Novel therapeutic drug identification and gene correlation for fatty liver disease using high-content screening: Proof of concept

被引:11
作者
Luo, Wei-Jia [1 ]
Cheng, Ting-Yu [1 ]
Wong, Keng-Ieng [1 ]
Fang, Woei-horng [1 ]
Liao, Keng-Mao [2 ,3 ]
Hsieh, Yun-Ting [1 ]
Su, Kang-Yi [1 ,2 ,3 ,4 ,5 ]
机构
[1] Natl Taiwan Univ, Coll Med, Dept Clin Lab Sci & Med Biotechnol, 1,Sec 1,Jen I Rd, Taipei 10055, Taiwan
[2] Natl Taiwan Univ, Genome & Syst Biol Degree Program, Taipei, Taiwan
[3] Acad Sinica, Taipei, Taiwan
[4] Natl Taiwan Univ, Ctr Genom Med, Taipei, Taiwan
[5] Natl Taiwan Univ Hosp, Dept Lab Med, Taipei, Taiwan
关键词
Non-alcoholic fatty liver disease; High-content screening; Lipid droplets; LOPAC; CREB1; Drug development; HEPATIC LIPID-METABOLISM; ALCOHOLIC HEPATITIS; NUCLEAR-FACTOR; STEATOSIS; INSULIN; PROTEIN; CELLS; EXPRESSION; ETHANOL; OBESITY;
D O I
10.1016/j.ejps.2018.05.018
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Non-alcoholic fatty liver disease (NAFLD) is a problem in obese people caused by increasing intake of high-calorie food such as fructose implicated in the elevated prevalence. It is necessary to identify novel drugs to develop effective therapies. In this study, we combined LOPAC (R) (The Library of Pharmacologically Active Compounds) and High-Content screening to identify compounds that significantly reduced intracellular lipid droplets (LD) after high fat medium (HFM) treatment. Among 1280 compounds, we identified 239 compounds that reduced LD by > 50%. Of these, 17 maintained cell viability. Nine of them were selected for validation using normal primary hepatocytes, of which five compounds showed dose-dependent efficacy. Whole genome transcriptomic network analysis was performed to construct the underlying regulatory network. There were 831 (711 up-regulated and 120 down-regulated genes) and 3480 (2009 up-regulated and 1471 down-regulated genes) genes that showed a significant change (> 2-fold; p < 0.05) after 12 and 24 h HFM treatment, respectively. Gene enrichment and pathway analysis showed several immune responses mediated by MIF, IL-17, TLR, and IL-6. These compounds modulate lipogenesis via GSK3 beta and CREB1, which is followed by an alteration in the expression of several downstream genes related to hepatocellular carcinoma and hepatitis. CREB1 is a core transcription factor and may be a potential therapeutic target for liver disease. In conclusion, this proof of concept provides a strategy for identifying novel drugs for treatment of fatty liver disease as well as elucidates their underlying mechanisms. This research provides opportunity for developing future pharmaceutical therapeutics.
引用
收藏
页码:106 / 117
页数:12
相关论文
共 65 条
  • [1] Health Effects of Overweight and Obesity in 195 Countries over 25 Years
    Afshin, Ashkan
    Forouzanfar, Mohammad H.
    Reitsma, Marissa B.
    Sur, Patrick
    Estep, Kara
    Lee, Alex
    Marczak, Laurie
    Mokdad, Ali H.
    Moradi-Lakeh, Maziar
    Naghavi, Mohsen
    Salama, Joseph S.
    Vos, Theo
    Abate, Kalkidan H.
    Abbafati, Cristiana
    Ahmed, Muktar B.
    Al-Aly, Ziyad
    Alkerwi, Ala'a
    Al-Raddadi, Rajaa
    Amare, Azmeraw T.
    Amberbir, Alemayehu
    Amegah, Adeladza K.
    Amini, Erfan
    Amrock, Stephen M.
    Anjana, Ranjit M.
    Arnlov, Johan
    Asayesh, Hamid
    Banerjee, Amitava
    Barac, Aleksandra
    Baye, Estifanos
    Bennett, Derrick A.
    Beyene, Addisu S.
    Biadgilign, Sibhatu
    Biryukov, Stan
    Bjertness, Espen
    Boneya, Dube J.
    Campos-Nonato, Ismael
    Carrero, Juan J.
    Cecilio, Pedro
    Cercy, Kelly
    Ciobanu, Liliana G.
    Cornaby, Leslie
    Damtew, Solomon A.
    Dandona, Lalit
    Dandona, Rakhi
    Dharmaratne, Samath D.
    Duncan, Bruce B.
    Eshrati, Babak
    Esteghamati, Alireza
    Feigin, Valery L.
    Fernandes, Joao C.
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 2017, 377 (01) : 13 - 27
  • [2] Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis
    Aithal, Guruprasad P.
    Thomas, James A.
    Kaye, Philip V.
    Lawson, Adam
    Ryder, Stephen D.
    Spendlove, Ian
    Austin, Andrew S.
    Freeman, Jan G.
    Morgan, Linda
    Weeber, Jonathan
    [J]. GASTROENTEROLOGY, 2008, 135 (04) : 1176 - 1184
  • [3] Dual effects of pituitary adenylate cyclase-activating polypeptide and isoproterenol on lipid metabolism and signaling in primary rat adipocytes
    Åkesson, L
    Ahrén, B
    Manganiello, VC
    Holst, LS
    Edgren, G
    Degerman, E
    [J]. ENDOCRINOLOGY, 2003, 144 (12) : 5293 - 5299
  • [4] Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: A double-blind, placebo-controlled trial
    Akriviadis, E
    Botla, R
    Briggs, W
    Han, S
    Reynolds, T
    Shakil, O
    [J]. GASTROENTEROLOGY, 2000, 119 (06) : 1637 - 1648
  • [5] Dietary fructose as a risk factor for non-alcoholic fatty liver disease (NAFLD)
    Alwahsh, Salamah Mohammad
    Gebhardt, Rolf
    [J]. ARCHIVES OF TOXICOLOGY, 2017, 91 (04) : 1545 - 1563
  • [6] Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia
    BakkerArkema, RG
    Davidson, MH
    Goldstein, RJ
    Davignon, J
    Isaacsohn, JL
    Weiss, SR
    Keilson, LM
    Brown, WV
    Miller, VT
    Shurzinske, LJ
    Black, DM
    [J]. JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 1996, 275 (02): : 128 - 133
  • [7] Mechanisms of disease - Nuclear factor-kappa b - A pivotal transcription factor in chronic inflammatory diseases
    Barnes, PJ
    Larin, M
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 1997, 336 (15) : 1066 - 1071
  • [8] Consequences of lipid droplet coat protein downregulation in liver cells: abnormal lipid droplet metabolism and induction of insulin resistance
    Bell, Ming
    Wang, Hong
    Chen, Hui
    McLenithan, John C.
    Gong, Da-Wei
    Yang, Rong-Zee
    Yu, Daozhan
    Fried, Susan K.
    Quon, Michael J.
    Londos, Constantine
    Sztalryd, Carole
    [J]. DIABETES, 2008, 57 (08) : 2037 - 2045
  • [9] Pharmacological IKK2 inhibition blocks liver steatosis and initiation of non-alcoholic steatohepatitis
    Beraza, N.
    Malato, Y.
    Borght, S. Vander
    Liedtke, C.
    Wasmuth, H. E.
    Dreano, M.
    de Vos, R.
    Roskams, T.
    Trautwein, C.
    [J]. GUT, 2008, 57 (05) : 655 - 663
  • [10] Protection against fatty liver but normal adipogenesis in mice lacking adipose differentiation-related protein
    Chang, BHJ
    Li, L
    Paul, A
    Taniguchi, S
    Nannegari, V
    Heird, WC
    Chan, L
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 2006, 26 (03) : 1063 - 1076