title: Inhibition of hepatic glycogen synthesis by hyperhomocysteinemia mediated by TRB3.
abstract: 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-3β 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)-γ coactivator-1α and TRB3. The inhibition of PPAR-α by its inhibitor, MK886, or knockdown of PPAR-α 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.
authors: Laboratory for Conservation and Utilization of Bio-Resources, Yunnan University, Yunnan, China.
authors: Wen-Jing
authors: WJ
authors: Liu
authors: Lan-Qing
authors: LQ
authors: Ma
authors: Wei-Hua
authors: WH
authors: Liu
authors: Wei
authors: W
authors: Zhou
authors: Ke-Qin
authors: KQ
authors: Zhang
authors: Cheng-Gang
authors: CG
authors: Zou
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D018450:Disease Progression; D006003:Glycogen / Q000378:metabolism; D006710:Homocysteine / Q000737:chemistry; D006801:Humans; D020138:Hyperhomocysteinemia / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D007333:Insulin Resistance; D008112:Liver Glycogen / Q000378:metabolism*; D008715:Methionine / Q000378:metabolism; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism* / Q000037:antagonists & inhibitors; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D002722:Chlorobenzenes
chemical_list: D018797:Cell Cycle Proteins; D006003:Glycogen; D006710:Homocysteine; D007211:Indoles; D008112:Liver Glycogen; D008715:Methionine; D047495:PPAR gamma; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C474831:TRIB3 protein, human; C060893:MK-886; D002722:Chlorobenzenes