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


CONCLUSIONS
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).
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.|Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria.
Martin
M
Wagner
Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA.
Sungwoo
S
Choi
Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria.
Katrin
K
Panzitt
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Jennifer L
JL
Mamrosh
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Jae Man
JM
Lee
Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria.
Alex
A
Zaufel
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Rui
R
Xiao
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Ruth
R
Wooton-Kee
Department of Molecular and Clinical Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
Marcus
M
Ståhlman
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA.
Christopher B
CB
Newgard
Department of Molecular and Clinical Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
Jan
J
Borén
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
David D
DD
Moore
D000818:Animals; D008099:Liver / Q000378:metabolism*; D008297:Male; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*
C082631:NR5A2 protein, human; D018160:Receptors, Cytoplasmic and Nuclear