Wolters, A.A.B. (Alba) (2019) Statins do not act as anti-inflammatory agents in Non-Alcoholic Fatty Liver Disease. thesis, Medicine.
Full text available on request.Abstract
Background and aim Non-alcoholic fatty liver disease (NAFLD) is a rising problem in the western world. Interplay between different hepatic cell types (hepatocyte, Kupffer cell, stellate cell, sinusoidal endothelial cell (LSECs)) play a critical and complex role in the development of NAFLD. At this time, cardiovascular disease (CVD) is de main cause of death in subjects with NAFLD and management of dyslipidaemia is mostly done with statins. We aimed to determine the cytoprotective and/or anti-inflammatory effect of statins on Kupffer cells and LSECs in the context of NAFLD. Methods Mouse macrophages (RAW 264.7), as a model for Kupffer cells, were pre-treated with atorvastatin, fluvastatin or pravastatin. An inflammation model in RAW cells was established using lipopolysaccharide (LPS). Kupffer cells and LSECs were isolated from the liver of male Wistar rats and pretreated with atorvastatin or pravastatin before establishing a NAFLD model with sodium palmitate (PA) or sodium oleate (OA). Cytotoxicity of atorvastatin, fluvastatin and pravastatin on RAW cells, Kupffer cells and LSECs was tested with a sytox green staining and a caspase-3 assay. The expressions of inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 10 (IL-10) and mannose receptor C-Type 1 (MRC1) were measured by quantitative real-time polymerase chain reaction (qRT-PCR) in RAW cells and Kupffer cells. Results Fluvastatin induced necrotic cell death in RAW cells and Kupffer cells, which is in contrast with atorvastatin and pravastatin. Furthermore, atorvastatin and pravastatin did not significantly decrease the LPS induced expression of iNOS, TNFα, IL-6, IL-10 and MRC1 in RAW cells (P>0.05). Additionally, the NAFLD model with PA in Kupffer cells did not cause an increase in iNOS, TNFα and IL-6. Moreover, 0.25 mmol/L OA seem to be cytotoxic for LSECs and atorvastatin and pravastatin did not alter this outcome. Conclusion Taken together, the present study demonstrates that [1] fluvastatin can be cytotoxic and therefore some precaution is needed with regard to the prescription of fluvastatin in clinical practice; [2] statins do not act as an anti-inflammatory agent in a LPS-stimulated environment and [3] the anti-inflammatory role of statins in Kupffer cells and LSECs in a NAFLD model needs more investigation.
| Item Type: | Thesis (Thesis) |
|---|---|
| Supervisor name: | Blokzijl, Dr. J. and Moshage, Prof. dr. A.J. and Department of Gastroenterology and Hepatology & Laboratory M |
| Faculty: | Medical Sciences |
| Date Deposited: | 25 Jun 2020 11:04 |
| Last Modified: | 25 Jun 2020 11:04 |
| URI: | https://umcg.studenttheses.ub.rug.nl/id/eprint/2375 |
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