PMID- 30706477
OWN - NLM
STAT- MEDLINE
DCOM- 20190902
LR  - 20190902
IS  - 1558-9307 (Electronic)
IS  - 0024-4201 (Linking)
VI  - 53
IP  - 11-12
DP  - 2018 Nov
TI  - Large-Scale Screening of Natural Products Transactivating Peroxisome 
      Proliferator-Activated Receptor alpha Identifies 
      9S-Hydroxy-10E,12Z,15Z-Octadecatrienoic Acid and Cymarin as Potential Compounds 
      Capable of Increasing Apolipoprotein A-I Transcription in Human Liver Cells.
PG  - 1021-1030
LID - 10.1002/lipd.12116 [doi]
AB  - Increasing apolipoprotein A-I (apoA-I), the predominant protein of high-density 
      lipoprotein (HDL) particles, has favorable effects on atherogenic risk factors. 
      Here, we investigated the effects of peroxisome proliferator-activated receptor alpha 
      (PPARalpha) transactivating compounds on apoA-I transcription in HepG2 cells. A 
      transient PPARalpha agonist transactivation assay was used to screen 2500 natural 
      compounds. To analyze the effects on apoA-I transcription, human hepatocellular 
      liver carcinoma (HepG2) were exposed to 0.1, 1, and 10 mug/mL of the natural PPARalpha 
      transactivators. ApoA-I mRNA expression was determined by quantitative polymerase 
      chain reaction. Extensive dose-response experiments were performed using 
      compounds that increased apoA-I transcription by minimally 20%. Kelch-like 
      ECH-associated protein 1 (KEAP) and carnitine palmitoyltransferase 1 alpha 
      (CPT1alpha) expression were used respectively to confirm Bromodomain-containing 
      protein 4 inhibition or PPARalpha activation. Twenty-eight natural compounds 
      increased PPARalpha transactivation by at least twofold. Despite the increased CPT1alpha 
      expression seen after the addition of most PPARalpha activating compounds, CPT1alpha 
      expression and PPARalpha transactivation did not correlate. Addition of 0.05 mug/mL 
      9S-hydroxy-10E,12Z,15Z-octadecatrienoic acid (9(S)-HOTrE) increased apoA-I mRNA 
      expression by 35%, whereas 10-25 mug/mL of cymarin increased apoA-I transcription 
      by 37%. However, combining cymarin and 9(S)-HOTrE did not result in a synergistic 
      effect, in contrast this combination even decreased apoA-I transcription. ApoA-I 
      transcription involves multiple regulatory players, and PPARalpha transactivation 
      alone is not sufficient. A search for natural compounds resembling the molecular 
      structure of 9(S)-HOTrE or cymarin could aid to find additional components that 
      increase apoA-I transcription.
CI  - (c) 2019 The Authors. Lipids published by AOCS.
FAU - van der Krieken, Sophie E
AU  - van der Krieken SE
AD  - NUTRIM School of Nutrition and Translational Research in Metabolism, Department 
      of Nutrition and Movement Sciences, Maastricht University, PO Box 616, 6200 MD, 
      Maastricht, The Netherlands.
FAU - Popeijus, Herman E
AU  - Popeijus HE
AD  - NUTRIM School of Nutrition and Translational Research in Metabolism, Department 
      of Nutrition and Movement Sciences, Maastricht University, PO Box 616, 6200 MD, 
      Maastricht, The Netherlands.
FAU - Bendik, Igor
AU  - Bendik I
AD  - DSM Nutritional Products Ltd, Research and Development, Human Nutrition and 
      Health, PO Box 2676, Basel, Switzerland.
FAU - Bohlendorf, Bettina
AU  - Bohlendorf B
AD  - DSM Nutritional Products Ltd, Research and Development, Human Nutrition and 
      Health, PO Box 2676, Basel, Switzerland.
FAU - Konings, Maurice C J M
AU  - Konings MCJM
AD  - NUTRIM School of Nutrition and Translational Research in Metabolism, Department 
      of Nutrition and Movement Sciences, Maastricht University, PO Box 616, 6200 MD, 
      Maastricht, The Netherlands.
FAU - Tayyeb, Jehad
AU  - Tayyeb J
AD  - NUTRIM School of Nutrition and Translational Research in Metabolism, Department 
      of Nutrition and Movement Sciences, Maastricht University, PO Box 616, 6200 MD, 
      Maastricht, The Netherlands.
FAU - Mensink, Ronald P
AU  - Mensink RP
AD  - NUTRIM School of Nutrition and Translational Research in Metabolism, Department 
      of Nutrition and Movement Sciences, Maastricht University, PO Box 616, 6200 MD, 
      Maastricht, The Netherlands.
FAU - Plat, Jogchum
AU  - Plat J
AD  - NUTRIM School of Nutrition and Translational Research in Metabolism, Department 
      of Nutrition and Movement Sciences, Maastricht University, PO Box 616, 6200 MD, 
      Maastricht, The Netherlands.
LA  - eng
GR  - Ministry of Economic Affairs/International
GR  - Netherlands Organization for Scientific Research (NWO)/International
GR  - 11349/Dutch Technology Foundation STW/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190201
PL  - United States
TA  - Lipids
JT  - Lipids
JID - 0060450
RN  - 0 (Apolipoprotein A-I)
RN  - 0 (Biological Products)
RN  - 0 (Dicarboxylic Acids)
RN  - 0 (PPAR alpha)
RN  - 565ZMT5QRG (octadecenedioic acid)
RN  - UK3LS8435E (Cymarine)
SB  - IM
MH  - Apolipoprotein A-I/*genetics
MH  - Biological Products/*pharmacology
MH  - Cell Survival/drug effects/genetics
MH  - Cymarine/*pharmacology
MH  - Dicarboxylic Acids/*pharmacology
MH  - HEK293 Cells
MH  - Hep G2 Cells
MH  - Humans
MH  - PPAR alpha/*metabolism
OTO - NOTNLM
OT  - 9(S)-HOTrE
OT  - Apolipoprotein A-I
OT  - Cymarin
OT  - Fatty acids
OT  - High-density lipoprotein
OT  - Peroxisome proliferator-activated receptor alpha
OT  - Transactivation
OT  - qPCR
EDAT- 2019/02/02 06:00
MHDA- 2019/09/03 06:00
CRDT- 2019/02/02 06:00
PHST- 2017/12/20 00:00 [received]
PHST- 2018/10/18 00:00 [revised]
PHST- 2018/11/27 00:00 [accepted]
PHST- 2019/02/02 06:00 [pubmed]
PHST- 2019/09/03 06:00 [medline]
PHST- 2019/02/02 06:00 [entrez]
AID - 10.1002/lipd.12116 [doi]
PST - ppublish
SO  - Lipids. 2018 Nov;53(11-12):1021-1030. doi: 10.1002/lipd.12116. Epub 2019 Feb 1.