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. 2022 Jun 19;23(12):6817.
doi: 10.3390/ijms23126817.

MCD Diet Rat Model Induces Alterations in Zinc and Iron during NAFLD Progression from Steatosis to Steatohepatitis

Giuseppina Palladini  1   2 , Laura Giuseppina Di Pasqua  1 , Marta Cagna  1 , Anna Cleta Croce  3 , Stefano Perlini  1   4 , Barbara Mannucci  5 , Antonella Profumo  6 , Andrea Ferrigno  1 , Mariapia Vairetti  1
Affiliations

MCD Diet Rat Model Induces Alterations in Zinc and Iron during NAFLD Progression from Steatosis to Steatohepatitis

Giuseppina Palladini et al. Int J Mol Sci. .

Abstract

We evaluate the effects of the methionine-choline-deficient (MCD) diet on serum and hepatic zinc (Zn) and iron (Fe) and their relationships with matrix metalloproteinases (MMPs) and their modulators (TIMPs and RECK) as well as hepatic fatty acids using male Wistar rats fed 2-, 4- and 8-week MCD diets. Serum and hepatic Zn decrease after an 8-week MCD diet. Serum Fe increases after an 8-week MCD diet and the same occurs for hepatic Fe. An increase in hepatic MMP activity, associated with a decrease in RECK and TIMPs, is found in the MCD 8-week group. Liver Fe shows a positive correlation versus MMPs and RECK, and an inverse correlation versus TIMPs. A positive correlation is found comparing liver Zn with stearic, vaccenic and arachidonic acids, and an inverse correlation is found with linolenic and docosatetraenoic acids. An opposite trend is found between liver Fe versus these fatty acids. During NAFLD progression from steatosis to steatohepatitis, MCD rats exhibit an increase in Zn and a decrease in Fe levels both in serum and tissue associated with alterations in hepatic MMPs and their inhibitors, and fatty acids. The correlations detected between Zn and Fe versus extracellular matrix modulators and fatty acids support their potential role as therapeutic targets.

Keywords: Fe; MMPs; NAFLD; NASH; RECK; Zn; iron; liver; steatohepatitis; steatosis; zinc.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Time-course of changes in serum enzymes (AST, ALT and ALPH) using rats fed with MCD diet for 2-, 4- and 8-weeks. * p ≤ 0.05 versus MCD 2 wk; § p ≤ 0.05 versus MCD 4 wk; # p ≤ 0.05 versus respective control. AST, ALT and ALPH: mU/mL; weeks (wk).
Figure 2
Figure 2
Changes in serum and tissue Zn and Fe in rats fed with MCD diet. Panel (a) and panel (b), serum and liver Zn; panel (c) and panel (d), serum and liver Fe; weeks (wk). * p ≤ 0.05.
Figure 3
Figure 3
Time-dependent changes in liver Zn, Fe, MMPs, TIMPs and RECK. Zn, Fe, MMPs, TIMPs and RECK are expressed as a fold of increase/decrease in their respective control. Weeks (wk).
Figure 4
Figure 4
Examples of images collected from the cryostatic liver tissue sections following the Sirius red staining procedure. Fibrous collagen is evidenced as red structures. Control 2 weeks (a), 4 weeks (c), 8 weeks (e); MCD diet, 2 weeks (b), 4 weeks (d) and 8 weeks (f). Bar: 200 μm.
Figure 5
Figure 5
Time-dependent changes in serum Zn, Fe and MMPs (a) and in IL-1beta, IL-6 and TNF-alpha (b), expressed as a fold increase/decrease in their respective controls. Weeks (wk).
Figure 6
Figure 6
Time-dependent changes in liver fatty acids expressed as a fold increase/decrease in their respective controls. Tissue SFA and MUFA, panel (a); tissue PUFA panel (b). Weeks (wk).
See this image and copyright information in PMC

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