Metabolic and Steatohepatitis
Non-alcoholic steatohepatitis weakens the acute phase response to endotoxin in rats
Article first published online: 9 APR 2014
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Volume 34, Issue 10, pages 1584–1592, November 2014
How to Cite
Liver Int. 2014; 34: 1584–1592
- Issue published online: 13 OCT 2014
- Article first published online: 9 APR 2014
- Accepted manuscript online: 26 MAR 2014 06:35AM EST
- Manuscript Accepted: 19 MAR 2014
- Manuscript Received: 8 OCT 2013
- Fonden til Lægevidenskabens Fremme
- Danske Lægers Forsikring
- NOVO Nordisk foundation
- Aarhus University Research Foundation and Clinical Institute
- Sydney Medical Foundation
- University of Sydney
- NHMRC. Grant Numbers: 632630, 1049857, APP1053206
- acute phase response;
- non-alcoholic fatty liver disease;
- non-alcoholic steatohepatitis;
Background & Aims
Patients with non-alcoholic steatohepatitis (NASH) have increased mortality, including from infections. We, therefore, tested in a rodent model of steatohepatitis whether the hepatic acute phase response is intact.
Steatohepatitis was induced in rats by feeding a high-fat, high-cholesterol diet for 4 (early) and 16 weeks (advanced NASH). 2 h after low-dose LPS (0.5 mg/kg i.p.), we measured the serum concentrations of tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6). We also measured liver mRNA's and the serum concentrations of acute phase proteins 24 h after LPS.
Non-alcoholic steatohepatitis in itself increased the liver mRNA levels of TNF-α and IL-6 and also the liver mRNA and serum levels of the acute phase proteins. The exposure to LPS increased serum TNF-α in both early and advanced NASH and more so than in the control rats. However, the increases in acute phase protein genes in liver tissue and proteins in the blood were lower than in the control rats.
In rats with early or advanced experimental NASH, LPS despite an increased interleukin release resulted in a blunted acute phase protein response. This tachyphylaxis may be part of the mechanism for the increased infection susceptibility of patients with NASH. We speculate that the steatosis-related interleukin release desensitises the signalling pathway leading to acute phase protein synthesis.