Hepatic retinoid stores are required for normal liver regeneration

Igor O Shmarakov,Hongfeng Jiang,Kryscilla Jian Zhang Yang,Ira J Goldberg,William S Blaner

doi:10.1194/jlr.m029801

Igor O Shmarakov, Hongfeng Jiang + Show 3 more

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https://doi.org/10.1194/jlr.m029801

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Abstract

Preliminary studies of liver regeneration induced by partial hepatectomy (PHE) identified a substantial depletion of hepatic retinoid stores, by greater than 70%, in regenerating livers of wild-type C57Bl/6J mice. To understand this, we compared responses of wild-type and lecithin:retinol acyltransferase (Lrat)-deficient mice, which totally lack hepatic retinoid stores, to PHE. The Lrat-deficient livers showed delayed regeneration in the first 24 h after PHE. At 12 h after PHE, we observed significantly less mRNA expression for growth factors and cytokines implicated in regulating the priming phase of liver regeneration, specifically for Hgf and Tgfα, but not Tgfβ. Compared with wild-type mice, the changes in mRNA levels for p21 and cyclins E1, B1, and A2 mRNAs and for hepatocellular BrdU incorporation and mitoses were delayed (i.e., shifted to later times) in regenerating Lrat(-/-) livers. Concentrations of all-trans-retinoic acid were significantly lower in the livers of Lrat(-/-) mice following PHE, and this was accompanied by diminished expression of known retinoid-responsive genes. At later times after PHE, the rate of liver weight restoration for Lrat(-/-) mice was parallel to that of wild-type mice, although additional biochemical differences were observed. Thus, hepatic retinoid stores are required for maintaining expression of signaling molecules that regulate cell proliferation and differentiation immediately after hepatic injury, accounting for the delayed restoration of liver mass in Lrat(-/-) mice.

Highlights

Preliminary studies of liver regeneration induced by partial hepatectomy (PHE) identified a substantial depletion of hepatic retinoid stores, by greater than 70%, in regenerating livers of wild-type C57Bl/6J mice
No differences in postoperative morbidity, mortality, or behavior between the two strains were observed. Both wild-type and LratϪ/Ϫ mice showed the same level of serum alanine aminotransferase (ALT) activity following PHE (Fig. 1B), except at the initial stages of liver regeneration 12 h after PHE, when the serum ALT activity was significantly greater for LratϪ/Ϫ than for wild-type mice
No retinyl ester is detectable in the livers of LratϪ/Ϫ mice, these livers still possess retinol, albeit at concentrations which are about 5% of those of wild-type mice

Summary

Introduction

Preliminary studies of liver regeneration induced by partial hepatectomy (PHE) identified a substantial depletion of hepatic retinoid stores, by greater than 70%, in regenerating livers of wild-type C57Bl/6J mice. To gain understanding of the role of hepatic retinoid stores in liver regeneration, we assessed the restoration of liver mass, expressed as liver/body weight ratio, in wild-type and LratϪ/Ϫ mice at time intervals up to 7 days following PHE (Fig. 1A).

Results

Conclusion