Liver receptor homolog-1 is a critical determinant of methyl-pool metabolism.

Published

Journal Article

UNLABELLED: Balance of labile methyl groups (choline, methionine, betaine, and folate) is important for normal liver function. Quantitatively, a significant use of labile methyl groups is in the production of phosphatidylcholines (PCs), which are ligands for the nuclear liver receptor homolog-1 (LRH-1). We studied the role of LRH-1 in methyl-pool homeostasis and determined its metabolic effects using the methionine and choline-deficient (MCD) diet, which depletes methyl groups and results in a deleterious decrease in the PC-to-phosphatidylethanolamine ratio. We found that MCD diet-fed, liver-specific LRH-1 knockout mice (Lrh-1(-/-) ) do not show the expected decreased methyl-pool and PC/phosphatidylethanolamine ratio and are resistant to the hepatitis and fibrosis normally induced by the diet. Adaptive responses observed in wild-type mice on the MCD diet were also observed in Lrh-1(-/-) mice on a normal diet. This includes reduced expression of the highly active glycine-n-methyltransferase and the biliary phospholipid floppase multidrug-resistance protein 2 (Mdr2/Abcb4), resulting in reduced consumption of methyl groups and biliary PC secretion. In vitro studies confirm that Gnmt and Mdr2 are primary LRH-1 target genes. Additional similarities between hepatic gene expression profiles in MCD diet-fed wild-type and untreated Lrh-1(-/-) mice suggest that methyl-pool deficiency decreases LRH-1 activity, and this was confirmed by in vitro functional results in cells maintained in MCD medium. CONCLUSION: LRH-1 is a novel transcriptional regulator of methyl-pool balance; when the methyl-pool is depleted, decreased LRH-1 transactivation suppresses expression of key genes to minimize loss of labile methyl groups. (Hepatology 2016;63:95-106).

Full Text

Duke Authors

Cited Authors

  • Wagner, M; Choi, S; Panzitt, K; Mamrosh, JL; Lee, JM; Zaufel, A; Xiao, R; Wooton-Kee, R; Ståhlman, M; Newgard, CB; Borén, J; Moore, DD

Published Date

  • January 2016

Published In

Volume / Issue

  • 63 / 1

Start / End Page

  • 95 - 106

PubMed ID

  • 26267291

Pubmed Central ID

  • 26267291

Electronic International Standard Serial Number (EISSN)

  • 1527-3350

Digital Object Identifier (DOI)

  • 10.1002/hep.28124

Language

  • eng

Conference Location

  • United States