Review for 10.1186/1471-230X-14-32 (2014)

Reviewer's report
Title:Psychological stress induced zinc accumulation and up-regulation of ZIP14
and metallothionein in rat liver
Version: 1Date:20 June 2013
Reviewer: Kurt Grungreiff
Reviewer's report:
In their manuscript Tao et al. study in an experimental model the effects of
psychological stress ( PS ) on the corticosteron ( CORT ) content in serum, the
zinc contents in serum and liver, the metallothionein ( MT ) level in the liver and
the ZIP 14 mRNA expression in liver in 50 Sprague Dawley rats. After 3 d of
adaptation the rats were divided randomly into three groups : control group, PS
group and foot shock group. The control and PS groups were subdivided into two
subgroups each: 7 d and 14 d surveillance ). The zinc content in the normal chow
diet was 50mg/kg.
Investigations of such parameters under the conditions of PS similar to stress
situations in chronic liver disease are certainly of interest.
Zinc in the liver is stored in two forms – one from which it can be mobilized
rapidly , and one with only slow mobilization. The regulatory process depends
almost completely on hormonal control by insulin, glucagon and the
glucocorticoids. Depending on the metabolic situation, these substances trigger a
transient dysregulation of zinc metabolism with subsequent serum zinc deficiency
and redistribution in various tissues, particularly in liver. Mediator substances
have similar effects (1). There are tight interactions between MT, an acute –
phase protein, interleukin-6 ( IL-6 ) and zinc. IL-6, the most important
proinflammatory cytokine regulating the acute – phase protein production
regulates ZIP 14 in liver and contributes to the zinc deficiency of acute – phase
response ( 2 ). Maintaining cellular zinc homeostasis is of crucial importance for
the functions and effects of zinc (3). This is accomplished by specific transporter
proteins, the so-called zinc transporters Zn T ( SLC30 family) ( 4) and ZIP
(SLC39 family) (5 ) and MT.
Endotoxins detected in patients with liver cirrhosis lead to infection and
inflammation with features of acute-phase reaction including increased
gluconeogenesis, protein catabolism, increased hepatic amino acid uptake, and
dysregulation of iron and zinc (1 , 6).
The results in this study presented with a decreased zinc content in the serum
and increased content of zinc and MT in liver, and the ZIP 14 mRNA expression
in the liver reinforce the role of zinc in acute phase reaction.
Furthermore, the results support the use of supplementation of zinc and
branched amino acids in liver cirrhosis patients with ascites . Liver cirrhosis is
frequently accompanied by malnutrition and zinc deficiency, a state closely
associated with the development of ascites ( 7) . The administration of branched
amino acids and zinc leads to an increase of zinc and albumin levels in the
serum ( 8 ) and an improvement in nutrition state(9 ). The substrates albumin and
zinc stimulate each other reciprocally. Zinc is a very important factor in albumin
synthesis and albumin is the primary transport medium for zinc ( 10).
References :
1. Grüngreiff K, Reinhold D: Zinc and Liver, in Zinc in Human Health, Ed. L. Rink,
IOS Press, Amsterdam, 2011, pp 473 – 492
2. Liuzzi JP, Lichten LA, Rivera S et al.. Interleukin-6 regulates the zinc
transporter Zip 14 in liver and contributes to the hypozincemia of the acute-
phase response. PNAS 2005; 102: 6843 – 6848.
3. Maret W. Zinc biochemistry: From a Single Zinc Enzyme to a Key Element of
Life. Adv Nutr 2013; 4: 82 - 91
4. Huang L, Tepaamorndech The SLC30 family of zinc transporters- A review of
current understanding of their biological and pathophysiological roles. Mol Asp
Med 2013; 34: 548-560.
5. Jeong J, Eide D. The SLC39 family of zinc transporters. Mol Asp Med 2013,
34: 612 – 619.
6. Schröder JJ, Cousins RJ. Interleukin-6 regulates metallothionein expression
and zinc metabolism in hepatocyte monolayer cultures. Proc Natl Acad Sci 1990;
87: 3137 – 3141.
7. Kuiper JJ, de MA RA, van Buhren HR. Management of ascites and associated
complications in patients with cirrhosis. Aliment Pharmacol Ther 2007;26(Suppl
2):183 – 193
8. Grüngreiff K. Branched chain amino acids ( BCAAs) and zinc in treatment of
ascites in liver cirrhosis. Hepatol Int 2011;5:345
9. Nishitani S, Takehana K. Pharmacological activities of branched amino acids:
Augmentation of albumin synthesis in liver and improvement in skeletal muscle.
Hepatol Res 2004; 30(Suppl 1):S19-S24.
10. LuJ, Stewart AJ, Sadler PJ, Pinheiro TJ, Blindauer CA. Albumin as a zinc
carrier: properties of its high-affinity zinc-binding site. Biochem Soc Trans. 2008;
36(Pt 6):1317 – 1321.