Infliximab reverses steatosis and improves insulin signal transduction in liver of rats fed a high-fat diet.
Non-alcoholic fatty liver disease, induced by nutritional factors, is one of the leading causes of hepatic dysfunction in the modern world. The activation of proinflammatory signaling in the liver, which is induced by systemic and locally produced cytokines, and the development of hepatic insulin resistance are two important factors associated with the progression from steatosis to steatohepatitis, a pre-cirrhotic condition. The objective of the present study was to evaluate the effect of inhibition of tumour necrosis factor (TNF)-alpha , using the monoclonal antibody infliximab, on the expression of cytokines, induction of steatosis and fibrosis, and insulin signal transduction in the liver of Wistar rats fed a high-fat diet. Ten days of treatment with infliximab significantly reduced the expression of the proinflammatory markers, TNF-alpha , IL-6, IL-1beta , and SOCS-3, in the liver of rats fed a high-fat diet. This was accompanied by reduced fat deposition and fibrosis and by improved insulin signal transduction through insulin receptor (IR)/IR substrate/Akt/FOXO1 and JAK2/STAT3 pathways. In conclusion, short-term inhibition of TNF-alpha with infliximab reduces inflammation and steatosis/fibrosis, while improving insulin signal transduction in an animal model treated with a high-fat diet.
Barbuio
Raquel
R
Department of Internal Medicine and Gastrocentro, State University of Campinas, Campinas, SP 13083-970, Brazil.
Milanski
Marciane
M
Bertolo
Manoel B
MB
Saad
Mário J
MJ
Velloso
Lício A
LA
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D005234:Fatty Liver / Q000188:drug therapy* / Q000378:metabolism; D005355:Fibrosis / Q000188:drug therapy; D000069285:Infliximab; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D008297:Male; D023421:Models, Animal; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D016207:Cytokines; D004041:Dietary Fats; D007328:Insulin; C491410:Socs3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab