A model of insulin resistance and nonalcoholic steatohepatitis in rats: Role of peroxisome proliferator-activated receptor-α and n-3 polyunsaturated fatty acid treatment on liver injury

Gianluca Svegliati-Baroni, Cinzia Candelaresi, Stefania Saccomanno, Gianna Ferretti, Tiziana Bachetti, Marco Marzioni, Samuele De Minicis, Liliana Nobili, Renata Salzano, Alessia Omenetti, Deborah Pacetti, Soeren Sigmund, Antonio Benedetti, Alessandro Casini

Research output: Contribution to journalArticle

Abstract

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)-α mRNA and in circulating free fatty acids. HFD also decreased adiponectin mRNA and peroxisome proliferator-activated receptor (PPAR)-a expression in the visceral adipose tissue and the liver, respectively, and induced hepatic insulin resistance through TNF-α-mediated c-Jun N-terminal kinase (JNK)-dependent insulin receptor substrate-1Ser307 phosphorylation. These modifications lead to hepatic steatosis accompanied by oxidative stress phenomena, necroinfianimation, and hepatocyte apoptosis at 4 weeks and by pericentral fibrosis at 6 months. Supplementation of n-3 polyunsaturated fatty acid, a PPARα ligand, to HFD-treated animals restored hepatic adiponectin and PPARα expression, reduced TNF-a 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 PPARα down-regulation) and to define any future experimental therapy, such as n-3 polyunsaturated fatty acid, which ameliorated the degree of liver injury.

Original languageEnglish
Pages (from-to)846-860
Number of pages15
JournalAmerican Journal of Pathology
Volume169
Issue number3
DOIs
Publication statusPublished - Sep 2006

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Peroxisome Proliferator-Activated Receptors
Omega-3 Fatty Acids
Insulin Resistance
Liver
Wounds and Injuries
Intra-Abdominal Fat
Tumor Necrosis Factor-alpha
Adiponectin
Therapeutics
Messenger RNA
Investigational Therapies
Non-alcoholic Fatty Liver Disease
JNK Mitogen-Activated Protein Kinases
Insulin Receptor
Fatty Liver
Nonesterified Fatty Acids
Hepatocytes
Oxidative Stress
Fibrosis
Down-Regulation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

A model of insulin resistance and nonalcoholic steatohepatitis in rats : Role of peroxisome proliferator-activated receptor-α and n-3 polyunsaturated fatty acid treatment on liver injury. / Svegliati-Baroni, Gianluca; Candelaresi, Cinzia; Saccomanno, Stefania; Ferretti, Gianna; Bachetti, Tiziana; Marzioni, Marco; De Minicis, Samuele; Nobili, Liliana; Salzano, Renata; Omenetti, Alessia; Pacetti, Deborah; Sigmund, Soeren; Benedetti, Antonio; Casini, Alessandro.

In: American Journal of Pathology, Vol. 169, No. 3, 09.2006, p. 846-860.

Research output: Contribution to journalArticle

Svegliati-Baroni, G, Candelaresi, C, Saccomanno, S, Ferretti, G, Bachetti, T, Marzioni, M, De Minicis, S, Nobili, L, Salzano, R, Omenetti, A, Pacetti, D, Sigmund, S, Benedetti, A & Casini, A 2006, 'A model of insulin resistance and nonalcoholic steatohepatitis in rats: Role of peroxisome proliferator-activated receptor-α and n-3 polyunsaturated fatty acid treatment on liver injury', American Journal of Pathology, vol. 169, no. 3, pp. 846-860. https://doi.org/10.2353/ajpath.2006.050953
Svegliati-Baroni, Gianluca ; Candelaresi, Cinzia ; Saccomanno, Stefania ; Ferretti, Gianna ; Bachetti, Tiziana ; Marzioni, Marco ; De Minicis, Samuele ; Nobili, Liliana ; Salzano, Renata ; Omenetti, Alessia ; Pacetti, Deborah ; Sigmund, Soeren ; Benedetti, Antonio ; Casini, Alessandro. / A model of insulin resistance and nonalcoholic steatohepatitis in rats : Role of peroxisome proliferator-activated receptor-α and n-3 polyunsaturated fatty acid treatment on liver injury. In: American Journal of Pathology. 2006 ; Vol. 169, No. 3. pp. 846-860.
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AU - Candelaresi, Cinzia

AU - Saccomanno, Stefania

AU - Ferretti, Gianna

AU - Bachetti, Tiziana

AU - Marzioni, Marco

AU - De Minicis, Samuele

AU - Nobili, Liliana

AU - Salzano, Renata

AU - Omenetti, Alessia

AU - Pacetti, Deborah

AU - Sigmund, Soeren

AU - Benedetti, Antonio

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