A model of insulin resistance and nonalcoholic steatohepatitis in rats: role of peroxisome proliferator-activated receptor-alpha and n-3 polyunsaturated fatty acid treatment on liver injury.
Insulin resistance induces nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH). We used a high-fat, high-calorie solid diet (HFD) to create a model of insulin resistance and NASH in nongenetically modified rats and to study the relationship between visceral adipose tissue and liver. Obesity and insulin resistance occurred in HFD rats, accompanied by a progressive increase in visceral adipose tissue tumor necrosis factor (TNF)-alpha mRNA and in circulating free fatty acids. HFD also decreased adiponectin mRNA and peroxisome proliferator-activated receptor (PPAR)-alpha expression in the visceral adipose tissue and the liver, respectively, and induced hepatic insulin resistance through TNF-alpha-mediated c-Jun N-terminal kinase (JNK)-dependent insulin receptor substrate-1Ser307 phosphorylation. These modifications lead to hepatic steatosis accompanied by oxidative stress phenomena, necroinflammation, and hepatocyte apoptosis at 4 weeks and by pericentral fibrosis at 6 months. Supplementation of n-3 polyunsaturated fatty acid, a PPARalpha ligand, to HFD-treated animals restored hepatic adiponectin and PPARalpha expression, reduced TNF-alpha hepatic levels, and ameliorated fatty liver and the degree of liver injury. Thus, our model mimics the most common features of NASH in humans and provides an ideal tool to study the role of individual pathogenetic events (as for PPARalpha down-regulation) and to define any future experimental therapy, such as n-3 polyunsaturated fatty acid, which ameliorated the degree of liver injury.
Svegliati-Baroni
Gianluca
G
Department of Gastroenterology, Institute of Biochemistry, Polytechnic University of Marche, Ancona, Italy. g.svegliati@univpm.it
Candelaresi
Cinzia
C
Saccomanno
Stefania
S
Ferretti
Gianna
G
Bachetti
Tiziana
T
Marzioni
Marco
M
De Minicis
Samuele
S
Nobili
Liliana
L
Salzano
Renata
R
Omenetti
Alessia
A
Pacetti
Deborah
D
Sigmund
Soeren
S
Benedetti
Antonio
A
Casini
Alessandro
A
D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D015536:Down-Regulation; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D005526:Food, Formulated / Q000009:adverse effects; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000378:metabolism* / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009336:Necrosis / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D010750:Phosphoproteins / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D015525:Fatty Acids, Omega-3; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases