Non-alcoholic steatohepatitis weakens the acute phase response to endotoxin in rats

Thomsen, Karen L., Hebbard, Lionel, Glavind, Emilie, Clouston, Andrew, Vilstrup, Hendrik, George, Jacob, and Grønbæk, Henning (2014) Non-alcoholic steatohepatitis weakens the acute phase response to endotoxin in rats. Liver international, 34 (10). pp. 1584-1592.

[img] PDF (Published Version) - Published Version
Restricted to Repository staff only

View at Publisher Website: http://dx.doi.org/10.1111/liv.12547
 
7
6


Abstract

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.

Methods

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.

Results

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.

Conclusion

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.

Item ID: 40184
Item Type: Article (Research - C1)
ISSN: 1478-3231
Keywords: acute phase response; cytokines; inflammation; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; rats
Funders: Fonden til Lægevidenskabens Fremme, Danske Lægers Forsikring under Codan, NOVO Nordisk Foundation, Aarhus University, Robert W. Storr Bequest to the Sydney Medical Foundation of the University of Sydney, National Health and Medical Research Council (NHMRC)
Projects and Grants: NHMRC project grant 632630, NHMRC project grant 1049857, NHMRC Program grant APP1053206
Date Deposited: 26 Aug 2015 02:23
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1115 Pharmacology and Pharmaceutical Sciences > 111501 Basic Pharmacology @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920105 Digestive System Disorders @ 100%
Downloads: Total: 6
More Statistics

Actions (Repository Staff Only)

Item Control Page Item Control Page