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Lab Invest. 2014 May;94(5):491-502. doi: 10.1038/labinvest.2014.11. Epub 2014 Feb 24.

Metabolically induced liver inflammation leads to NASH and differs from LPS- or IL-1β-induced chronic inflammation.

Author information

1
1] The Netherlands Organization for Applied Scientific Research (TNO), Department of Metabolic Health Research, TNO Metabolic Health Research, Leiden, The Netherlands [2] Departments of Endocrinology and Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
2
Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands.
3
TNO-Triskelion, Zeist, The Netherlands.
4
Department of Molecular Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
5
The Netherlands Organization for Applied Scientific Research (TNO), Department of Metabolic Health Research, TNO Metabolic Health Research, Leiden, The Netherlands.
6
1] The Netherlands Organization for Applied Scientific Research (TNO), Department of Metabolic Health Research, TNO Metabolic Health Research, Leiden, The Netherlands [2] Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands.

Abstract

The nature of the chronic inflammatory component that drives the development of non-alcoholic steatohepatitis (NASH) is unclear and possible inflammatory triggers have not been investigated systematically. We examined the effect of non-metabolic triggers (lipopolysaccharide (LPS), interleukin-1β (IL-1β), administered by slow-release minipumps) and metabolic dietary triggers (carbohydrate, cholesterol) of inflammation on the progression of bland liver steatosis (BS) to NASH. Transgenic APOE3*Leiden.huCETP (APOE3L.CETP) mice fed a high-fat diet (HFD) developed BS after 10 weeks. Then, inflammatory triggers were superimposed or not (control) for six more weeks. Mouse livers were analyzed with particular emphasis on hallmarks of inflammation which were defined in human liver biopsies with and without NASH. Livers of HFD-treated control mice remained steatotic and did not progress to NASH. All four inflammatory triggers activated hepatic nuclear factor-κB (NF-κB) significantly and comparably (≥5-fold). However, HFD+LPS or HFD+IL-1β did not induce a NASH-like phenotype and caused intrahepatic accumulation of almost exclusively mononuclear cells. By contrast, mice treated with metabolic triggers developed NASH, characterized by enhanced steatosis, hepatocellular hypertrophy, and formation of mixed-type inflammatory foci containing myeloperoxidase-positive granulocytes (neutrophils) as well as mononuclear cells, essentially as observed in human NASH. Specific for the metabolic inducers was an activation of the proinflammatory transcription factor activator protein-1 (AP-1), neutrophil infiltration, and induction of risk factors associated with human NASH, that is, dyslipidemia (by cholesterol) and insulin resistance (by carbohydrate). In conclusion, HFD feeding followed by NF-κB activation per se (LPS, IL-1β) does not promote the transition from BS to NASH. HFD feeding followed by metabolically evoked inflammation induces additional inflammatory components (neutrophils, AP-1 pathway) and causes NASH.

PMID:
24566933
DOI:
10.1038/labinvest.2014.11
[Indexed for MEDLINE]
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