PMID- 21435438
OWN - NLM
STAT- MEDLINE
DCOM- 20110715
LR  - 20211203
IS  - 1525-2191 (Electronic)
IS  - 0002-9440 (Print)
IS  - 0002-9440 (Linking)
VI  - 178
IP  - 4
DP  - 2011 Apr
TI  - Inhibition of hepatic glycogen synthesis by hyperhomocysteinemia mediated by 
      TRB3.
PG  - 1489-99
LID - 10.1016/j.ajpath.2010.12.052 [doi]
AB  - Recently, epidemiological and experimental studies have linked 
      hyperhomocysteinemia (HHcy) to insulin resistance. However, whether HHcy impairs 
      glucose homeostasis by affecting glycogenesis in the liver is not clear. In the 
      present study, we investigated the effect of HHcy on hepatic glycogen synthesis. 
      Hyperhomocysteinemia was induced in mice by drinking water containing two percent 
      methionine. Mice with HHcy showed an increase in the phosphorylation of glycogen 
      synthase and a significant decrease in hepatic glycogen content and the rate of 
      glycogen synthesis. The expression of TRB3 (tribbles-related protein 3) was 
      up-regulated in the liver of mice with HHcy, concomitantly with the 
      dephosphorylation of glycogen synthase kinase-3beta and Akt. The knockdown of TRB3 
      by short hairpin RNA suppressed the dephosphorylation of these two kinases. 
      Homocysteine induced an increase in the levels of hepatic cAMP and cAMP response 
      element-binding protein phosphorylation, which in turn up-regulated the 
      expression of peroxisome proliferator-activated receptor (PPAR)-gamma coactivator-1alpha 
      and TRB3. The inhibition of PPAR-alpha by its inhibitor, MK886, or knockdown of 
      PPAR-alpha by small interfering RNA significantly inhibited the expression of TRB3 
      induced by homocysteine. The current study demonstrates that HHcy impairs hepatic 
      glycogen synthesis by inducing the expression of TRB3. These results provide a 
      novel explanation for the development and progression of insulin resistance in 
      HHcy.
CI  - Copyright (c) 2011 American Society for Investigative Pathology. Published by 
      Elsevier Inc. All rights reserved.
FAU - Liu, Wen-Jing
AU  - Liu WJ
AD  - Laboratory for Conservation and Utilization of Bio-Resources, Yunnan University, 
      Yunnan, China.
FAU - Ma, Lan-Qing
AU  - Ma LQ
FAU - Liu, Wei-Hua
AU  - Liu WH
FAU - Zhou, Wei
AU  - Zhou W
FAU - Zhang, Ke-Qin
AU  - Zhang KQ
FAU - Zou, Cheng-Gang
AU  - Zou CG
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Am J Pathol
JT  - The American journal of pathology
JID - 0370502
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Indoles)
RN  - 0 (Liver Glycogen)
RN  - 0 (PPAR gamma)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Repressor Proteins)
RN  - 0 (TRIB3 protein, human)
RN  - 080626SQ8C (MK-886)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 9005-79-2 (Glycogen)
RN  - AE28F7PNPL (Methionine)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Cell Cycle Proteins/*metabolism
MH  - Disease Progression
MH  - Glycogen/metabolism
MH  - Homocysteine/chemistry
MH  - Humans
MH  - Hyperhomocysteinemia/*metabolism
MH  - Indoles/pharmacology
MH  - Insulin Resistance
MH  - Liver Glycogen/*metabolism
MH  - Methionine/metabolism
MH  - Mice
MH  - PPAR gamma/metabolism
MH  - Phosphorylation
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - RNA, Small Interfering/metabolism
MH  - Repressor Proteins/*metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
PMC - PMC3078444
EDAT- 2011/03/26 06:00
MHDA- 2011/07/16 06:00
PMCR- 2012/04/01
CRDT- 2011/03/26 06:00
PHST- 2010/08/06 00:00 [received]
PHST- 2010/12/21 00:00 [revised]
PHST- 2010/12/30 00:00 [accepted]
PHST- 2011/03/26 06:00 [entrez]
PHST- 2011/03/26 06:00 [pubmed]
PHST- 2011/07/16 06:00 [medline]
PHST- 2012/04/01 00:00 [pmc-release]
AID - S0002-9440(11)00053-8 [pii]
AID - AJPA228 [pii]
AID - 10.1016/j.ajpath.2010.12.052 [doi]
PST - ppublish
SO  - Am J Pathol. 2011 Apr;178(4):1489-99. doi: 10.1016/j.ajpath.2010.12.052.