Nicotinic alpha-7 acetylcholine receptor deficiency exacerbates hepatic inflammation and fibrosis in a mouse model of non-alcoholic steatohepatitis.

Abstract

AIMS/INTRODUCTION:

Non-alcoholic steatohepatitis (NASH), which occurs in association with insulin resistance and hepatic fat accumulation, is characterized by chronic liver injury and fibrosis. NASH onset and progression is closely related to hepatic inflammation, which is partly regulated by the vagus nerve through the α7 nicotinic acetylcholine receptor (α7nAchR). Hepatic α7nAchR action is impeded in obesity and insulin resistance. In the present study, using α7nAchR knockout (α7KO) mice, we elucidated the effect of α7nAchR deficiency on NASH-related inflammation and fibrosis.

MATERIALS AND METHODS:

α7KO mice were fed an atherogenic high-fat diet (AD) for 32 weeks or methionine/choline-deficient diet (MCD) for 6 weeks, both of which induce NASH. Mice were then examined for the degree of NASH-related inflammation and fibrosis by hepatic gene expression analysis and Sirius red histological staining.

RESULTS:

Hepatic triglyceride accumulation and elevated plasma transaminase levels were observed in both AD and MCD mice, but the plasma transaminase level increase was higher in α7KO mice than in control mice. α7KO mice fed an AD showed significant upregulation of the Col1a1 gene encoding alpha-1 type I collagen, which is involved in liver fibrosis, and the Ccl2 gene encoding C-C motif chemokine ligand 2, a pro-inflammatory chemokine; α7KO mice fed an MCD had significant upregulation of the Col1a1 gene and the Tnf gene, an inflammatory cytokine. Histological analysis showed that AD and MCD exacerbated liver fibrosis in α7KO mice.

CONCLUSIONS:

The results of this study suggest that α7nAchR deficiency exacerbates hepatic inflammation and fibrosis in a diet-induced mouse model of NASH.

• Authors: Kumi Kimura, Yuka Inaba, Hitoshi Watanabe, Toshiya Matsukawa, Michihiro Matsumoto, Hiroshi Inoue
• Journal: Journal of diabetes investigation (J Diabetes Investig) Vol. 10 Issue 3 Pg. 659-666 (May 2019) ISSN: 2040-1124 [Electronic] Japan
• PMID: 30369082 (Publication Type: Journal Article)
• Copyright: © 2018 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Chemical References

• Collagen Type I
• Collagen Type I, alpha 1 Chain
• Cytokines
• Receptors, Nicotinic
• Methionine

Topics

• Animals
• Choline Deficiency (complications)
• Collagen Type I (metabolism)
• Collagen Type I, alpha 1 Chain
• Cytokines (metabolism)
• Diet, High-Fat (adverse effects)
• Disease Models, Animal
• Inflammation (etiology, pathology)
• Liver Cirrhosis (etiology, pathology)
• Male
• Methionine (deficiency)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Non-alcoholic Fatty Liver Disease (etiology, physiopathology)
• Receptors, Nicotinic (physiology)