PMID- 37298094
OWN - NLM
STAT- MEDLINE
DCOM- 20230612
LR  - 20230612
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 24
IP  - 11
DP  - 2023 May 23
TI  - Epigenetic Histone Methylation of PPARgamma and CPT1A Signaling Contributes to 
      Betahistine Preventing Olanzapine-Induced Dyslipidemia.
LID - 10.3390/ijms24119143 [doi]
LID - 9143
AB  - As a partial histamine H1 receptor agonist and H3 antagonist, betahistine has 
      been reported to partially prevent olanzapine-induced dyslipidemia and obesity 
      through a combination therapy, although the underlying epigenetic mechanisms are 
      still not known. Recent studies have revealed that histone regulation of key 
      genes for lipogenesis and adipogenesis in the liver is one of the crucial 
      mechanisms for olanzapine-induced metabolic disorders. This study investigated 
      the role of epigenetic histone regulation in betahistine co-treatment preventing 
      dyslipidemia and fatty liver caused by chronic olanzapine treatment in a rat 
      model. In addition to abnormal lipid metabolism, the upregulation of peroxisome 
      proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer binding protein 
      (C/EBPalpha), as well as the downregulation of carnitine palmitoyltransferase 1A 
      (CPT1A) in the liver induced by olanzapine, were significantly attenuated by 
      betahistine co-treatment. In addition, betahistine co-treatment significantly 
      enhanced the global expression of H3K4me and the enrichment of H3K4me binding on 
      the promoter of Cpt1a gene as revealed by ChIP-qPCR, but inhibited the expression 
      of one of its site-specific demethylases, lysine (K)-specific demethylase 1A 
      (KDM1A). Betahistine co-treatment also significantly enhanced the global 
      expression of H3K9me and the enrichment of H3K9me binding on the promoter of the 
      Pparg gene, but inhibited the expression of two of its site-specific 
      demethylases, lysine demethylase 4B (KDM4B) and PHD finger protein 2 (PHF2). 
      These results suggest that betahistine attenuates abnormal adipogenesis and 
      lipogenesis triggered by olanzapine through modulating hepatic histone 
      methylation, and thus inhibiting the PPARgamma pathway-mediated lipid storage, while 
      at the same time promoting CP1A-mediated fatty acid oxidation.
FAU - Su, Yueqing
AU  - Su Y
AD  - Fujian Maternity and Child Health Hospital, College of Clinical Medicine for 
      Obstetrics & Gynaecology and Paediatrics, Fujian Medical University, Fuzhou 
      350005, China.
AD  - Antipsychotic Research Laboratory, Illawarra Health and Medical Research 
      Institute, Wollongong, NSW 2522, Australia.
AD  - School of Medical, Indigenous and Health Sciences, and Molecular Horizons, 
      University of Wollongong, Wollongong, NSW 2522, Australia.
FAU - Deng, Chao
AU  - Deng C
AUID- ORCID: 0000-0003-1147-5741
AD  - Antipsychotic Research Laboratory, Illawarra Health and Medical Research 
      Institute, Wollongong, NSW 2522, Australia.
AD  - School of Medical, Indigenous and Health Sciences, and Molecular Horizons, 
      University of Wollongong, Wollongong, NSW 2522, Australia.
FAU - Liu, Xuemei
AU  - Liu X
AD  - School of Pharmaceutical Sciences, Medical Research Institute, Southwest 
      University, Chongqing 400716, China.
FAU - Lian, Jiamei
AU  - Lian J
AD  - Antipsychotic Research Laboratory, Illawarra Health and Medical Research 
      Institute, Wollongong, NSW 2522, Australia.
AD  - School of Medical, Indigenous and Health Sciences, and Molecular Horizons, 
      University of Wollongong, Wollongong, NSW 2522, Australia.
LA  - eng
GR  - 1104184/National Health and Medical Research Council/
GR  - 1125937/National Health and Medical Research Council/
GR  - 2021CXB014/Fujian Provincial Health Technology Project/
GR  - 2020Y9144/Joint Funds for the Innovation of Science and Technology, Fujian 
      Province/
PT  - Journal Article
DEP - 20230523
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - N7U69T4SZR (Olanzapine)
RN  - X32KK4201D (Betahistine)
RN  - 0 (PPAR gamma)
RN  - 0 (Histones)
RN  - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
RN  - K3Z4F929H6 (Lysine)
RN  - 12794-10-4 (Benzodiazepines)
SB  - IM
MH  - Rats
MH  - Animals
MH  - Olanzapine/adverse effects
MH  - *Betahistine/pharmacology
MH  - PPAR gamma/genetics/metabolism
MH  - Histones/metabolism
MH  - Methylation
MH  - Carnitine O-Palmitoyltransferase/genetics/metabolism
MH  - Lysine/metabolism
MH  - Benzodiazepines/pharmacology
MH  - *Dyslipidemias/genetics
MH  - Epigenesis, Genetic
PMC - PMC10253033
OTO - NOTNLM
OT  - CPT1A
OT  - PPARgamma
OT  - betahistine
OT  - dyslipidemia
OT  - histone methylation
OT  - olanzapine
COIS- None of the authors has a conflict of interest.
EDAT- 2023/06/10 15:13
MHDA- 2023/06/12 06:43
PMCR- 2023/05/23
CRDT- 2023/06/10 01:10
PHST- 2023/04/12 00:00 [received]
PHST- 2023/05/08 00:00 [revised]
PHST- 2023/05/21 00:00 [accepted]
PHST- 2023/06/12 06:43 [medline]
PHST- 2023/06/10 15:13 [pubmed]
PHST- 2023/06/10 01:10 [entrez]
PHST- 2023/05/23 00:00 [pmc-release]
AID - ijms24119143 [pii]
AID - ijms-24-09143 [pii]
AID - 10.3390/ijms24119143 [doi]
PST - epublish
SO  - Int J Mol Sci. 2023 May 23;24(11):9143. doi: 10.3390/ijms24119143.