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Naz T, Zhao XY, Li S, Saeed T, Ullah S, Nazir Y, Liu Q, Mohamed H, Song Y. The interplay of transcriptional regulator SREBP1 with AMPK promotes lipid biosynthesis in Mucor circinelloides WJ11. Biochim Biophys Acta Mol Cell Biol Lipids 2025; 1870:159592. [PMID: 39733936 DOI: 10.1016/j.bbalip.2024.159592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 12/18/2024] [Accepted: 12/24/2024] [Indexed: 12/31/2024]
Abstract
SREBP1 is a transcription factor that influences lipogenesis by regulating key genes associated with lipid biosynthesis, while AMPK, modulates lipid metabolism by regulating acetyl-CoA carboxylase. The exact role of these metabolic regulators in oleaginous microbes remains unclear. This study identified and manipulated the genes encoding SREBP1 (sre1) and α1 subunit of AMPK (ampk-α1) in Mucor circinelloides WJ11. Individual overexpression of sre1 yielded 32.5 % lipids and 21 g/L biomass, while ampk-α1 deletion combined with sre1 overexpression yielded 42.5 % lipids and 25 g/L biomass in mutant strains. This increase correlated with upregulated expression of key lipogenic genes and enzyme activity, enhancing lipid production and biomass. These surges were correlated with the increased mRNA levels of key genes (acl, acc1, acc2, cme1, fas1, g6pdh1, g6pdh2 and 6pgdh2). Enzyme activity analysis further showed that upregulation of ACL, ACC, ME, FAS, G6PDH and 6PGDH might provide more precursors and NADPH for lipid biosynthesis in sre1 overexpressing strains. Conversely, the activities of these genes and enzymes were markedly downregulated in sre1 deleted mutants consistent with lower lipid production and biomass than the control. These findings open new avenues for research by exploring the coordinated role of sre1 and ampk-α1 in lipid metabolism in M. circinelloides.
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Affiliation(s)
- Tahira Naz
- Colin Ratledge Center for Microbial Lipids, School of Agricultural Engineering and Food Science, Shandong University of Technology, Zibo 255000, China; State Key Laboratory of Crop Biology, College of Life Sciences, Shandong Agricultural University, Taian, Shandong 271018, China
| | - Xiang Yu Zhao
- State Key Laboratory of Crop Biology, College of Life Sciences, Shandong Agricultural University, Taian, Shandong 271018, China.
| | - Shaoqi Li
- Colin Ratledge Center for Microbial Lipids, School of Agricultural Engineering and Food Science, Shandong University of Technology, Zibo 255000, China
| | - Tariq Saeed
- Colin Ratledge Center for Microbial Lipids, School of Agricultural Engineering and Food Science, Shandong University of Technology, Zibo 255000, China; Department of Diet and Nutritional Sciences, Ibadat International University, Islamabad 45750, Pakistan.
| | - Samee Ullah
- Colin Ratledge Center for Microbial Lipids, School of Agricultural Engineering and Food Science, Shandong University of Technology, Zibo 255000, China; University Institute of Diet and Nutritional Sciences, Faculty of Allied Health Sciences, The University of Lahore, Lahore 54000, Pakistan
| | - Yusuf Nazir
- Colin Ratledge Center for Microbial Lipids, School of Agricultural Engineering and Food Science, Shandong University of Technology, Zibo 255000, China; Department of Food Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi 43600, Malaysia
| | - Qing Liu
- Colin Ratledge Center for Microbial Lipids, School of Agricultural Engineering and Food Science, Shandong University of Technology, Zibo 255000, China.
| | - Hassan Mohamed
- Colin Ratledge Center for Microbial Lipids, School of Agricultural Engineering and Food Science, Shandong University of Technology, Zibo 255000, China; Department of Botany and Microbiology, Faculty of Science, Al-Azhar University, Assiut 71524, Egypt.
| | - Yuanda Song
- Colin Ratledge Center for Microbial Lipids, School of Agricultural Engineering and Food Science, Shandong University of Technology, Zibo 255000, China.
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2
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Jin J, Wang Y, Hu Y. STAMBPL1, transcriptionally regulated by SREBP1, promotes malignant behaviors of hepatocellular carcinoma cells via Wnt/β-catenin signaling pathway. Mol Carcinog 2024; 63:2158-2173. [PMID: 39150093 DOI: 10.1002/mc.23801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 07/15/2024] [Accepted: 07/24/2024] [Indexed: 08/17/2024]
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. STAM binding protein-like 1 (STAMBPL1), a key member of the COP9 signalosome subunit 5/serine protease 27/proteasome 26S subunit non-ATPase 7 (JAMM) family, is closely associated with tumor development. In this work, data from GSE101728 and GSE84402 chips were analyzed, and STAMBPL1 was selected as the target factor. This study aimed to reveal the potential function of STAMBPL1 in HCC. Clinical results showed that STAMBPL1 was significantly increased in tumor tissues of HCC patients, and its expression was strongly associated with tumor size and TNM stage. Furthermore, STAMBPL1-overexpressed Hep3B2.1-7 cell line or STAMBPL1-silenced SNU-182 cell line were established using lentivirus carrying cDNA encoding STAMBPL1 mRNA or shRNA targeting STAMBPL1, respectively. STAMBPL1-overexpressed cells exhibited a pronounced enhancement of proliferation in vitro and in vivo. Exogenous expression of STAMBPL1 increased the percentage of cells in the S phase and upregulated the expressions of CyclinD1 and Survivin. As expected, STAMBPL1 knockdown exhibited completely opposite effects, resulting in impaired tumorigenicity in vitro and in vivo. Mechanistically, STAMBPL1 activated Wnt/β-catenin pathway and increased the expression of downstream cancer-promoting genes. Interestingly, we found that STAMBPL1 was transcriptionally regulated by sterol regulatory element-binding protein 1 (SREBP1), a modulator of lipid metabolism, as evidenced by luciferase reporter and chromatin-immunoprecipitation (Ch-IP) assays. Notably, STAMBPL1 overexpression increased lipid accumulation in HCC cells and xenograft tumors. Totally our findings suggest that STAMBPL1 plays a vital role in the tumorigenicity of HCC cells. Modulation of Wnt/β-catenin and lipid metabolism may contribute to its pro-cancer effects. STAMBPL1 may serve as a therapeutic target of HCC.
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Affiliation(s)
- Junyi Jin
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yihui Wang
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yaoyuan Hu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
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An M, Heo H, Park J, Jeong HS, Kim Y, Lee J. Unsaponifiable Matter from Wheat Bran Cultivated in Korea Inhibits Hepatic Lipogenesis by Activating AMPK Pathway. Foods 2023; 12:4016. [PMID: 37959135 PMCID: PMC10650137 DOI: 10.3390/foods12214016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 10/26/2023] [Accepted: 10/31/2023] [Indexed: 11/15/2023] Open
Abstract
Unsaponifiable matter (USM) from wheat bran, a by-product obtained from wheat milling, is abundant in health-promoting compounds such as phytosterols, tocopherols, policosanols, and alkylresorcinols. This study aimed to examine the effects of USM from the wheat bran of normal and waxy type wheat, Saekeumkang (SKK) and Shinmichal (SMC), on hepatic lipid accumulation in free fatty acid (FFA)-induced hepatocytes and to investigate the cellular mechanism. The total phytochemical contents were 46.562 g/100 g USM and 38.130 g/100 g USM from SKK and SMC, respectively. FFA treatment increased intracellular lipid accumulation by approximately 260% compared to the control group; however, treatment with USM from SKK and SMC significantly attenuated lipid accumulation in the hepatocytes in a dose-dependent manner. Moreover, USM downregulated the expression of lipogenic factors such as fatty acid synthase and sterol regulatory-element-binding protein 1c by approximately 40% compared to the FFA treatment group. Treatment with USM promoted lipolysis and positively regulated the expression of the proteins involved in β-oxidation, including peroxisome proliferator-activated receptor α and its downstream protein, carnitine palmitoyltransferase 1A. Moreover, the blockade of AMPK activation significantly abolished the inhibitory effects of USM on hepatic lipid accumulation. These results indicated that the USM from both SKK and SMC can alleviate lipid accumulation in hepatocytes in an AMPK-dependent manner. Therefore, USM from wheat bran may be useful as a therapeutic intervention for treating metabolic-dysfunction-associated fatty liver disease.
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Affiliation(s)
- Minju An
- Department of Food Science and Biotechnology, Chungbuk National University, Cheongju 28644, Republic of Korea; (M.A.); (H.H.); (H.-S.J.)
| | - Huijin Heo
- Department of Food Science and Biotechnology, Chungbuk National University, Cheongju 28644, Republic of Korea; (M.A.); (H.H.); (H.-S.J.)
| | - Jinhee Park
- Wheat Research Team, National Institute of Crop Science, Rural Development Administration, Wanju 55365, Republic of Korea;
| | - Heon-Sang Jeong
- Department of Food Science and Biotechnology, Chungbuk National University, Cheongju 28644, Republic of Korea; (M.A.); (H.H.); (H.-S.J.)
| | - Younghwa Kim
- Department of Food Science and Biotechnology, Kyungsung University, Busan 48434, Republic of Korea
| | - Junsoo Lee
- Department of Food Science and Biotechnology, Chungbuk National University, Cheongju 28644, Republic of Korea; (M.A.); (H.H.); (H.-S.J.)
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Gozdzik P, Czumaj A, Sledzinski T, Mika A. Branched-chain fatty acids affect the expression of fatty acid synthase and C-reactive protein genes in the hepatocyte cell line. Biosci Rep 2023; 43:BSR20230114. [PMID: 37850622 PMCID: PMC10619197 DOI: 10.1042/bsr20230114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 10/03/2023] [Accepted: 10/17/2023] [Indexed: 10/19/2023] Open
Abstract
Fatty acids (FAs) are known to play an important role in human metabolism; however, still little is known about the functions of certain FA classes present in blood at relatively low concentrations. Examples of such compounds include branched-chain fatty acids (BCFAs). Recently, lowered BCFAs blood concentration was noticed in obese patients. An inverse correlation was found between serum concentrations of BCFAs and triglyceride levels, as well as C-reactive protein (CRP) concentration. Obesity is the most frequently observed component of metabolic syndrome and both disorders are accompanied by the dysregulation of FAs metabolism. However, not all of them are well understood. Our study is the first attempt at presenting the opposite effects of an iso-BCFA (14-methylpentadecanoic acid, 14-MPA) and an anteiso-BCFA (12-methyltetradecanoic acid, 12-MTA) on selected genes related to fatty acid synthesis and inflammation: FASN, SREBP1, CRP, and IL-6 in the HepG2 cell line. We observed lowered expression of FASN, SREBP1, CRP, and IL-6 in cells treated with 14-MPA in comparison with control cells. In contrast, supplementation with 12-MTA caused opposite effects: increased mRNA levels of FASN, CRP, and IL-6. 12-MTA did not influence SREBP1 expression. The results of our preliminary study may suggest potential benefits of the supplementation of iso-BCFAs in obese patients, for inflammation and hypertriglyceridemia prevention.
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Affiliation(s)
- Paulina Gozdzik
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk, Poland
| | - Aleksandra Czumaj
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk, Poland
| | - Tomasz Sledzinski
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk, Poland
| | - Adriana Mika
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk, Poland
- Department of Environmental Analysis, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland
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Li X, Dai X, Pan Y, Sun Y, Yang B, Chen K, Wang Y, Xu JF, Dong Y, Yang YR, Yan LT, Liu D. Studies on the Synergistic Effect of Tandem Semi-Stable Complementary Domains on Sequence-Defined DNA Block Copolymers. J Am Chem Soc 2022; 144:21267-21277. [DOI: 10.1021/jacs.2c08930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Xin Li
- Engineering Research Center of Advanced Rare Earth Materials (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China
| | - Xiaobin Dai
- State Key Laboratory of Chemical Engineering, Department of Chemical Engineering, Tsinghua University, Beijing 100084, China
| | - Yufan Pan
- Engineering Research Center of Advanced Rare Earth Materials (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China
| | - Yawei Sun
- State Key Laboratory of Heavy Oil Processing, College of Chemical Engineering, China University of Petroleum (Huadong), Qingdao 258000, China
| | - Bo Yang
- Engineering Research Center of Advanced Rare Earth Materials (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China
| | - Kun Chen
- CAS Key Laboratory of Nanosystem and Hierarchical Fabrication, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China
| | - You Wang
- Engineering Research Center of Advanced Rare Earth Materials (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China
| | - Jiang-Fei Xu
- Key Lab of Organic Optoelectronics & Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing 100084, China
| | - Yuanchen Dong
- CAS Key Laboratory of Colloid Interface and Chemical Thermodynamics, Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
- University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - Yuhe Renee Yang
- CAS Key Laboratory of Nanosystem and Hierarchical Fabrication, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China
| | - Li-Tang Yan
- State Key Laboratory of Chemical Engineering, Department of Chemical Engineering, Tsinghua University, Beijing 100084, China
| | - Dongsheng Liu
- Engineering Research Center of Advanced Rare Earth Materials (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China
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Nezhadebrahimi A, Sepehri H, Jahanshahi M, Marjani M, Marjani A. The effect of simvastatin on gene expression of low-density lipoprotein receptor, sterol regulatory element-binding proteins, stearoyl-CoA desaturase 1 mRNA in rat hepatic tissues. Arch Physiol Biochem 2022; 128:1383-1390. [PMID: 32643419 DOI: 10.1080/13813455.2020.1772829] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
The study aimed to assess the effect of simvastatin on gene expression of LDLR, SREBPs, and SCD1 in rat hepatic tissues fed with high-fat diets (HFD) and its association with some biochemical parameters. Thirty-two male Wister albino rats were divided into four equal groups (three test and one control groups). The biochemical parameters were determined by using spectrophotometer techniques and the Elisa method. Low-density lipoprotein receptor, sterol regulatory element-binding proteins, stearoyl-CoA desaturase1, Beta-actin were analysed by real-time quantitative polymerase chain reaction (RT-PCR) method. At the end of study, the livers of the rats were separated and changes of hepatic tissue were determined. LDLR, SREBP2, and SCD1 expression increased significantly when compared G1 versus G4 and G2 versus G4. The expression of LDLR, SREBP2, and SCD1 also increased significantly when compared G2 versus G3, G1versus G3 and G1 versus G3 and G2 versus G3. The serum level of cholesterol, triglyceride, glucose, LDL, and HDL increased significantly when compared G1 versus G3. LDL showed significantly decreased when compared G1 versus G2. Cholesterol, glucose and HDL and triglyceride levels were increased significantly when compared G1 versus G4 and G2. Treatment of rats with HFD and simvastatin 20 mg/kg, triglyceride and LDL were almost the same as a control group and LDLR expression increased 98% in liver tissue. Gene expressions may be up-regulated in liver tissue and they showed different effects on biochemical parameters.
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Affiliation(s)
- Abbas Nezhadebrahimi
- Department of Biochemistry and Biophysics, Student Research Center, Metabolic Disorders Research Center, Gorgan Faculty of Medicine, Golestan University Medical Sciences, Gorgan, Iran
- Department of Physiology, Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Hamid Sepehri
- Department of Physiology, Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Mehrdad Jahanshahi
- Neuroscience Research Center, Department of Anatomy, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Majid Marjani
- Faculty of Pharmacy, Eastern Mediterranean University, Famagusta, North Cyprus, Turkey
| | - Abdoljalal Marjani
- Metabolic Disorders Research Center, Department of Biochemistry and Biophysics, Gorgan Faculty of Medicine, Golestan University Medical Sciences, Gorgan, Iran
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Hu S, Liu X, Wang Y, Zhang R, Wei S. Melatonin protects against body weight gain induced by sleep deprivation in mice. Physiol Behav 2022; 257:113975. [PMID: 36183851 DOI: 10.1016/j.physbeh.2022.113975] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 07/10/2022] [Accepted: 09/27/2022] [Indexed: 10/14/2022]
Abstract
Sleep deprivation is an epidemic phenomenon in modern society. Lack of sleep has been shown to result in metabolic and endocrine disorders that predispose to obesity and other chronic metabolic diseases. Melatonin is a sleep-related neurohormone and affected by the circadian rhythm and light/dark cycles. Melatonin has recently been used to ameliorate diet-induced or night light-induced energy metabolic imbalance. However, the effect of melatonin on sleep deprivation-induced obesity has been poorly characterized. This study focuses on the protective effects of melatonin on lipid metabolism and body weight homeostasis in sleep-deprived mice. Mice subjected to sleep deprivation had significantly decreased plasma melatonin content and increased food intake and body weight gain compared to that of control. Meanwhile, the transcription factor PPARγ protein in liver increased, but there were no significant changes in hepatic circadian proteins BMAL1 and REV-ERBα after 10 consecutive days of sleep deprivation. Moreover, melatonin supplementation increased liver AMPKα/PPARα signaling pathway activity, which leads to lipid catabolism and reduced fat accumulation. These findings suggested that melatonin may be a potential agent for protecting against sleep deprivation-induced obesity.
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Affiliation(s)
- Shuang Hu
- Department of Child, Adolescent and Women's Health, School of Public Health, Capital Medical University, Beijing, China
| | - Xuan Liu
- Department of Child, Adolescent and Women's Health, School of Public Health, Capital Medical University, Beijing, China
| | - Yuefan Wang
- Department of Child, Adolescent and Women's Health, School of Public Health, Capital Medical University, Beijing, China
| | - Rong Zhang
- Department of Child, Adolescent and Women's Health, School of Public Health, Capital Medical University, Beijing, China
| | - Shougang Wei
- Department of Child, Adolescent and Women's Health, School of Public Health, Capital Medical University, Beijing, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, China.
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8
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Sommerauer C, Kutter C. Noncoding RNAs in liver physiology and metabolic diseases. Am J Physiol Cell Physiol 2022; 323:C1003-C1017. [PMID: 35968891 DOI: 10.1152/ajpcell.00232.2022] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The liver holds central roles in detoxification, energy metabolism and whole-body homeostasis but can develop malignant phenotypes when being chronically overwhelmed with fatty acids and glucose. The global rise of metabolic-associated fatty liver disease (MAFLD) is already affecting a quarter of the global population. Pharmaceutical treatment options against different stages of MAFLD do not yet exist and several clinical trials against hepatic transcription factors and other proteins have failed. However, emerging roles of noncoding RNAs, including long (lncRNA) and short noncoding RNAs (sRNA), in various cellular processes pose exciting new avenues for treatment interventions. Actions of noncoding RNAs mostly rely on interactions with proteins, whereby the noncoding RNA fine-tunes protein function in a process termed riboregulation. The developmental stage-, disease stage- and cell type-specific nature of noncoding RNAs harbors enormous potential to precisely target certain cellular pathways in a spatio-temporally defined manner. Proteins interacting with RNAs can be categorized into canonical or non-canonical RNA binding proteins (RBPs) depending on the existence of classical RNA binding domains. Both, RNA- and RBP-centric methods have generated new knowledge of the RNA-RBP interface and added an additional regulatory layer. In this review, we summarize recent advances of how of RBP-lncRNA interactions and various sRNAs shape cellular physiology and the development of liver diseases such as MAFLD and hepatocellular carcinoma.
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Affiliation(s)
- Christian Sommerauer
- Science for Life Laboratory, Department of Microbiology, Tumor and Cell Biology, grid.4714.6Karolinska Institute, Stockholm, Sweden
| | - Claudia Kutter
- Science for Life Laboratory, Department of Microbiology, Tumor and Cell Biology, grid.4714.6Karolinska Institute, Stockholm, Sweden
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Dinh TTT, Nguyen TT, Ngo HT, Tran TH, Le BV, Pham TH, Pham HTT, Pham TK, Do TH. Dammarane-type triterpenoids from Gynostemma compressum X. X. Chen & D. R. Liang (Cucurbitaceae) and their AMPK activation effect in 3T3-L1 cells. PHYTOCHEMISTRY 2022; 200:113218. [PMID: 35490775 DOI: 10.1016/j.phytochem.2022.113218] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 04/07/2022] [Accepted: 04/22/2022] [Indexed: 06/14/2023]
Abstract
Bioassay-guided fractionation of the 80% ethanol extract of Gynostemma compressum X. X. Chen & D. R. Liang (Cucurbitaceae) resulted in the isolation and identification of eight undescribed triterpenoids, gycomol VN1, gycomol VN2, and gycomosides VN1-6 from the bioactive n-butanol fraction. The structures of these compounds were elucidated by one- and two-dimensional nuclear magnetic resonance spectroscopy, high-resolution electrospray ionisation mass spectrometry, and chemical methods. All isolated compounds were evaluated for their 5'-adenosine monophosphate-activated protein kinase (AMPK) and acetyl-coenzyme A carboxylase (ACC) activation effects on 3T3-L1 cells. Importantly, gycomol VN2, gycomoside VN1, and gycomosides VN3-5 activated the phosphorylation of AMPK and its downstream substrate ACC in 3T3-L1 cells at a dose of 10 μM. These effects imply that the activation of AMPK and ACC by active compounds from G. compressum has considerable potential for the prevention of obesity and its related disorders by activating AMPK signaling pathways.
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Affiliation(s)
- Thi Thanh Thuy Dinh
- National Institute of Medicinal Materials (NIMM), 3B Quang Trung, Hoan Kiem, Hanoi, Viet Nam; National Hospital for Tropical Diseases, Dong Anh, Hanoi, Viet Nam
| | - Thi Thu Nguyen
- National Institute of Medicinal Materials (NIMM), 3B Quang Trung, Hoan Kiem, Hanoi, Viet Nam
| | - Huy Trung Ngo
- National Institute of Medicinal Materials (NIMM), 3B Quang Trung, Hoan Kiem, Hanoi, Viet Nam
| | - Thi Hien Tran
- Thai Binh University Medicine and Pharmacy, 373 Ly Bon, Thai Binh, Viet Nam
| | - Ba Vinh Le
- College of Pharmacy, Korea University, Sejong, 47236, Republic of Korea; Institute of Marine Biochemistry (IMBC), Vietnam Academy of Science and Technology (VAST), 18-Hoang Quoc Viet Cau Giay, Hanoi, Viet Nam
| | - Thanh Huyen Pham
- National Institute of Medicinal Materials (NIMM), 3B Quang Trung, Hoan Kiem, Hanoi, Viet Nam
| | - Ha Thanh Tung Pham
- Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hoan Kiem, Hanoi, Viet Nam
| | - Thanh Ky Pham
- Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hoan Kiem, Hanoi, Viet Nam
| | - Thi Ha Do
- National Institute of Medicinal Materials (NIMM), 3B Quang Trung, Hoan Kiem, Hanoi, Viet Nam.
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Rondini EA, Ramseyer VD, Burl RB, Pique-Regi R, Granneman JG. Single cell functional genomics reveals plasticity of subcutaneous white adipose tissue (WAT) during early postnatal development. Mol Metab 2021; 53:101307. [PMID: 34298199 PMCID: PMC8385178 DOI: 10.1016/j.molmet.2021.101307] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/09/2021] [Accepted: 07/16/2021] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE The current study addresses the cellular complexity and plasticity of subcutaneous (inguinal) white adipose tissue (iWAT) in mice during the critical periods of perinatal growth and establishment. METHODS We performed a large-scale single cell transcriptomic (scRNA-seq) and epigenomic (snATAC-seq) characterization of cellular subtypes (adipose stromal cells (ASC) and adipocyte nuclei) during inguinal WAT (subcutaneous; iWAT) development in mice, capturing the early postnatal period (postnatal days (PND) 06 and 18) through adulthood (PND56). RESULTS Perinatal and adult iWAT contain 3 major ASC subtypes that can be independently identified by RNA expression profiles and DNA transposase accessibility. Furthermore, the transcriptomes and enhancer landscapes of both ASC and adipocytes dynamically change during postnatal development. Perinatal ASC (PND06) are highly enriched for several imprinted genes (IGs; e.g., Mest, H19, Igf2) and extracellular matrix proteins whose expression then declines prior to weaning (PND18). By comparison, adult ASC (PND56) are more enriched for transcripts associated with immunoregulation, oxidative stress, and integrin signaling. Two clusters of mature adipocytes, identified through single nuclei RNA sequencing (snRNA-seq), were distinctive for proinflammatory/immune or metabolic gene expression patterns that became more transcriptionally diverse in adult animals. Single nuclei assay for transposase-accessible chromatin (snATAC-seq) revealed that differences in gene expression were associated with developmental changes in chromatin accessibility and predicted transcription factor motifs (e.g., Plagl1, Ar) in both stromal cells and adipocytes. CONCLUSIONS Our data provide new insights into transcriptional and epigenomic signaling networks important during iWAT establishment at a single cell resolution, with important implications for the field of metabolic programming.
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Affiliation(s)
- Elizabeth A Rondini
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA
| | - Vanesa D Ramseyer
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA
| | - Rayanne B Burl
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA
| | - Roger Pique-Regi
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA
| | - James G Granneman
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA; Center for Integrative Metabolic and Endocrine Research, Wayne State University, Detroit, MI, USA.
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11
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Zhang Y, Fan X, Qiu L, Zhu W, Huang L, Miao Y. Liver X receptor α promotes milk fat synthesis in buffalo mammary epithelial cells by regulating the expression of FASN. J Dairy Sci 2021; 104:12980-12993. [PMID: 34593221 DOI: 10.3168/jds.2021-20596] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 08/16/2021] [Indexed: 01/14/2023]
Abstract
Liver X receptor α (LXRα; NR1H3) is an important transcription factor that can facilitate milk fat synthesis by regulating the transcription of FASN in mice and goats. Nevertheless, the lipid synthesis related to LXRα and its regulation on FASN in the buffalo mammary gland remain elusive. Here, we demonstrated that the mRNA and protein expression of LXRα in buffalo mammary tissue increased in lactation compared with that in the dry-off period. Overexpression of NR1H3 enhanced the lipid droplet formation and triacylglycerol concentration in buffalo mammary epithelial cells (BuMEC), whereas the knockdown of NR1H3 resulted in a decrease in the number of lipid droplets. At the same time, NR1H3 also affected the expression of regulatory factors (INSIG1, INSIG2, SREBF1, and PPARG) related to milk fat synthesis and that of genes involved in de novo synthesis (FASN, ACACA, and SCD), and uptake and transport (LPL, CD36, and FABP3) of fatty acids as well as triacylglycerol synthesis (GPAM, APGAT6, and DGAT1). Luciferase reporter assays indicated that overexpression of NR1H3 resulted in an increase in the activity of FASN promoter, whereas the knockdown of NR1H3 had an opposite effect. When NR1H3 was overexpressed, mutations in LXRE or SRE could decrease the promoter activity of FASN. Furthermore, mutagenesis of both LXRE and SRE within the FASN promoter completely eliminated the induced activity of LXRα. Our results reveal that buffalo LXRα promotes milk fat synthesis through regulating the expression of FASN by directly interacting with FASN promoter and affecting the SREBF1 expression. This study underscores a crucial role of LXRα in regulating lipid synthesis of the buffalo mammary gland.
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Affiliation(s)
- Yongyun Zhang
- Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, Yunnan, China; Teaching Demonstration Center of the Basic Experiments of Agricultural Majors, Yunnan Agricultural University, Kunming 650201, Yunnan, China
| | - Xinyang Fan
- Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, Yunnan, China
| | - Lihua Qiu
- Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, Yunnan, China
| | - Wei Zhu
- College of Veterinary Medicine, Yunnan Agricultural University, Kunming 650201, Yunnan, China
| | - Lige Huang
- Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, Yunnan, China
| | - Yongwang Miao
- Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, Yunnan, China.
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12
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Agastache rugosa Extract and Its Bioactive Compound Tilianin Suppress Adipogenesis and Lipogenesis on 3T3-L1 Cells. APPLIED SCIENCES-BASEL 2021. [DOI: 10.3390/app11167679] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Agastache rugosa, or Korean mint, is an herb used as a spice, food additive and traditional medicinal ingredient. It has desirable effects, such as its antibacterial, antifungal and antioxidant properties. A. rugosa contains many phenolic compounds studied for their various health benefits, with the primary components being tilianin. A. rugosa extract (ARE), which was extracted with ethanol and freeze-dried, contained 21.14 ± 0.15 mg/g of tilianin with a total polyphenol content of 38.11 ± 0.88 mg/g. Next, the antiadipogenic effect of A. rugosa and tilianin was clarified using 3T3-L1 cells, which differentiate into adipocytes and develop lipid droplets. 3T3-L1 cells were treated with ARE or tilianin and lipid accumulation (%) was calculated through oil red O staining. Tilianin elicited dose-dependent decrease in lipid accumulation (% of positive control) (30 μM 92.10 ± 1.19%; 50 μM 69.25 ± 1.78%; 70 μM 54.86 ± 1.76%; non-differentiation 18.10 ± 0.32%), assessed by oil-red-O staining, whereas ARE treatments caused consistent diminution in lipid accumulation regardless of dose (100 μM 86.90 ± 4.97%; 200 μM 87.25 ± 4.34%; 400 μM 88.54 ± 2.27%; non-differentiation 17.96 ± 1.30%), indicating that both compounds have anti-obesity effects on adipocytes. Treatment with ARE lowered the mRNA (PPARγ; C/EBPα; FABP4; SREBP1; ACC; FAS) and protein (PPARγ; C/EBPα; SREBP1) levels of adipogenesis and lipogenesis-related factors. Tilianin showed a greater effect on the mRNA levels compared with ARE. Thus, tilianin and ARE may have anti-adipogenic and anti-lipogenic effects on 3T3-L1 cells and be possible candidates of obesity-related supplements.
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13
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Salunkhe SA, Chitkara D, Mahato RI, Mittal A. Lipid based nanocarriers for effective drug delivery and treatment of diabetes associated liver fibrosis. Adv Drug Deliv Rev 2021; 173:394-415. [PMID: 33831474 DOI: 10.1016/j.addr.2021.04.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 03/02/2021] [Accepted: 04/02/2021] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a cluster of several liver diseases like hepatic steatosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver (NAFL), liver fibrosis, and cirrhosis which may eventually progress to liver carcinoma. One of the primary key factors associated with the development and pathogenesis of NAFLD is diabetes mellitus. The present review emphasizes on diabetes-associated development of liver fibrosis and its treatment using different lipid nanoparticles such as stable nucleic acid lipid nanoparticles, liposomes, solid lipid nanoparticles, nanostructured lipid carriers, self-nanoemulsifying drug delivery systems, and conjugates including phospholipid, fatty acid and steroid-based. We have comprehensively described the various pathological and molecular events linking effects of elevated free fatty acid levels, insulin resistance, and diabetes with the pathogenesis of liver fibrosis. Various passive and active targeting strategies explored for targeting hepatic stellate cells, a key target in liver fibrosis, have also been discussed in detail in this review.
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14
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Geiger R, Fatima N, Schooley JF, Smyth JT, Haigney MC, Flagg TP. Novel cholesterol-dependent regulation of cardiac K ATP subunit expression revealed using histone deacetylase inhibitors. Physiol Rep 2021; 8:e14675. [PMID: 33356020 PMCID: PMC7757372 DOI: 10.14814/phy2.14675] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 11/18/2020] [Indexed: 12/16/2022] Open
Abstract
We recently discovered that the histone deacetylase inhibitor, trichostatin A (TSA), increases expression of the sulfonylurea receptor 2 (SUR2; Abcc9) subunit of the ATP-sensitive K+ (KATP ) channel in HL-1 cardiomyocytes. Interestingly, the increase in SUR2 was abolished with exogenous cholesterol, suggesting that cholesterol may regulate channel expression. In the present study, we tested the hypothesis that TSA increases SUR2 by depleting cholesterol and activating the sterol response element binding protein (SREBP) family of transcription factors. Treatment of HL-1 cardiomyocytes with TSA (30 ng/ml) caused a time-dependent increase in SUR2 mRNA expression that correlates with the time course of cholesterol depletion assessed by filipin staining. Consistent with the cholesterol-dependent regulation of SREBP increasing SUR2 mRNA expression, we observe a significant increase in SREBP cleavage and translocation to the nucleus following TSA treatment that is inhibited by exogenous cholesterol. Further supporting the role of SREBP in mediating the effect of TSA on KATP subunit expression, SREBP1 significantly increased luciferase reporter gene expression driven by the upstream SUR2 promoter. Lastly, HL-1 cardiomyocytes treated with the SREBP inhibitor PF429242 significantly suppresses the effect of TSA on SUR2 gene expression. These results demonstrate that SREBP is an important regulator of KATP channel expression and suggest a novel method by which hypercholesterolemia may exert negative effects on the cardiovascular system, namely, by suppressing expression of the KATP channel.
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Affiliation(s)
- Robert Geiger
- Department of Anatomy, Physiology, and GeneticsUniformed Services University for the Health SciencesBethesdaMDUSA
| | - Naheed Fatima
- Department of Anatomy, Physiology, and GeneticsUniformed Services University for the Health SciencesBethesdaMDUSA
| | - James F. Schooley
- Department of Anatomy, Physiology, and GeneticsUniformed Services University for the Health SciencesBethesdaMDUSA
| | - Jeremy T. Smyth
- Department of Anatomy, Physiology, and GeneticsUniformed Services University for the Health SciencesBethesdaMDUSA
| | - Mark C. Haigney
- Department of MedicineUniformed Services University for the Health SciencesBethesdaMDUSA
| | - Thomas P. Flagg
- Department of Anatomy, Physiology, and GeneticsUniformed Services University for the Health SciencesBethesdaMDUSA
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15
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Uddandrao VVS, Rameshreddy P, Brahmanaidu P, Ponnusamy P, Balakrishnan S, Ramavat RN, Swapna K, Pothani S, Nemani H, Meriga B, Vadivukkarasi S, P R N, Ganapathy S. Antiobesity efficacy of asiatic acid: down-regulation of adipogenic and inflammatory processes in high fat diet induced obese rats. Arch Physiol Biochem 2020; 126:453-462. [PMID: 30739501 DOI: 10.1080/13813455.2018.1555668] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 12/01/2018] [Indexed: 12/18/2022]
Abstract
In the current study, we evaluated the effects of Asiatic acid (AA) on lipid metabolic markers in HFD-induced obese Sprague-Dawley rat model. AA (20 mg/kg BW) was administered orally to HFD-fed rats for 42 days. Changes in body composition, glucose, insulin resistance (IR) and lipid profiles of tissues, plasma and the pattern of gene expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) and its target genes fatty-acid synthase (FAS), adipocyte protein-2 (aP2) and uncoupling protein-2 (UCP-2) and pro-inflammatory factor tumor necrosis factor (TNF)-α were observed in experimental rats. Oral administration of AA exerts therapeutic effects similar to orlistat in attenuating body weight gain, glucose, IR, plasma and tissue lipids and mRNA levels of PPAR-γ, FAS, aP2 and inflammatory factor TNF-α and increasing UCP-2 expression in HFD-fed rats. Hence, these findings concluded that AA attenuate HFD-induced obesity by modulating PPAR-γ and its target genes and regulate lipid metabolism, suggesting their possible antiobesity effects.
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Affiliation(s)
- V V Sathibabu Uddandrao
- Centre for Biological Sciences, Department of Biochemistry, K.S. Rangasamy College of Arts and Science (Autonomous), Tiruchengode, India
| | - P Rameshreddy
- Centre for Biological Sciences, Department of Biochemistry, K.S. Rangasamy College of Arts and Science (Autonomous), Tiruchengode, India
| | - P Brahmanaidu
- Animal Physiology and Biochemistry Laboratory, ICMR-National Animal Resource Facility for Biomedical Research, Hyderabad, India
| | | | - Santhanaraj Balakrishnan
- College of Applied Medical Sciences, Majmaah University, Al Majmaah, The Kingdom of Saudi Arabia
- Department of Bio-Medical Engineering, Velalar College of Engineering and Technology, Thindal, Tamil Nadu, India
| | - Ravindar Naik Ramavat
- Animal Physiology and Biochemistry Laboratory, ICMR-National Animal Resource Facility for Biomedical Research, Hyderabad, India
| | - K Swapna
- Centre for Biological Sciences, Department of Biochemistry, K.S. Rangasamy College of Arts and Science (Autonomous), Tiruchengode, India
| | - Suresh Pothani
- Animal Physiology and Biochemistry Laboratory, ICMR-National Animal Resource Facility for Biomedical Research, Hyderabad, India
| | - Harishankar Nemani
- Animal Physiology and Biochemistry Laboratory, ICMR-National Animal Resource Facility for Biomedical Research, Hyderabad, India
| | - Balaji Meriga
- Department of Biochemistry, Animal Physiology and Biochemistry Laboratory, Sri Venkateswara University, Tirupati, India
| | - S Vadivukkarasi
- Centre for Biological Sciences, Department of Biochemistry, K.S. Rangasamy College of Arts and Science (Autonomous), Tiruchengode, India
| | - Nivedha P R
- Centre for Biological Sciences, Department of Biochemistry, K.S. Rangasamy College of Arts and Science (Autonomous), Tiruchengode, India
| | - Saravanan Ganapathy
- Centre for Biological Sciences, Department of Biochemistry, K.S. Rangasamy College of Arts and Science (Autonomous), Tiruchengode, India
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16
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Ritter MJ, Amano I, Hollenberg AN. Thyroid Hormone Signaling and the Liver. Hepatology 2020; 72:742-752. [PMID: 32343421 DOI: 10.1002/hep.31296] [Citation(s) in RCA: 118] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 03/30/2020] [Accepted: 04/17/2020] [Indexed: 12/11/2022]
Abstract
Thyroid hormone (TH) plays a critical role in maintaining metabolic homeostasis throughout life. It is well known that the liver and thyroid are intimately linked, with TH playing important roles in de novo lipogenesis, beta-oxidation (fatty acid oxidation), cholesterol metabolism, and carbohydrate metabolism. Indeed, patients with hypothyroidism have abnormal lipid panels with higher levels of low-density lipoprotein levels, triglycerides (triacylglycerol; TAG), and apolipoprotein B levels. Even in euthyroid patients, lower serum-free thyroxine levels are associated with higher total cholesterol levels, LDL, and TAG levels. In addition to abnormal serum lipids, the risk of nonalcoholic fatty liver disease (NAFLD) increases with lower free thyroxine levels. As free thyroxine rises, the risk of NAFLD is reduced. This has led to numerous animal studies and clinical trials investigating TH analogs and TH receptor agonists as potential therapies for NAFLD and hyperlipidemia. Thus, TH plays an important role in maintaining hepatic homeostasis, and this continues to be an important area of study. A review of TH action and TH actions on the liver will be presented here.
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Affiliation(s)
- Megan J Ritter
- Division of Endocrinology, Weill Cornell Medicine, New York, NY
| | - Izuki Amano
- Division of Endocrinology, Weill Cornell Medicine, New York, NY.,Department of Integrative Physiology, Gunma University Graduate School of Medicine, Maebashi, Japan
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17
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Chua NK, Coates HW, Brown AJ. Squalene monooxygenase: a journey to the heart of cholesterol synthesis. Prog Lipid Res 2020; 79:101033. [DOI: 10.1016/j.plipres.2020.101033] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 04/21/2020] [Accepted: 04/24/2020] [Indexed: 02/07/2023]
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18
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Emerging Therapeutic Activity of Davallia formosana on Prostate Cancer Cells through Coordinated Blockade of Lipogenesis and Androgen Receptor Expression. Cancers (Basel) 2020; 12:cancers12040914. [PMID: 32276528 PMCID: PMC7226131 DOI: 10.3390/cancers12040914] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 03/27/2020] [Accepted: 04/02/2020] [Indexed: 11/17/2022] Open
Abstract
Background: Prostate cancer (PCa) is the most prevalent malignancy diagnosed in men in Western countries. There is currently no effective therapy for advanced PCa aggressiveness, including castration-resistant progression. The aim of this study is to evaluate the potential efficacy and determine the molecular basis of Davallia formosana (DF) in PCa. Methods: LNCaP (androgen-sensitive) and C4-2 (androgen-insensitive/castration-resistant) PCa cells were utilized in this study. An MTT-based method, a wound healing assay, and the transwell method were performed to evaluate cell proliferation, migration, and invasion. Intracellular fatty acid levels and lipid droplet accumulation were analyzed to determine lipogenesis. Moreover, apoptotic assays and in vivo experiments were conducted. Results: DF ethanol extract (DFE) suppressed proliferation, migration, and invasion in PCa cells. DFE attenuated lipogenesis through inhibition of the expression of sterol regulatory element-binding protein-1 (SREBP-1) and fatty acid synthase (FASN). Moreover, DFE decreased androgen receptor (AR) and prostate-specific antigen (PSA) expression in PCa cells. We further showed the potent therapeutic activity of DFE by repressing the growth and leading to apoptosis of subcutaneous C4-2 tumors in a xenograft mouse model. Conclusions: These data provide a new molecular basis of DFE in PCa cells, and co-targeting SREBP-1/FASN/lipogenesis and the AR axis by DFE could be employed as a novel and promising strategy for the treatment of PCa.
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19
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Shirouchi B, Yanagi S, Okawa C, Koga M, Sato M. 6-Ketocholestanol suppresses lipid accumulation by decreasing FASN gene expression through SREBP-dependent regulation in HepG2 cells. Cytotechnology 2020; 72:175-187. [PMID: 31933103 DOI: 10.1007/s10616-019-00368-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 12/30/2019] [Indexed: 12/20/2022] Open
Abstract
Nuclear receptors, such as liver X receptors (LXRs) and sterol regulatory element-binding proteins (SREBPs), are key regulators of lipogenic genes, including fatty acid synthase (FASN). It has been reported that several oxycholesterols (OCs) act as LXR ligands; however, it is unclear whether all OC molecular species act as ligands. We previously demonstrated that the absorption rate of dietary 6-ketocholestanol (6-keto), an oxycholesterol, is the highest of all the OCs using thoracic lymph duct-cannulated rats. However, limited information is available about the physiological significance of 6-keto. In this study, we investigated whether treatment with 6-keto increases intracellular triacylglycerol (TAG) levels through up-regulation of lipogenic gene expression in HepG2 cells. 6-Keto treatment significantly reduced intracellular TAG levels through down-regulation of lipogenic genes including FASN. Although 6-keto significantly suppressed FASN gene promoter activities, the action was completely diminished when mutations were present in the SREBP promoter site. TO901317 (TO) significantly increased FASN gene promoter activities, whereas simultaneous treatment with TO and 6-keto significantly reduced this activity. We also compared the effects of several OCs that are oxidized at the carbon-6 and -7 in the B-ring of cholesterol on FASN gene promoter activities. Similar to 6-keto, 6α-OH and 6β-OH significantly reduced the activity of the FASN gene promoter, which suggests that oxidation of carbon-6 in the B-ring may play an important role in the reduction of FASN expression. Our results indicate that 6-keto suppresses lipid accumulation by decreasing FASN gene expression through SREBP-dependent regulation in HepG2 cells.
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Affiliation(s)
- Bungo Shirouchi
- Laboratory of Nutrition Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Graduate School, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan
| | - Shuhei Yanagi
- Laboratory of Nutrition Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Graduate School, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan
| | - Chinami Okawa
- Laboratory of Nutrition Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Graduate School, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan
| | - Maiko Koga
- Laboratory of Nutrition Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Graduate School, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan
| | - Masao Sato
- Laboratory of Nutrition Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Graduate School, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan.
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20
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Zhang C, Zhang H, Zhang M, Lin C, Wang H, Yao J, Wei Q, Lu Y, Chen Z, Xing G, Cao X. OSBPL2 deficiency upregulate SQLE expression increasing intracellular cholesterol and cholesteryl ester by AMPK/SP1 and SREBF2 signalling pathway. Exp Cell Res 2019; 383:111512. [PMID: 31356817 DOI: 10.1016/j.yexcr.2019.111512] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 07/25/2019] [Accepted: 07/26/2019] [Indexed: 12/12/2022]
Abstract
Previous studies have shown that oxysterol binding protein like 2 (OSBPL2) knockdown is closely related to cholesterol metabolism. However, whether there is a direct relation between OSBPL2 and cholesterol synthesis is unknown. This study explored the mechanism of OSBPL2 deficiency in the upregulation of squalene epoxidase (SQLE) and the subsequent accumulation of intracellular cholesterol and cholesteryl ester. Here, we constructed an OSBPL2-deleted HeLa cell line using CRISPR/Cas9 technology, screened differentially expressed genes and examined the transcriptional regulation of SQLE using a dual-luciferase reporter gene. RNA-seq analysis showed that SQLE was upregulated significantly and the dual luciferase reporter gene assay revealed that two new functional transcription factor binding sites of Sp1 transcription factor (SP1) and sterol regulatory element-binding transcription factor 2 (SREBF2) in the SQLE promoter participated in the SQLE transcription and expression. In addition, we also observed that OSBPL2 deletion inhibited the AMPK signalling pathway and that the inhibition of AMPK signalling promoted SP1 and SREBF2 entry into the nuclear to upregulate SQLE expression. Therefore, these data support that OSBPL2 deficiency upregulates SQLE expression and increases the accumulation of cholesterol and cholesteryl ester by suppressing AMPK signalling, which provides new evidence of the connection between OSBPL2 and cholesterol synthesis.
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Affiliation(s)
- Cui Zhang
- Department of Medical Genetics, School of Basic Medical Science, Nanjing Medical University, Nanjing, China
| | - Hongdu Zhang
- Department of Medical Genetics, School of Basic Medical Science, Nanjing Medical University, Nanjing, China
| | - Min Zhang
- Department of Medical Genetics, School of Basic Medical Science, Nanjing Medical University, Nanjing, China
| | - Changsong Lin
- Department of Medical Genetics, School of Basic Medical Science, Nanjing Medical University, Nanjing, China
| | - Hongshun Wang
- Department of Medical Genetics, School of Basic Medical Science, Nanjing Medical University, Nanjing, China
| | - Jun Yao
- Department of Medical Genetics, School of Basic Medical Science, Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China
| | - Qinjun Wei
- Department of Medical Genetics, School of Basic Medical Science, Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China; The Laboratory Center for Basic Medical Sciences, Nanjing Medical University, Nanjing, China
| | - Yajie Lu
- Department of Medical Genetics, School of Basic Medical Science, Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China
| | - Zhibin Chen
- Department of Otolaryngology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Guangqian Xing
- Department of Otolaryngology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xin Cao
- Department of Medical Genetics, School of Basic Medical Science, Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China; The Laboratory Center for Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
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21
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A K, Uddandrao VVS, Parim B, Ganapathy S, P R N, Kancharla SC, P R, K S, Sasikumar V. Reversal of high fat diet-induced obesity through modulating lipid metabolic enzymes and inflammatory markers expressions in rats. Arch Physiol Biochem 2019; 125:228-234. [PMID: 29553847 DOI: 10.1080/13813455.2018.1452036] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
In this study, we evaluated the ameliorative potential of Cucurbita maxima seeds oil (CSO (100 mg/kg body weight)) supplementation to high fat diet (HFD)-induced obese rats for 30 days on the changes in body weight, markers of lipid metabolism such as LDL, HDL, triglycerides, total cholesterol, adiponectin, leptin, amylase, and lipase. We also investigated the effects of CSO on the changes of lipid metabolic enzymes such as fatty-acid synthase, acetyl CoA carboxylase, carnitine palmitoyl transferase-1, HMG CoA reductase, and inflammatory markers (TNF-α and IL-6). Administration of CSO revealed significant diminution in body weight gain, altered the activity, expressions of lipid marker enzymes and inflammatory markers. It demonstrated that CSO had considerably altered these parameters when evaluated with HFD control rats. In conclusion, this study suggested that CSO might ameliorate the HFD-induced obesity by altering the enzymes and mRNA expressions important to lipid metabolism.
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Affiliation(s)
- Kalaivani A
- a Department of Biochemistry , Centre for Biological Sciences, K. S. Rangasamy College of Arts and Science (Autonomous) , Tiruchengode , India
- b Department of Biochemistry , PGP College of Art and Science , Namakkal , India
| | - V V Sathibabu Uddandrao
- a Department of Biochemistry , Centre for Biological Sciences, K. S. Rangasamy College of Arts and Science (Autonomous) , Tiruchengode , India
| | - Brahmanaidu Parim
- c ICMR-National Animal Resource Facility for Biomedical Research (NARFBR) , Hyderabad , India
| | - Saravanan Ganapathy
- a Department of Biochemistry , Centre for Biological Sciences, K. S. Rangasamy College of Arts and Science (Autonomous) , Tiruchengode , India
| | - Nivedha P R
- a Department of Biochemistry , Centre for Biological Sciences, K. S. Rangasamy College of Arts and Science (Autonomous) , Tiruchengode , India
| | | | - Rameshreddy P
- a Department of Biochemistry , Centre for Biological Sciences, K. S. Rangasamy College of Arts and Science (Autonomous) , Tiruchengode , India
| | - Swapna K
- a Department of Biochemistry , Centre for Biological Sciences, K. S. Rangasamy College of Arts and Science (Autonomous) , Tiruchengode , India
| | - Vadivukkarasi Sasikumar
- a Department of Biochemistry , Centre for Biological Sciences, K. S. Rangasamy College of Arts and Science (Autonomous) , Tiruchengode , India
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22
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Rohrbach TD, Asgharpour A, Maczis MA, Montefusco D, Cowart LA, Bedossa P, Sanyal AJ, Spiegel S. FTY720/fingolimod decreases hepatic steatosis and expression of fatty acid synthase in diet-induced nonalcoholic fatty liver disease in mice. J Lipid Res 2019; 60:1311-1322. [PMID: 31110049 DOI: 10.1194/jlr.m093799] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 05/16/2019] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), a leading cause of liver dysfunction, is a metabolic disease that begins with steatosis. Sphingolipid metabolites, particularly ceramide and sphingosine-1-phosphate (S1P), have recently received attention for their potential roles in insulin resistance and hepatic steatosis. FTY720/fingolimod, a prodrug for the treatment of multiple sclerosis, is phosphorylated in vivo to its active phosphorylated form by sphingosine kinase 2 and has been shown to interfere with the actions of S1P and to inhibit ceramide biosynthesis. Therefore, in this study we investigated the effects of FTY720 in a diet-induced animal model of NAFLD (DIAMOND) that recapitulates the hallmarks of the human disease. The oral administration of FTY720 to these mice fed a high-fat diet and sugar water improved glucose tolerance and reduced steatosis. In addition to decreasing liver triglycerides, FTY720 also reduced hepatic sphingolipid levels, including ceramides, monohexosylceramides, and sphingomyelins, particularly the C16:0 and C24:1 species, as well as S1P and dihydro-S1P. FTY720 administration decreased diet-induced fatty acid synthase (FASN) expression in DIAMOND mice without affecting other key enzymes in lipogenesis. FTY720 had no effect on the expression of SREBP-1c, which transcriptionally activates FASN. However, in agreement with the notion that the active phosphorylated form of FTY720 is an inhibitor of histone deacetylases, FTY720-P accumulated in the liver, and histone H3K9 acetylation was markedly increased in these mice. Hence, FTY720 might be useful for attenuating FASN expression and triglyceride accumulation associated with steatosis.
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Affiliation(s)
- Timothy D Rohrbach
- Department of Biochemistry and Molecular Biology Virginia Commonwealth University School of Medicine, Richmond, VA
| | - Amon Asgharpour
- Division of Gastroenterology, Hepatology, and Nutrition Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA
| | - Melissa A Maczis
- Department of Biochemistry and Molecular Biology Virginia Commonwealth University School of Medicine, Richmond, VA
| | - David Montefusco
- Department of Biochemistry and Molecular Biology Virginia Commonwealth University School of Medicine, Richmond, VA
| | - L Ashley Cowart
- Department of Biochemistry and Molecular Biology Virginia Commonwealth University School of Medicine, Richmond, VA.,Hunter Holmes McGuire Veterans Administration Medical Center, Richmond, VA
| | - Pierre Bedossa
- Division of Gastroenterology, Hepatology, and Nutrition Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA
| | - Arun J Sanyal
- Division of Gastroenterology, Hepatology, and Nutrition Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA
| | - Sarah Spiegel
- Department of Biochemistry and Molecular Biology Virginia Commonwealth University School of Medicine, Richmond, VA
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Molecular characterization and tissue distribution of SREBP-1 and PPARα in Onychostoma macrolepis and their mRNA expressions in response to thermal exposure. Comp Biochem Physiol A Mol Integr Physiol 2019; 230:16-27. [DOI: 10.1016/j.cbpa.2018.12.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 12/16/2018] [Accepted: 12/17/2018] [Indexed: 01/06/2023]
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Gnoni A, Siculella L, Paglialonga G, Damiano F, Giudetti AM. 3,5-diiodo-L-thyronine increases de novo lipogenesis in liver from hypothyroid rats by SREBP-1 and ChREBP-mediated transcriptional mechanisms. IUBMB Life 2019; 71:863-872. [PMID: 30707786 DOI: 10.1002/iub.2014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 12/21/2018] [Accepted: 01/04/2019] [Indexed: 12/12/2022]
Abstract
Hepatic de novo lipogenesis (DNL), the process by which carbohydrates are converted into lipids, is strictly controlled by nutritional and hormonal status. 3,5-Diiodo-L-thyronine (T2), a product of the 3,5,3'-triiodo-L-thyronine (T3) peripheral metabolism, has been shown to mimic some T3 effects on lipid metabolism by a short-term mechanism independent of protein synthesis. Here, we report that T2, administered for 1 week to hypothyroid rats, increases total fatty acid synthesis from acetate in isolated hepatocytes. Studies carried out on liver subcellular fractions demonstrated that T2 not only increases the activity and the expression of acetyl-CoA carboxylase and fatty acid synthase but also of other proteins linked to DNL such as the mitochondrial citrate carrier and the cytosolic ATP citrate lyase. Parallelly, T2 stimulates the activities of enzymes supplying cytosolic NADPH needed for the reductive steps of DNL. With respect to both euthyroid and hypothyroid rats, T2 administration decreases the hepatic mRNA level of SREBP-1, a transcription factor which represents a master regulator of DNL. However, when compared to hypothyroid rats T2 significantly increases, without bringing to the euthyroid value, the content of both mature (nSREBP-1), and precursor (pSREBP-1) forms of the SREBP-1 protein as well as their ratio. Moreover, T2 administration strongly augmented the nuclear content of ChREBP, another crucial transcription factor involved in the regulation of lipogenic genes. Based on these results, we can conclude that in the liver of hypothyroid rats the transcriptional activation by T2 of DNL genes could depend, at least in part, on SREBP-1- and ChREBP-dependent mechanisms. © 2019 IUBMB Life, 2019.
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Affiliation(s)
- Antonio Gnoni
- Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", 70124, Bari, Italy
| | - Luisa Siculella
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100, Lecce, Italy
| | - Giuseppina Paglialonga
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100, Lecce, Italy
| | - Fabrizio Damiano
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100, Lecce, Italy
| | - Anna Maria Giudetti
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100, Lecce, Italy
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Yang L, Zhao Y, Pan Y, Li D, Zheng G. Dietary supplement of Smilax china L. ethanol extract alleviates the lipid accumulation by activating AMPK pathways in high-fat diet fed mice. Nutr Metab (Lond) 2019; 16:6. [PMID: 30679938 PMCID: PMC6341655 DOI: 10.1186/s12986-019-0333-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Accepted: 01/07/2019] [Indexed: 01/21/2023] Open
Abstract
Background Obesity has become a public health concern worldwide because it is linked to numerous metabolic disorders, such as hyperlipidemia, hypertension and cardiovascular disease. Therefore, there is an urgent need to develop new therapeutic strategies that are efficacious and have minimal side effects in obesity treatment. This study examined the effect of dietary supplement of Smilax china L. ethanol extract (SCLE) on high-fat diet (HFD) induced obesity. Methods Fifty ICR mice were fed a normal diet, high-fat diet (HFD) or HFD supplemented with 0.25, 0.5% or 1% SCLE for 8 weeks. Body weight, intraperitioneal adipose tissue (IPAT) weight, serum biochemical parameters, and liver lipids were measured. Activity, mRNA and protein expressions of lipid metabolism-related enzymes were analyzed. Results Over 0.5% SCLE had reduced cholesterol biosynthesis by the activation of AMP-activated protein kinase (AMPK), which subsequently suppressed the mRNA expression of both sterol regulatory element binding protein-2 and 3-hydroxy-3-methyl-glutaryl-CoA reductase. Thus, the plasma and liver cholesterol concentrations in the HFD-fed mice were decreased. AMPK activation caused by SCLE also significantly upregulated lipolysis by enhancing adipose triglyceride lipase and hormone-sensitive lipase activities. This accelerated triglyceride hydrolysis and fatty acid release. Finally, SCLE increased carnitine palmitoyltransferase 1 and acyl-CoA oxidase activities, which further promoted fatty acid β-oxidation. Conclusion SCLE could lead to a decrease in body weight gain and fat mass by inhibiting the lipid synthesis and promoting lipolysis and β-oxidation in HFD fed mice. The underlying mechanism is probably associated with regulating AMPK pathway.
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Affiliation(s)
- Licong Yang
- Jiangxi Key Laboratory of Natural Product and Functional Food, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang, 330045 China
| | - Yan Zhao
- Jiangxi Key Laboratory of Natural Product and Functional Food, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang, 330045 China
| | - Yongfang Pan
- Jiangxi Key Laboratory of Natural Product and Functional Food, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang, 330045 China
| | - Dongming Li
- Jiangxi Key Laboratory of Natural Product and Functional Food, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang, 330045 China
| | - Guodong Zheng
- Jiangxi Key Laboratory of Natural Product and Functional Food, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang, 330045 China
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26
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Jun S, Datta S, Wang L, Pegany R, Cano M, Handa JT. The impact of lipids, lipid oxidation, and inflammation on AMD, and the potential role of miRNAs on lipid metabolism in the RPE. Exp Eye Res 2018; 181:346-355. [PMID: 30292489 DOI: 10.1016/j.exer.2018.09.023] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 08/31/2018] [Accepted: 09/30/2018] [Indexed: 12/17/2022]
Abstract
The accumulation of lipids within drusen, the epidemiologic link of a high fat diet, and the identification of polymorphisms in genes involved in lipid metabolism that are associated with disease risk, have prompted interest in the role of lipid abnormalities in AMD. Despite intensive investigation, our understanding of how lipid abnormalities contribute to AMD development remains unclear. Lipid metabolism is tightly regulated, and its dysregulation can trigger excess lipid accumulation within the RPE and Bruch's membrane. The high oxidative stress environment of the macula can promote lipid oxidation, impairing their original function as well as producing oxidation-specific epitopes (OSE), which unless neutralized, can induce unwanted inflammation that additionally contributes to AMD progression. Considering the multiple layers of lipid metabolism and inflammation, and the ability to simultaneously target multiple pathways, microRNA (miRNAs) have emerged as important regulators of many age-related diseases including atherosclerosis and Alzheimer's disease. These diseases have similar etiologic characteristics such as lipid-rich deposits, oxidative stress, and inflammation with AMD, which suggests that miRNAs might influence lipid metabolism in AMD. In this review, we discuss the contribution of lipids to AMD pathobiology and introduce how miRNAs might affect lipid metabolism during lesion development. Establishing how miRNAs contribute to lipid accumulation in AMD will help to define the role of lipids in AMD, and open new treatment avenues for this enigmatic disease.
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Affiliation(s)
- Sujung Jun
- Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD, 21287, United States
| | - Sayantan Datta
- Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD, 21287, United States
| | - Lei Wang
- Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD, 21287, United States
| | - Roma Pegany
- Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD, 21287, United States
| | - Marisol Cano
- Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD, 21287, United States
| | - James T Handa
- Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD, 21287, United States.
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27
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Chen A, Chen X, Cheng S, Shu L, Yan M, Yao L, Wang B, Huang S, Zhou L, Yang Z, Liu G. FTO promotes SREBP1c maturation and enhances CIDEC transcription during lipid accumulation in HepG2 cells. Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1863:538-548. [PMID: 29486327 DOI: 10.1016/j.bbalip.2018.02.003] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Revised: 02/06/2018] [Accepted: 02/17/2018] [Indexed: 10/17/2022]
Abstract
The fat mass and obesity-associated (FTO) gene is tightly related to body weight and fat mass, and plays a pivotal role in regulating lipid accumulation in hepatocytes. However, the mechanisms underlying its function are poorly understood. Sterol regulatory element binding protein-1c (SREBP1c) is a transcription factor that regulates lipogenesis. Cell death-inducing DFFA (DNA fragmentation factor-α)-like effector c (CIDEC) plays a crucial role in lipid droplets (LDs) size controlling and lipid accumulation. In this report, we first observed that FTO overexpression in HepG2 cells resulted in an increase of lipogenesis and up-regulation of SREBP1c and CIDEC, two key regulatory factors in lipogenesis. In contrast, FTO knockdown in HepG2 cells resulted in a decrease of lipogenesis and down-regulation of SREBP1c and CIDEC expression. Moreover, SREBP1c knockdown resulted in a decrease of lipogenesis in HepG2 cells with FTO overexpression. In addition, FTO demethylation defect mutant presented less transcription of the key genes, and less nuclear translocation and maturation of SREBP1c. Further investigation demonstrated that overexpression of SREBP1c in HepG2 cells also promoted high CIDEC expression. Luciferase reporter assays showed that SREBP1c significantly stimulated CIDEC gene promoter activity. Finally, CIDEC knockdown reduced SREBP1c-induced lipogenesis. In conclusion, our studies suggest that FTO increased the lipid accumulation in hepatocytes by increasing nuclear translocation of SREBP1c and SREBP1c maturation, thus improving the transcriptional activity of LD-associated protein CIDEC. Our studies may provide new mechanistic insight into nonalcoholic fatty liver disease (NAFLD) mediated by FTO.
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Affiliation(s)
- Ao Chen
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei Province, PR China
| | - Xiaodong Chen
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, Hubei Province, PR China
| | - Shiqiang Cheng
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei Province, PR China
| | - Le Shu
- Laboratory for Marine Biology and Biotechnology of Qingdao National Laboratory for Marine Science and Technology, College of Life Sciences, Zhejiang University, Hangzhou 310058, Zhejiang Province, PR China
| | - Meiping Yan
- Key Laboratory of Epigenetics and Oncology, the Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Lun Yao
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei Province, PR China
| | - Binyu Wang
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei Province, PR China
| | - Shuguang Huang
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei Province, PR China
| | - Lei Zhou
- State Key Laboratory for Conservation and Utilization of Subtropical Agrobioresources, College of Animal Science and Technology, Guangxi University, Nanning 530000, PR China
| | - Zaiqing Yang
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, Hubei Province, PR China
| | - Guoquan Liu
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei Province, PR China.
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Glehnia littoralis Root Extract Inhibits Fat Accumulation in 3T3-L1 Cells and High-Fat Diet-Induced Obese Mice by Downregulating Adipogenic Gene Expression. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 2018:1243049. [PMID: 29849691 PMCID: PMC5932452 DOI: 10.1155/2018/1243049] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 03/04/2018] [Indexed: 11/17/2022]
Abstract
Glehnia littoralis has been reported to have several pharmacological properties but no reports describing the antiadipogenic effect of this plant have been published. This study was conducted to investigate the effects of Glehnia littoralis root hot water extract (GLE) and its underlying mechanism on 3T3-L1 cell adipogenesis and in high-fat diet- (HFD-) induced obese mice. We measured intracellular lipid accumulation using oil red O staining in vitro. For in vivo study, twenty-eight C57BL/6J male mice were randomly divided into four groups, Control, HFD, HFD + 1% GLE, and HFD + 5% GLE, which was performed for eight weeks. We determined the expression levels of the adipogenesis-related proteins by RT-PCR and western blotting in HFD-induced obese mice. The GLE dose-dependently inhibited 3T3-L1 adipocyte differentiation and intracellular lipid accumulation in differentiated adipocytes. Further, body weight gain and fat accumulation were significantly lower in the GLE-treated HFD mice than in the untreated HFD mice. GLE treatment suppressed the expression of adipogenic genes such as peroxisome proliferator-activated receptor (PPAR) γ, CCAAT/enhancer-binding protein (C/EBP) α, fatty acid synthase (aP2), and fatty acid synthase (FAS). These results suggest that the GLE inhibits adipocyte differentiation and intracellular lipid accumulation by downregulating the adipogenic gene expression both in vitro and in vivo.
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Tay SS, Kuah MK, Shu-Chien AC. Transcriptional activation of zebrafish fads2 promoter and its transient transgene expression in yolk syncytial layer of zebrafish embryos. Sci Rep 2018; 8:3874. [PMID: 29497119 PMCID: PMC5832746 DOI: 10.1038/s41598-018-22157-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 02/16/2018] [Indexed: 12/12/2022] Open
Abstract
The front-end desaturases (Fads) are rate-limiting enzymes responsible for production of long-chain polyunsaturated fatty acids (LC-PUFA). The full spectrum of the transcriptional regulation of fads is still incomplete, as cloning of fads promoter is limited to a few species. Here, we described the cloning and characterisation of the zebrafish fads2 promoter. Using 5'-deletion and mutation analysis on this promoter, we identified a specific region containing the sterol regulatory element (SRE) which is responsible for the activation of the fads2 promoter. In tandem, two conserved CCAAT boxes were also present adjacent to the SRE and mutation of either of these binding sites attenuates the transcriptional activation of the fads2 promoter. An in vivo analysis employing GFP reporter gene in transiently transfected zebrafish embryos showed that this 1754 bp upstream region of the fads2 gene specifically directs GFP expression in the yolk syncytial layer (YSL) region. This indicates a role for LC-PUFA in the transport of yolk lipids through this tissue layer. In conclusion, besides identifying novel core elements for transcriptional activation in zebrafish fads2 promoter, we also reveal a potential role for fads2 or LC-PUFA in YSL during development.
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Affiliation(s)
- Shu-Shen Tay
- School of Biological Sciences, Universiti Sains Malaysia, 11800, Minden, Penang, Malaysia
| | - Meng-Kiat Kuah
- Centre for Chemical Biology, Universiti Sains Malaysia, Sains@USM, Block B No. 10, Persiaran Bukit Jambul, 11900, Bayan Lepas, Penang, Malaysia
| | - Alexander Chong Shu-Chien
- School of Biological Sciences, Universiti Sains Malaysia, 11800, Minden, Penang, Malaysia. .,Centre for Chemical Biology, Universiti Sains Malaysia, Sains@USM, Block B No. 10, Persiaran Bukit Jambul, 11900, Bayan Lepas, Penang, Malaysia.
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Meriga B, Parim B, Chunduri VR, Naik RR, Nemani H, Suresh P, Ganapathy S, VVU SB. Antiobesity potential of Piperonal: promising modulation of body composition, lipid profiles and obesogenic marker expression in HFD-induced obese rats. Nutr Metab (Lond) 2017; 14:72. [PMID: 29176994 PMCID: PMC5693419 DOI: 10.1186/s12986-017-0228-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 11/06/2017] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Black pepper or Piper nigrum is a well-known spice, rich in a variety of bioactive compounds, and widely used in many cuisines across the world. In the Indian traditional systems of medicine, it is used to treat gastric and respiratory ailments. The purpose of this investigation is to study the antihyperlipidemic and antiobesity effects of piperonal in high-fat diet (HFD)-induced obese rats. METHODS Piperonal, an active constituent of Piper nigrum seeds, was isolated and confirmed by HPLC, 1H and 13C NMR spectroscopy. Male SD rats were fed on HFD for 22 weeks; Piperonal was supplemented from the 16th week as mentioned in the experimental design. Changes in body weight and body composition were measured by TOBEC, bone mineral composition and density were measured by DXA, and adipose tissue distribution was measured by 7 T-MRI. Plasma levels of glucose, insulin, insulin resistance and lipid profiles of plasma, liver and kidney, adipocyte hormones and liver antioxidants were evaluated using standard kit methods. Expression levels of adipogenic and lipogenic genes, such as PPAR-γ, FAS, Fab-4, UCP-2, SREBP-1c, ACC, HMG-COA and TNF-α were measured by RT-PCR. Histopathological examination of adipose and liver tissues was also carried out in experimental rats. RESULTS HFD substantially induced body weight, fat%, adipocyte size, circulatory and tissue lipid profiles. It elevated the plasma levels of insulin, insulin resistance and leptin but decreased the levels of adiponectin, BMC and BMD. Increased expression of PPAR-γ, FAS, Fab-4, UCP-2, SREBP-1c, ACC, and TNF-α was noticed in HFD-fed rats. However, supplementation of piperonal (20, 30 and 40 mg/kg b.wt) for 42 days considerably and dose-dependently attenuated the HFD-induced alterations, with the maximum therapeutic activity being noticed at 40 mg/kg b.wt. CONCLUSIONS Piperonal significantly attenuated HFD-induced body weight and biochemical changes through modulation of key lipid metabolizing and obesogenic genes. Our findings demonstrate the efficacy of piperonal as a potent antiobesity agent, provide scientific evidence for its traditional use and suggest the possible mechanism of action.
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Affiliation(s)
- Balaji Meriga
- Animal Physiology and Biochemistry Laboratory, Department of Biochemistry, Sri Venkateswara University, Tirupati, Andhra Pradesh -517502 India
| | - Brahmanaidu Parim
- Animal Physiology and Biochemistry Laboratory, Department of Biochemistry, Sri Venkateswara University, Tirupati, Andhra Pradesh -517502 India
- Present Address: Department of Bio-Technology, VSU College of Sciences, Vikrama Simhapuri University, Nellore, Andhra Pradesh -524320 India
| | - Venkata Rao Chunduri
- Department of Chemistry, Sri Venkateswara University, Tirupati, Andhra Pradesh -517502 India
| | - Ramavat Ravindar Naik
- National Center for Laboratory Animal Sciences, National Institute of Nutrition (Indian Council of Medical Research), Hyderabad, India
| | - Harishankar Nemani
- National Center for Laboratory Animal Sciences, National Institute of Nutrition (Indian Council of Medical Research), Hyderabad, India
| | - Pothani Suresh
- National Center for Laboratory Animal Sciences, National Institute of Nutrition (Indian Council of Medical Research), Hyderabad, India
| | - Saravanan Ganapathy
- Department of Biochemistry, Center for Biological Sciences, K. S. Rangasamy College of Arts Science, Tiruchengode, Tamil Nadu India
| | - Satthi Babu VVU
- Department of Biochemistry, Center for Biological Sciences, K. S. Rangasamy College of Arts Science, Tiruchengode, Tamil Nadu India
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Kim YS, Kim M, Choi MY, Lee DH, Roh GS, Kim HJ, Kang SS, Cho GJ, Park KH, Kim SJ, Yoo JM, Choi WS. Aralia elata (Miq) Seem Extract Decreases O-GlcNAc Transferase Expression and Retinal Cell Death in Diabetic Mice. J Med Food 2017; 20:989-1001. [DOI: 10.1089/jmf.2016.3891] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Affiliation(s)
- Yoon Sook Kim
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, South Korea
| | - Minjun Kim
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, South Korea
| | - Mee Young Choi
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, South Korea
| | - Dong Hoon Lee
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, South Korea
| | - Gu Seob Roh
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, South Korea
| | - Hyun Joon Kim
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, South Korea
| | - Sang Soo Kang
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, South Korea
| | - Gyeong Jae Cho
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, South Korea
| | - Ki Hun Park
- Division of Applied Life Science, Institute of Agriculture Life Science, Graduate School of Gyeongsang National University, Jinju, South Korea
| | - Seong-Jae Kim
- Department of Ophthalmology, Gyeongsang National University School of Medicine, Jinju, South Korea
| | - Ji-Myong Yoo
- Department of Ophthalmology, Gyeongsang National University School of Medicine, Jinju, South Korea
| | - Wan Sung Choi
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, South Korea
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Costa R, Rodrigues I, Guardão L, Rocha-Rodrigues S, Silva C, Magalhães J, Ferreira-de-Almeida M, Negrão R, Soares R. Xanthohumol and 8-prenylnaringenin ameliorate diabetic-related metabolic dysfunctions in mice. J Nutr Biochem 2017; 45:39-47. [DOI: 10.1016/j.jnutbio.2017.03.006] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Revised: 01/31/2017] [Accepted: 03/16/2017] [Indexed: 01/12/2023]
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Fatty acid synthase reprograms the epigenome in uterine leiomyosarcomas. PLoS One 2017; 12:e0179692. [PMID: 28654693 PMCID: PMC5487038 DOI: 10.1371/journal.pone.0179692] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 06/03/2017] [Indexed: 11/19/2022] Open
Abstract
SK-UT-1 uterine leiomyosarcomas (Ut-LMS) cells were transduced with a fatty acid synthase (FASN)-containing retroviral vector to recapitulate the "lipogenic phenotype of cancer." Consistent with this model, forced expression of FASN enhanced SK-UT-1 proliferation, migration, and cellular motion. Further investigation showed FASN promotes trimethylation of H3K9 (H3K9me3) and acetylation of H3K27 (H3K27ac) in SK-UT-1 cells. In contrast, siRNA targeting of FASN in high endogenous FASN expressing SK-LMS-1 Ut-LMS cells inhibits trimethylation of H3K9 and acetylation of H3K27. Palmitate, the predominant fatty acid product of FASN, increased H3K9me3, H3K27ac and H3K27me3 detection in SK-UT-1 cells. FASN promoted histone 3 methylation and acetylation through alteration of histone 3-modifying enzymatic activities (HDAC, HDM, HMT and HAT). ChIP-seq in SK-UT-1-FASN cells with anti-H3K9me3 antibody identified regions of enriched binding compared to vector-only cells. One differentially-enriched gene, CRISP1, was investigated further by ChIP-PCR. The transcriptionally repressive function of H3K9me3 was confirmed in CRISP1. Our results provide mechanistic insight into the pathobiology of the "lipogenic phenotype of cancer." Here, FASN reprograms the Ut-LMS epigenome through chromatin remodeling to promote the "malignant phenotype."
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Damiano F, Rochira A, Gnoni A, Siculella L. Action of Thyroid Hormones, T3 and T2, on Hepatic Fatty Acids: Differences in Metabolic Effects and Molecular Mechanisms. Int J Mol Sci 2017; 18:ijms18040744. [PMID: 28362337 PMCID: PMC5412329 DOI: 10.3390/ijms18040744] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2017] [Revised: 03/22/2017] [Accepted: 03/27/2017] [Indexed: 12/28/2022] Open
Abstract
The thyroid hormones (THs) 3,3′,5,5′-tetraiodo-l-thyronine (T4) and 3,5,3′-triiodo-l-thyronine (T3) influence many metabolic pathways. The major physiological function of THs is to sustain basal energy expenditure, by acting primarily on carbohydrate and lipid catabolism. Beyond the mobilization and degradation of lipids, at the hepatic level THs stimulate the de novo fatty acid synthesis (de novo lipogenesis, DNL), through both the modulation of gene expression and the rapid activation of cell signalling pathways. 3,5-Diiodo-l-thyronine (T2), previously considered only a T3 catabolite, has been shown to mimic some of T3 effects on lipid catabolism. However, T2 action is more rapid than that of T3, and seems to be independent of protein synthesis. An inhibitory effect on DNL has been documented for T2. Here, we give an overview of the mechanisms of THs action on liver fatty acid metabolism, focusing on the different effects exerted by T2 and T3 on the regulation of the DNL. The inhibitory action on DNL exerted by T2 makes this compound a potential and attractive drug for the treatment of some metabolic diseases and cancer.
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Affiliation(s)
- Fabrizio Damiano
- Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy.
| | - Alessio Rochira
- Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy.
| | - Antonio Gnoni
- Department of Basic Medical Sciences, Section of Medical Biochemistry, University of Bari Aldo Moro, 70125 Bari, Italy.
| | - Luisa Siculella
- Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy.
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Kang M, Kim J, An HT, Ko J. Human leucine zipper protein promotes hepatic steatosis via induction of apolipoprotein A-IV. FASEB J 2017; 31:2548-2561. [PMID: 28246167 DOI: 10.1096/fj.201601227r] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 02/07/2017] [Indexed: 12/13/2022]
Abstract
The molecular mechanism of stress-induced hepatic steatosis is not well known. Human leucine zipper protein (LZIP) regulates the expression of genes involved in inflammation, cell migration, and stress response. The aim of this study was to determine the regulatory role of LZIP in stress-induced hepatic steatosis. We used a microarray analysis to identify LZIP-induced genes involved in hepatic lipid metabolism. LZIP increased the expression of apolipoprotein A-IV (APOA4) mRNA. In the presence of stress inducer, APOA4 promoter analysis was performed, and LZIP-induced lipid accumulation was monitored in mouse primary cells and human tissues. Under Golgi stress conditions, LZIP underwent proteolytic cleavage and was phosphorylated by AKT to protect against proteasome degradation. The stabilized N-terminal LZIP was translocated to the nucleus, where it directly bound to the APOA4 promoter, leading to APOA4 induction. LZIP-induced APOA4 expression resulted in increased absorption of surrounding free fatty acids. LZIP also promoted hepatic steatosis in mouse liver. Both LZIP and APOA4 were highly expressed in human steatosis samples. Our findings indicate that LZIP is a novel modulator of APOA4 expression and hepatic lipid metabolism. LZIP might be a therapeutic target for developing treatment strategies for hepatic steatosis and related metabolic diseases.-Kang, M., Kim, J., An, H.-T., Ko, J. Human leucine zipper protein promotes hepatic steatosis via induction of apolipoprotein A-IV.
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Affiliation(s)
| | | | | | - Jesang Ko
- Division of Life Sciences, Korea University, Seoul, South Korea
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Burr R, Stewart EV, Espenshade PJ. Coordinate Regulation of Yeast Sterol Regulatory Element-binding Protein (SREBP) and Mga2 Transcription Factors. J Biol Chem 2017; 292:5311-5324. [PMID: 28202541 DOI: 10.1074/jbc.m117.778209] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Indexed: 11/06/2022] Open
Abstract
The Mga2 and Sre1 transcription factors regulate oxygen-responsive lipid homeostasis in the fission yeast Schizosaccharomyces pombe in a manner analogous to the mammalian sterol regulatory element-binding protein (SREBP)-1 and SREBP-2 transcription factors. Mga2 and SREBP-1 regulate triacylglycerol and glycerophospholipid synthesis, whereas Sre1 and SREBP-2 regulate sterol synthesis. In mammals, a shared activation mechanism allows for coordinate regulation of SREBP-1 and SREBP-2. In contrast, distinct pathways activate fission yeast Mga2 and Sre1. Therefore, it is unclear whether and how these two related pathways are coordinated to maintain lipid balance in fission yeast. Previously, we showed that Sre1 cleavage is defective in the absence of mga2 Here, we report that this defect is due to deficient unsaturated fatty acid synthesis, resulting in aberrant membrane transport. This defect is recapitulated by treatment with the fatty acid synthase inhibitor cerulenin and is rescued by addition of exogenous unsaturated fatty acids. Furthermore, sterol synthesis inhibition blocks Mga2 pathway activation. Together, these data demonstrate that Sre1 and Mga2 are each regulated by the lipid product of the other transcription factor pathway, providing a source of coordination for these two branches of lipid synthesis.
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Affiliation(s)
- Risa Burr
- From the Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Emerson V Stewart
- From the Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Peter J Espenshade
- From the Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
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Mukherjee A, Ma Y, Yuan F, Gong Y, Fang Z, Mohamed EM, Berrios E, Shao H, Fang X. Lysophosphatidic Acid Up-Regulates Hexokinase II and Glycolysis to Promote Proliferation of Ovarian Cancer Cells. Neoplasia 2016; 17:723-734. [PMID: 26476080 PMCID: PMC4611075 DOI: 10.1016/j.neo.2015.09.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Revised: 09/04/2015] [Accepted: 09/15/2015] [Indexed: 02/04/2023] Open
Abstract
Lysophosphatidic acid (LPA), a blood-borne lipid mediator, is present in elevated concentrations in ascites of ovarian cancer patients and other malignant effusions. LPA is a potent mitogen in cancer cells. The mechanism linking LPA signal to cancer cell proliferation is not well understood. Little is known about whether LPA affects glucose metabolism to accommodate rapid proliferation of cancer cells. Here we describe that in ovarian cancer cells, LPA enhances glycolytic rate and lactate efflux. A real time PCR-based miniarray showed that hexokinase II (HK2) was the most dramatically induced glycolytic gene to promote glycolysis in LPA-treated cells. Analysis of the human HK2 gene promoter identified the sterol regulatory element-binding protein as the primary mediator of LPA-induced HK2 transcription. The effects of LPA on HK2 and glycolysis rely on LPA2, an LPA receptor subtype overexpressed in ovarian cancer and many other malignancies. We further examined the general role of growth factor-induced glycolysis in cell proliferation. Like LPA, epidermal growth factor (EGF) elicited robust glycolytic and proliferative responses in ovarian cancer cells. Insulin-like growth factor 1 (IGF-1) and insulin, however, potently stimulated cell proliferation but only modestly induced glycolysis. Consistent with their differential effects on glycolysis, LPA and EGF-dependent cell proliferation was highly sensitive to glycolytic inhibition while the growth-promoting effect of IGF-1 or insulin was more resistant. These results indicate that LPA- and EGF-induced cell proliferation selectively involves up-regulation of HK2 and glycolytic metabolism. The work is the first to implicate LPA signaling in promotion of glucose metabolism in cancer cells.
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Affiliation(s)
- Abir Mukherjee
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298
| | - Yibao Ma
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298
| | - Fang Yuan
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298
| | - Yongling Gong
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298
| | - Zhenyu Fang
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298
| | - Esraa M Mohamed
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298
| | - Erika Berrios
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298
| | - Huanjie Shao
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298
| | - Xianjun Fang
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298.
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Lipid droplet-associated proteins in atherosclerosis (Review). Mol Med Rep 2016; 13:4527-34. [PMID: 27082419 PMCID: PMC4878557 DOI: 10.3892/mmr.2016.5099] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Accepted: 01/29/2016] [Indexed: 01/01/2023] Open
Abstract
Accumulation of atherosclerotic plaques in arterial walls leads to major cardiovascular diseases and stroke. Macrophages/foam cells are central components of atherosclerotic plaques, which populate the arterial wall in order to remove harmful modified low‑density lipoprotein (LDL) particles, resulting in the accumulation of lipids, mostly LDL‑derived cholesterol ester, in cytosolic lipid droplets (LDs). At present, LDs are recognized as dynamic organelles that govern cellular metabolic processes. LDs consist of an inner core of neutral lipids surrounded by a monolayer of phospholipids and free cholesterol, and contain LD‑associated proteins (LDAPs) that regulate LD functions. Foam cells are characterized by an aberrant accumulation of cytosolic LDs, and are considered a hallmark of atherosclerotic lesions through all stages of development. Previous studies have investigated the mechanisms underlying foam cell formation, aiming to discover therapeutic strategies that target foam cells and intervene against atherosclerosis. It is well established that LDAPs have a major role in the pathogenesis of metabolic diseases caused by dysfunction of lipid metabolism, and several studies have linked LDAPs to the development of atherosclerosis. In this review, several foam cell‑targeting pathways have been described, with an emphasis on the role of LDAPs in cholesterol mobilization from macrophages. In addition, the potential of LDAPs as therapeutic targets to prevent the progression and/or facilitate the regression of the disease has been discussed.
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39
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MicroRNA-132 cause apoptosis of glioma cells through blockade of the SREBP-1c metabolic pathway related to SIRT1. Biomed Pharmacother 2016; 78:177-184. [DOI: 10.1016/j.biopha.2016.01.022] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Revised: 12/24/2015] [Accepted: 01/13/2016] [Indexed: 12/19/2022] Open
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Huo J, Ma Y, Liu JJ, Ho YS, Liu S, Soh LY, Chen S, Xu S, Han W, Hong A, Lim SC, Lam KP. Loss of Fas apoptosis inhibitory molecule leads to spontaneous obesity and hepatosteatosis. Cell Death Dis 2016; 7:e2091. [PMID: 26866272 PMCID: PMC4849152 DOI: 10.1038/cddis.2016.12] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Revised: 11/20/2015] [Accepted: 01/08/2016] [Indexed: 12/26/2022]
Abstract
Altered hepatic lipogenesis is associated with metabolic diseases such as obesity and hepatosteatosis. Insulin resistance and compensatory hyperinsulinaemia are key drivers of these metabolic imbalances. Fas apoptosis inhibitory molecule (FAIM), a ubiquitously expressed antiapoptotic protein, functions as a mediator of Akt signalling. Since Akt acts at a nodal point in insulin signalling, we hypothesize that FAIM may be involved in energy metabolism. In the current study, C57BL/6 wild-type (WT) and FAIM-knockout (FAIM-KO) male mice were fed with normal chow diet and body weight changes were monitored. Energy expenditure, substrate utilization and physical activities were analysed using a metabolic cage. Liver, pancreas and adipose tissue were subjected to histological examination. Serum glucose and insulin levels and lipid profiles were determined by biochemical assays. Changes in components of the insulin signalling pathway in FAIM-KO mice were examined by immunoblots. We found that FAIM-KO mice developed spontaneous non-hyperphagic obesity accompanied by hepatosteatosis, adipocyte hypertrophy, dyslipidaemia, hyperglycaemia and hyperinsulinaemia. In FAIM-KO liver, lipogenesis was elevated as indicated by increased fatty acid synthesis and SREBP-1 and SREBP-2 activation. Notably, protein expression of insulin receptor beta was markedly reduced in insulin target organs of FAIM-KO mice. Akt phosphorylation was also lower in FAIM-KO liver and adipose tissue as compared with WT controls. In addition, phosphorylation of insulin receptor substrate-1 and Akt2 in response to insulin treatment in isolated FAIM-KO hepatocytes was also markedly attenuated. Altogether, our data indicate that FAIM is a novel regulator of insulin signalling and plays an essential role in energy homoeostasis. These findings may shed light on the pathogenesis of obesity and hepatosteatosis.
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Affiliation(s)
- J Huo
- Immunology Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research, 20 Biopolis Way, #06-01 Centros, Singapore 138668, Singapore
| | - Y Ma
- Institute of Biomedicine, Ji Nan University, 601 HUANG PO DA DAO XI, Guang Zhou 510632, P.R. China
| | - J-J Liu
- Clinical Research Unit, Khoo Teck Puat Hospital, ALEXANDRA HEALTH PTE LTD, 90 Yishun Central, Singapore 768828, Singapore
| | - Y S Ho
- Metabolomics Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research, 20 Biopolis Way, #02-01 Centros, Singapore 138668, Singapore
| | - S Liu
- Clinical Research Unit, Khoo Teck Puat Hospital, ALEXANDRA HEALTH PTE LTD, 90 Yishun Central, Singapore 768828, Singapore
| | - L Y Soh
- Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, Biomedical Sciences Institutes, 11 Biopolis Way, Helios, Singapore 138667, Singapore
| | - S Chen
- Metabolomics Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research, 20 Biopolis Way, #02-01 Centros, Singapore 138668, Singapore
| | - S Xu
- Immunology Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research, 20 Biopolis Way, #06-01 Centros, Singapore 138668, Singapore
| | - W Han
- Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, Biomedical Sciences Institutes, 11 Biopolis Way, Helios, Singapore 138667, Singapore
| | - A Hong
- Institute of Biomedicine, Ji Nan University, 601 HUANG PO DA DAO XI, Guang Zhou 510632, P.R. China
| | - S C Lim
- Diabetes Center, Khoo Teck Puat Hospital, ALEXANDRA HEALTH PTE LTD, 90 Yishun Central, Singapore 768828, Singapore
| | - K-P Lam
- Immunology Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research, 20 Biopolis Way, #06-01 Centros, Singapore 138668, Singapore.,Department of Physiology, National University of Singapore, NUS Yong Loo Lin School of Medicine, Block MD9, 2 Medical Drive #04-01, Singapore 117597, Singapore.,Department of Microbiology, National University of Singapore, 5 Science Drive 2, Blk MD4, Level 3, Singapore 117545, Singapore.,School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore
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Brahma Naidu P, Uddandrao VVS, Ravindar Naik R, Suresh P, Meriga B, Begum MS, Pandiyan R, Saravanan G. Ameliorative potential of gingerol: Promising modulation of inflammatory factors and lipid marker enzymes expressions in HFD induced obesity in rats. Mol Cell Endocrinol 2016; 419:139-147. [PMID: 26493465 DOI: 10.1016/j.mce.2015.10.007] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Revised: 10/10/2015] [Accepted: 10/11/2015] [Indexed: 01/12/2023]
Abstract
Obesity, generally linked to hyperlipidemia, has been occurring of late with distressing alarm and has now become a global phenomenon casting a huge economic burden on the health care system of countries around the world. The present study investigated the effects of gingerol over 30 days on the changes in HFD-induced obese rats in marker enzymes of lipid metabolism such as fatty-acid synthase (FAS), Acetyl CoA Carboxylase (ACC), Carnitine Palmitoyl Transferase-1(CPT-1), HMG co-A Reductase (HMGR), Lecithin Choline Acyl Transferase (LCAT) and Lipoprotein Lipase (LPL) and inflammatory markers (TNF-α and IL-6). The rats were treated orally with gingerol (75 mg kg(-1)) once daily for 30 days with a lorcaserin-treated group (10 mg kg(-1)) included for comparison. Changes in body weight, glucose, insulin resistance and expressions of lipid marker enzymes and inflammatory markers in tissues were observed in experimental rats. The administration of gingerol resulted in a significant reduction in body weight gain, glucose and insulin levels, and insulin resistance, which altered the activity, expressions of lipid marker enzymes and inflammatory markers. It showed that gingerol had significantly altered these parameters when compared with HFD control rats. This study confirms that gingerol prevents HFD-induced hyperlipidemia by modulating the expression of enzymes important to cholesterol metabolism.
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Affiliation(s)
- Parim Brahma Naidu
- Department of Biochemistry, Animal Physiology & Biochemistry Lab, Sri Venkateswara University, Tirupati, 517502, India
| | - V V Sathibabu Uddandrao
- Department of Biochemistry, Centre for Biological Sciences, K.S. Rangasamy College of Arts and Science, Thokkavadi, Tiruchengode, 637215, Tamil Nadu, India
| | - Ramavat Ravindar Naik
- National Centre for Laboratory Animal Sciences, National Institute of Nutrition (ICMR-New Delhi), Hydrabad, Andhrapradesh, India
| | - Pothani Suresh
- National Centre for Laboratory Animal Sciences, National Institute of Nutrition (ICMR-New Delhi), Hydrabad, Andhrapradesh, India
| | - Balaji Meriga
- Department of Biochemistry, Animal Physiology & Biochemistry Lab, Sri Venkateswara University, Tirupati, 517502, India
| | - Mustapha Shabana Begum
- Department of Biochemistry, Muthayammal College of Arts and Science, Rasipuram, Tamil Nadu, 637408, India
| | - Rajesh Pandiyan
- Department of Biochemistry, Centre for Biological Sciences, K.S. Rangasamy College of Arts and Science, Thokkavadi, Tiruchengode, 637215, Tamil Nadu, India
| | - Ganapathy Saravanan
- Department of Biochemistry, Centre for Biological Sciences, K.S. Rangasamy College of Arts and Science, Thokkavadi, Tiruchengode, 637215, Tamil Nadu, India.
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Emodin improves lipid and glucose metabolism in high fat diet-induced obese mice through regulating SREBP pathway. Eur J Pharmacol 2015; 770:99-109. [PMID: 26626587 DOI: 10.1016/j.ejphar.2015.11.045] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 11/17/2015] [Accepted: 11/23/2015] [Indexed: 12/17/2022]
Abstract
Currently, obesity has become a worldwide epidemic associated with Type 2 diabetes, dyslipidemia, cardiovascular disease and chronic metabolic diseases. Emodin is one of the active anthraquinone derivatives from Rheum palmatum and some other Chinese herbs with anti-inflammatory, anticancer and hepatoprotective properties. In the present study, we investigated the anti-obesity effects of emodin in obese mice and explore its potential pharmacological mechanisms. Male C57BL/6 mice were fed with high-fat diet for 12 weeks to induce obesity. Then the obese mice were divided into four groups randomly, HFD or emodin (40mg/kg/day and 80mg/kg/day) or lovastatin (30mg/kg/ day) for another 6 weeks. Body weight and food intake were recorded every week. At the end of the treatment, the fasting blood glucose, glucose and insulin tolerance test, serum and hepatic lipid levels were assayed. The gene expressions of liver and adipose tissues were analyzed with a quantitative PCR assay. Here, we found that emodin inhibited sterol regulatory element-binding proteins (SREBPs) transactivity in huh7 cell line. Furthermore, emodin (80mg/kg/day) treatment blocked body weight gain, decreased blood lipids, hepatic cholesterol and triglyceride content, ameliorated insulin sensitivity, and reduced the size of white and brown adipocytes. Consistently, SREBP-1 and SREBP-2 mRNA levels were significantly reduced in the liver and adipose tissue after emodin treatment. These data demonstrated that emodin could improve high-fat diet-induced obesity and associated metabolic disturbances. The underlying mechanism is probably associated with regulating SREBP pathway.
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Ku CS, Kim B, Pham TX, Yang Y, Weller CL, Carr TP, Park YK, Lee JY. Hypolipidemic Effect of a Blue-Green Alga (Nostoc commune) Is Attributed to Its Nonlipid Fraction by Decreasing Intestinal Cholesterol Absorption in C57BL/6J Mice. J Med Food 2015; 18:1214-22. [PMID: 26161942 DOI: 10.1089/jmf.2014.0121] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
We previously demonstrated that Nostoc commune var. sphaeroids Kützing (NO), a blue-green alga (BGA), exerts a hypolipidemic effect in vivo and its lipid extract regulates the expression of genes involved in cholesterol and lipid metabolism in vitro. The objective of this study was to investigate whether the hypolipidemic effect of NO is attributed to an algal lipid or a delipidated fraction in vivo compared with Spirulina platensis (SP). Male C57BL/6J mice were fed an AIN-93M diet containing 2.5% or 5% of BGA (w/w) or a lipid extract equivalent to 5% of BGA for 4 weeks to measure plasma and liver lipids, hepatic gene expression, intestinal cholesterol absorption, and fecal sterol excretion. Plasma total cholesterol (TC) was significantly lower in 2.5% and 5% NO-fed groups, while plasma triglyceride (TG) levels were decreased in the 5% NO group compared with controls. However, neither NO organic extract (NOE) nor SP-fed groups altered plasma lipids. Hepatic mRNA levels of sterol regulatory element-binding protein 2, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR), carnitine palmitoyltransferase-1α, and acyl-CoA oxidase 1 were induced in 5% NO-fed mice, while there were no significant changes in hepatic lipogenic gene expression between groups. NO, but not NOE and SP groups, significantly decreased intestinal cholesterol absorption. When HepG2 cells and primary mouse hepatocytes were incubated with NOE and SP organic extract (SPE), there were marked decreases in protein levels of HMGR, low-density lipoprotein receptor, and fatty acid synthase. In conclusion, the nonlipid fraction of NO exerts TC and TG-lowering effects primarily by inhibiting intestinal cholesterol absorption and by increasing hepatic fatty acid oxidation, respectively.
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Affiliation(s)
- Chai Siah Ku
- 1 Department of Nutritional Sciences, University of Connecticut , Storrs, Connecticut, USA
| | - Bohkyung Kim
- 1 Department of Nutritional Sciences, University of Connecticut , Storrs, Connecticut, USA
| | - Tho X Pham
- 1 Department of Nutritional Sciences, University of Connecticut , Storrs, Connecticut, USA
| | - Yue Yang
- 1 Department of Nutritional Sciences, University of Connecticut , Storrs, Connecticut, USA
| | - Curtis L Weller
- 2 Department of Biological Systems Engineering, University of Nebraska , Lincoln, Nebraska, USA
| | - Timothy P Carr
- 3 Department of Nutrition and Health Sciences, University of Nebraska , Lincoln, Nebraska, USA
| | - Young-Ki Park
- 1 Department of Nutritional Sciences, University of Connecticut , Storrs, Connecticut, USA
| | - Ji-Young Lee
- 1 Department of Nutritional Sciences, University of Connecticut , Storrs, Connecticut, USA
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Regulation of the fatty acid synthase promoter by liver X receptor α through direct and indirect mechanisms in goat mammary epithelial cells. Comp Biochem Physiol B Biochem Mol Biol 2015; 184:44-51. [DOI: 10.1016/j.cbpb.2015.02.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Revised: 02/20/2015] [Accepted: 02/23/2015] [Indexed: 11/20/2022]
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45
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Yang MY, Chan KC, Lee YJ, Chang XZ, Wu CH, Wang CJ. Sechium edule Shoot Extracts and Active Components Improve Obesity and a Fatty Liver That Involved Reducing Hepatic Lipogenesis and Adipogenesis in High-Fat-Diet-Fed Rats. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2015; 63:4587-4596. [PMID: 25912298 DOI: 10.1021/acs.jafc.5b00346] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Excess fat accumulation in the liver increases the risk of developing progressive liver injuries ranging from a fatty liver to hepatocarcinoma. In a previous study, we demonstrated that the polyphenol components of Sechium edule shoots attenuated hepatic lipid accumulation in vitro. Therefore, we investigated the effects and mechanisms of the extract of S. edule shoots (SWE) to modulate fat accumulation in a high-fat-diet (HFD)-induced animal model. In this study, we found that the SWE can reduce the body weight, adipose tissue fat, and regulate hepatic lipid contents (e.g., triglyceride and cholesterol). Additionally, treatment of caffeic acid (CA) and hesperetin (HPT), the main ingredients of SWE, also inhibited oleic acid (OA)-induced lipid accumulation in HepG2 cells. SWE enhanced the activation of AMP-activating protein kinase (AMPK) and decreased numerous lipogenic-related enzymes, such as sterol regulator element-binding proteins (SREBPs), e.g., SREBP-1 and SREBP-2, and HMG-CoA reductase (HMGCoR) proteins, which are critical regulators of hepatic lipid metabolism. Taken together, the results demonstrated that SWE can prevent a fatty liver and attenuate adipose tissue fat by inhibiting lipogenic enzymes and stimulating lipolysis via upregulating AMPK. It was also demonstrated that the main activation components of SWE are both CA and HPT.
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Affiliation(s)
| | | | | | | | - Cheng-Hsun Wu
- #Department of Anatomy, China Medical University, Taichung 40401, Taiwan
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Zhang J, Zhang LN, Chen DM, Fu YY, Zhang F, Yang LL, Xia CM, Jiang HW, Tang CL, Xie ZF, Yang F, Li J, Tang J, Li JY. 2-(3-Benzoylthioureido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ameliorates metabolic disorders in high-fat diet-fed mice. Acta Pharmacol Sin 2015; 36:483-96. [PMID: 25832429 DOI: 10.1038/aps.2014.149] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Accepted: 12/11/2014] [Indexed: 12/13/2022]
Abstract
AIM Sterol-regulatory element binding proteins (SREBPs) are major transcription factors that regulate liver lipid biosynthesis. In this article we reported a novel synthetic compound 2-(3-benzoylthioureido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (ZJ001) that inhibited the SREBP-1c pathway, and effectively reduced hepatic lipid accumulation in diet-induced obesity (DIO) mice. METHODS A luciferase reporter driven by an SRE-containing promoter transfected into HepG2 cells was used to discover the compound. Two approaches were used to evaluate the lipid-lowering effects of ZJ001: (1) diet-induced obesity (DIO) mice that were treated with ZJ001 (15 mg·kg(-1)·d(-1), po) for 7 weeks; and (2) HepG2 cells and primary hepatocytes used as in vitro models. RESULTS ZJ001 (10, 20 μmol/L) dose-dependently inhibited the activity of SRE-containing promoter. ZJ001 administration ameliorated lipid metabolism and improved glucose tolerance in DIO mice, accompanied by significantly reduced mRNA levels of SREBP-1C and SREBP-2, and their downstream genes. In HepG2 cells and insulin-treated hepatocytes, ZJ001 (10-40 μmol/L) dose-dependently inhibited lipid synthesis, and reduced mRNA levels of SREBP-1C and SREBP-2, and their downstream genes. Furthermore, ZJ001 dose-dependently increased the phosphorylation of AMPK and regulatory-associated protein of mTOR (Raptor), and suppressed the phosphorylation of mTOR in insulin-treated hepatocytes. Moreover, ZJ001 increased the ADP/ATP ratio in insulin-treated hepatocytes. CONCLUSION ZJ001 exerts multiple beneficial effects in diet-induced obesity mice. Its lipid-lowering effects may result from the suppression of mTORC1, which regulates SREBP-1c transcription. The results suggest that the SREBP-1c pathway may be a potential therapeutic target for the treatment of lipid metabolic disorders.
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Li J, Luo J, Xu H, Wang M, Zhu J, Shi H, Haile AB, Wang H, Sun Y. Fatty acid synthase promoter: Characterization, and transcriptional regulation by sterol regulatory element binding protein-1 in goat mammary epithelial cells. Gene 2015; 561:157-64. [DOI: 10.1016/j.gene.2015.02.034] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Revised: 01/22/2015] [Accepted: 02/12/2015] [Indexed: 12/18/2022]
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Sanders FWB, Griffin JL. De novo lipogenesis in the liver in health and disease: more than just a shunting yard for glucose. Biol Rev Camb Philos Soc 2015; 91:452-68. [PMID: 25740151 PMCID: PMC4832395 DOI: 10.1111/brv.12178] [Citation(s) in RCA: 361] [Impact Index Per Article: 36.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Revised: 01/07/2015] [Accepted: 01/20/2015] [Indexed: 02/06/2023]
Abstract
Hepatic de novo lipogenesis (DNL) is the biochemical process of synthesising fatty acids from acetyl‐CoA subunits that are produced from a number of different pathways within the cell, most commonly carbohydrate catabolism. In addition to glucose which most commonly supplies carbon units for DNL, fructose is also a profoundly lipogenic substrate that can drive DNL, important when considering the increasing use of fructose in corn syrup as a sweetener. In the context of disease, DNL is thought to contribute to the pathogenesis of non‐alcoholic fatty liver disease, a common condition often associated with the metabolic syndrome and consequent insulin resistance. Whether DNL plays a significant role in the pathogenesis of insulin resistance is yet to be fully elucidated, but it may be that the prevalent products of this synthetic process induce some aspect of hepatic insulin resistance.
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Affiliation(s)
- Francis W B Sanders
- MRC Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge CB1 9NL, U.K.,The Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, U.K
| | - Julian L Griffin
- MRC Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge CB1 9NL, U.K.,The Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, U.K
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Kim GH, Oh GS, Yoon J, Lee GG, Lee KU, Kim SW. Hepatic TRAP80 selectively regulates lipogenic activity of liver X receptor. J Clin Invest 2014; 125:183-93. [PMID: 25437875 DOI: 10.1172/jci73615] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Accepted: 10/30/2014] [Indexed: 01/08/2023] Open
Abstract
Inflammation in response to excess low-density lipoproteins in the blood is an important driver of atherosclerosis development. Due to its ability to enhance ATP-binding cassette A1-dependent (ABCA1-dependent) reverse cholesterol transport (RCT), liver X receptor (LXR) is an attractive target for the treatment of atherosclerosis. However, LXR also upregulates the expression of sterol regulatory element-binding protein 1c (SREBP-1c), leading to increased hepatic triglyceride synthesis, an independent risk factor for atherosclerosis. Here, we developed a strategy to separate the favorable and unfavorable effects of LXR by exploiting the specificity of the coactivator thyroid hormone receptor-associated protein 80 (TRAP80). Using human hepatic cell lines, we determined that TRAP80 selectively promotes the transcription of SREBP-1c but not ABCA1. Adenovirus-mediated expression of shTRAP80 inhibited LXR-dependent SREBP-1c expression and RNA polymerase II recruitment to the LXR responsive element (LXRE) of SREBP-1c, but not to the LXRE of ABCA1. In murine models, liver-specific knockdown of TRAP80 ameliorated liver steatosis and hypertriglyceridemia induced by LXR activation and maintained RCT stimulation by the LXR ligand. Together, these data indicate that TRAP80 is a selective regulator of hepatic lipogenesis and is required for LXR-dependent SREBP-1c activation. Moreover, targeting the interaction between TRAP80 and LXR should facilitate the development of potential LXR agonists that effectively prevent atherosclerosis.
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Xu J, Lee ES, Baek SH, Ahn SY, Kim S, Na KY, Chae DW, Chin HJ. Effect of bilirubin on triglyceride synthesis in streptozotocin-induced diabetic nephropathy. J Korean Med Sci 2014; 29 Suppl 2:S155-63. [PMID: 25317020 PMCID: PMC4194286 DOI: 10.3346/jkms.2014.29.s2.s155] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Accepted: 08/25/2014] [Indexed: 11/30/2022] Open
Abstract
We aimed to elucidate the effect of bilirubin on dyslipidemia and nephropathy in a diabetes mellitus (DM) type I animal model. Sprague-Dawley rats were separated into control, DM, and bilirubin-treated DM (Bil) groups. The Bil group was injected intraperitoneally with 60 mg/kg bilirubin 3 times per week and hepatoma cells were cultured with bilirubin at a concentration of 0.3 mg/dL. The Bil group showed lower serum creatinine levels 5 weeks after diabetes onset. Bilirubin treatment also decreased the amount of mesangial matrix, lowered the expression of renal collagen IV and transforming growth factor (TGF)-β1, and reduced the level of apoptosis in the kidney, compared to the DM group. These changes were accompanied by decreased tissue levels of hydrogen superoxide and NADPH oxidase subunit proteins. Bilirubin decreased serum total cholesterol, high-density lipoprotein cholesterol (HDL-C), free fatty acids, and triglycerides (TGs), as well as the TG content in the liver tissues. Bilirubin suppressed protein expression of LXRα, SREBP-1, SCD-1, and FAS, factors involved in TG synthesis that were elevated in the livers of DM rats and hepatoma cells under high-glucose conditions. In conclusion, bilirubin attenuates renal dysfunction and dyslipidemia in diabetes by suppressing LXRα and SREBP-1 expression and oxidative stress.
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Affiliation(s)
- Jianwei Xu
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Eun Seong Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Seon Ha Baek
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Shin-Young Ahn
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Sejoong Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Ki Young Na
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Dong-Wan Chae
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Ho Jun Chin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Department of Immunology, Seoul National University Postgraduate School, Seoul, Korea
- Renal Institute, Seoul National University Medical Research Center, Seoul, Korea
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