Hepatic retinoid stores are required for normal liver regeneration

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. 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. Retinoids (vitamin A and its metabolites) are potent regulators of cell proliferation, differentiation, and apoptosis (1Gudas L.J. Emerging roles for retinoids in regeneration and differentiation in normal and disease states.Biochim. Biophys. Acta. 2012; 1821: 213-221Crossref PubMed Scopus (115) Google Scholar, 2Noy N. Between death and survival: retinoic acid in regulation of apoptosis.Annu. Rev. Nutr. 2010; 30: 201-217Crossref PubMed Scopus (143) Google Scholar). Retinoic acid, the major transcriptionally active retinoid species, is reported to regulate over 500 genes (3Balmer J.E. Blomhoff R. Gene expression regulation by retinoic acid.J. Lipid Res. 2002; 43: 1773-1808Abstract Full Text Full Text PDF PubMed Scopus (766) Google Scholar). The all-trans- and 9-cis-isomers of retinoic acid regulate transcription upon binding to one of their six cognate nuclear receptors, the retinoic acid receptors (RARα, RARβ, and RARγ) and the retinoid X receptors (RXRα, RXRβ, and RXRγ) (4Chawla A. Repa J.J. Evans R.M. Mangelsdorf D.J. Nuclear receptors and lipid physiology: opening the X-files.Science. 2001; 294: 1866-1870Crossref PubMed Scopus (1685) Google Scholar, 5Duong V. Rochette-Egly C. The molecular physiology of nuclear retinoic acid receptors. From health to disease.Biochim. Biophys. Acta. 2011; 1812: 1023-1031Crossref PubMed Scopus (103) Google Scholar). All six of these ligand-dependent transcription factors are expressed within the liver (6Wagner M. Zollner G. Trauner M. Nuclear receptors in liver disease.Hepatology. 2011; 53: 1023-1034Crossref PubMed Scopus (217) Google Scholar). The liver accounts for approximately 70% of all retinoid that is present within the body of a healthy adult, with of this hepatic retinoid within the lipid of hepatic and of A in the Lipid Res. Full Text PDF PubMed Google Scholar, N. R. cell lipid a lipid for retinoid Biophys. Acta. PubMed Scopus Google Scholar). to the retinoid in cell proliferation, differentiation, and apoptosis (1Gudas L.J. Emerging roles for retinoids in regeneration and differentiation in normal and disease states.Biochim. Biophys. Acta. 2012; 1821: 213-221Crossref PubMed Scopus (115) Google is a to understand hepatic retinoid stores liver responses to and hepatic is accompanied by a depletion of retinoid stores, the their lipid and and Nutr. 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