bobryshev, Alexander N Orekhov
Formation of foam cells is a hallmark at the initial stages of atherosclerosis. Monocytes attracted by pro-inflammatory stimuli attach to the inflamed vascular endothelium and penetrate to the arterial intima where they differentiate to macrophages. Intimal macrophages phagocytize oxidized low-density lipoproteins (oxLDL). Several scavenger receptors (SR), including CD36, SR-A1 and lectin-like oxLDL receptor-1 (LOX-1), mediate oxLDL uptake. In late endosomes/lysosomes of macrophages, oxLDL are catabolysed. Lysosomal acid lipase (LAL) hydrolyses cholesterol esters that are enriched in LDL to free cholesterol and free fatty acids...
January 2016: Journal of Cellular and Molecular Medicine
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