Modulation of hepatic microsomal triglyceride transfer protein (MTP) induced by S-nitroso-N-acetylcysteine in ob/ob mice.
We evaluated the effects of a potent NO donor, S-nitroso-N-acetylcysteine (SNAC), on microsomal triglyceride transfer protein (MTP) expression in ob/ob mice. NAFLD was induced in male ob/ob mice using a methionine-choline deficient diet (MCD) concomitantly with oral SNAC fed solution (n=5) or vehicle (control; n=5) by gavage daily for 4 weeks. Livers were collected for histology and for assessing MTP by RT-qPCR, Western blot, immunohistochemistry and immunogold electron microscopy analyses. Histological analysis showed diffuse macro and microvesicular steatosis, moderate hepatocellular ballooning and moderate inflammatory infiltrate in ob/ob mice fed the MCD diet. With SNAC, mice showed a marked reduction in liver steatosis (p<0.01), in parenchymal inflammation (p=0.02) and in MTP protein immunoexpression in zone III (p=0.05). Moreover, SNAC caused reduction of MTP protein in Western blot analysis (p<0.05). In contrast, MTP mRNA content was significantly higher (p<0.05) in mice receiving SNAC. Immuno-electron microscopy showed MTP localized in the rough endoplasmic reticulum of hepatocytes in both treated and untreated groups. However with SNAC treatment, MTP was also observed surrounding fat globules. Histological improvement mediated by a nitric oxide donor is associated with significantly altered expression and distribution of MTP in this animal model of fatty liver disease. Further studies are in progress to examine possible mechanisms and to develop SNAC as a possible therapy for human fatty liver disease.
Oliveira
Claudia P M S
CP
Department of Gastroenterology, University of São Paulo School of Medicine, Brazil. cpm@usp.br
Alves
Venâncio A F
VA
Lima
Vicência M R
VM
Stefano
José Tadeu
JT
Debbas
Victor
V
Sá
Sandra Valéria
SV
Wakamatsu
Alda
A
Corrêa-Giannella
Maria Lúcia
ML
de Mello
Evandro Sobroza
ES
Havaki
Sofia
S
Tiniakos
Dina G
DG
Marinos
Evangelos
E
de Oliveira
Marcelo G
MG
Giannella-Neto
Daniel
D
Laurindo
Francisco R
FR
Caldwell
Stephen
S
Carrilho
Flair J
FJ
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics*; D005234:Fatty Liver / Q000188:drug therapy; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008820:Mice, Obese; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002352:Carrier Proteins; D012333:RNA, Messenger; C106092:microsomal triglyceride transfer protein; C024940:S-nitroso-N-acetylcysteine; D000111:Acetylcysteine