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Titre du document / Document title

Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis

Auteur(s) / Author(s)

YAMAGUCHI Kanji (1) ; LIU YANG (1) ; MCCALL Shannon (2) ; JIAWEN HUANG (1) ; XING XIAN YU (3) ; PANDEY Sanjay K. (3) ; BHANOT Sanjay (3) ; MONIA Brett P. (3) ; LI Yin-Xiong (1) ; DIEHL Anna Mae (1) ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

(1) Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina, ETATS-UNIS
(2) Department of Pathology, Duke University Medical Center, Durham, North Carolina, ETATS-UNIS
(3) Department of Antisense Drug Discovery, Isis Phamaceuticals, Inc., Carlsbad, California, ETATS-UNIS

Résumé / Abstract

In the early stages of nonalcoholic fatty liver disease (NAFLD), triglycerides accumulate in hepatocytes. Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step in hepatocyte triglyceride biosynthesis. DGAT2 antisense oligonucleotide (ASO) treatment improved hepatic steatosis dramatically in a previous study of obese mice. According to the 2-hit hypothesis for progression of NAFLD, hepatic steatosis is a risk factor for nonalcoholic steatohepatitis (NASH) and fibrosis. To evaluate this hypothesis, we inhibited DGAT2 in a mouse model of NASH induced by a diet deficient in methionine and choline (MCD). Six-week-old genetically obese and diabetic male db/db mice were fed either the control or the MCD diet for 4 or 8 weeks. The MCD diet group was treated with either 25 mg/kg DGAT2 ASO or saline intraperitoneally twice weekly. Hepatic steatosis, injury, fibrosis, markers of lipid peroxidation/oxidant stress, and systemic insulin sensitivity were evaluated. Hepatic steatosis, necroinflammation, and fibrosis were increased in saline-treated MCD diet-fed mice compared to controls. Treating MCD diet-fed mice with DGAT2 ASO for 4 and 8 weeks decreased hepatic steatosis, but increased hepatic free fatty acids, cytochrome P4502E1, markers of lipid peroxidation/oxidant stress, lobular necroinflammation, and fibrosis. Progression of liver damage occurred despite reduced hepatic expression of tumor necrosis factor alpha, increased serum adiponectin, and striking improvement in systemic insulin sensitivity. Conclusion: Results from this mouse model would suggest accumulation of triglycerides may be a protective mechanism to prevent progressive liver damage in NAFLD.

Revue / Journal Title

Hepatology    ISSN  0270-9139   CODEN HPTLD9 

Source / Source

2007, vol. 45, no6, pp. 1366-1374 [9 page(s) (article)] (32 ref.)

Langue / Language

Anglais

Editeur / Publisher

Wiley, Hoboken, NJ, ETATS-UNIS  (1981) (Revue)

Mots-clés anglais / English Keywords

Cytokine

;

Endocrinopathy

;

Thiol

;

Sulfur containing aminoacid

;

Nutrition disorder

;

Digestive diseases

;

Vertebrata

;

Mammalia

;

Rodentia

;

Hepatic fibrosis

;

Hepatoprotector

;

Choleretic

;

Antiseptic

;

Nutritional status

;

Oxidative stress

;

Experimental disease

;

Tumor necrosis factor α

;

Diabetes mellitus

;

Treatment

;

Mouse

;

Animal

;

Obesity

;

Synthesis

;

Triglyceride

;

Choline

;

Methionine

;

Non alcoholic steatohepatitis

;

Hepatic disease

;

Fatty liver

;

Mots-clés français / French Keywords

Cytokine

;

Endocrinopathie

;

Thiol

;

Aminoacide soufré

;

Trouble nutrition

;

Appareil digestif pathologie

;

Vertebrata

;

Mammalia

;

Rodentia

;

Fibrose hépatique

;

Hépatoprotecteur

;

Cholérétique

;

Antiseptique

;

Etat nutritionnel

;

Stress oxydatif

;

Pathologie expérimentale

;

Facteur nécrose tumorale α

;

Diabète

;

Traitement

;

Souris

;

Animal

;

Obésité

;

Synthèse

;

Triglycéride

;

Choline

;

Méthionine

;

Stéatohépatite non alcoolique

;

Foie pathologie

;

Stéatose hépatique

;

Mots-clés espagnols / Spanish Keywords

Citoquina

;

Endocrinopatía

;

Tiol

;

Aminoácido azufrado

;

Trastorno nutricíon

;

Aparato digestivo patología

;

Vertebrata

;

Mammalia

;

Rodentia

;

Hepatoprotector

;

Colerético

;

Antiséptico

;

Estado nutricional

;

Estrés oxidativo

;

Patología experimental

;

Factor necrosis tumoral α

;

Diabetes

;

Tratamiento

;

Ratón

;

Animal

;

Obesidad

;

Síntesis

;

Triglicérido

;

Colina

;

Metionina

;

Esteatohepatitis no alcohólica

;

Hígado patología

;

Hígado graso

;

Localisation / Location

INIST-CNRS, Cote INIST : 19427, 35400016232952.0060

Nº notice refdoc (ud4) : 18811452



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