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

item WAGNER, MARTIN - Baylor College Of Medicine
item CHOI, SUNGWOO - Baylor College Of Medicine
item PANZITT, KATRIN - Medical University Of Graz
item MAMROSH, JENNIFER - Baylor College Of Medicine
item LEE, JAE - Baylor College Of Medicine
item ZAUFEL, ALEX - Medical University Of Graz
item XIAO, RUI - Baylor College Of Medicine
item WOOTON-KEE, RUTH - Baylor College Of Medicine
item STAHLMAN, MARCUS - University Of Gothenburg
item NEWGARD, CHRISTOPHER - Duke University School Of Medicine
item BOREN, JAN - University Of Gothenburg
item MOORE, DAVID - Baylor College Of Medicine

Submitted to: Hepatology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/11/2015
Publication Date: 1/1/2016
Citation: Wagner, M., Choi, S., Panzitt, K., Mamrosh, J.L., Lee, J.M., Zaufel, A., Xiao, R., Wooton-Kee, R., Stahlman, M., Newgard, C.B., Boren, J., Moore, D.D. 2016. Liver receptor homolog-1 is a critical determinant of methyl-pool metabolism. Hepatology. 63(1):95-106.

Interpretive Summary: Diets deficient in certain important nutrients, including choline, methionine, betaine, and folate, cause several problems in the liver, including fat accumulation, overactivation of the immune system, and formation of scar tissue. It is known that these nutrients are sources of chemical methyl groups, which are a single carbon atom with associated hydrogens: CH3. An important use of these methyl groups is the formation of components of the cell membrane called phosphatidylcholines. Phosphatidylcholines are activators of a receptor protein expressed in the liver called LRH-1. LRH-1 was known to regulate fat accumulation in the liver, but its relationship with methyl group nutrients and phosphatidylcholine synthesis was not known. We compared gene expression in mice engineered to lack LRH-1 expression in the liver, and mice fed a methionine and choline deficient diet. We saw very similar patterns of gene expression, suggesting that the impact of the deficient diet could act to decrease the normal activity of LRH-1. These results identified the receptor LRH-1 as a sensor of the nutrient status of the liver, particularly the level of key nutrients that act as chemical donors of methyl groups for production of new cellular components such as membranes. This provides new understanding of how the liver controls fat levels and suggests new approaches to treat liver disease by changing activity of LRH-1.

Technical Abstract: 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. 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.