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SHR Neuro Krebs Kardio Lipid Stoffw Microb

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.
Liver receptor homolog-1 is a critical determinant of methyl-pool metabolism.
Hepatology. 2016; 63(1):95-106 Doi: 10.1002/hep.28124 [OPEN ACCESS]
Web of Science PubMed PUBMED Central FullText FullText_MUG

 

Führende Autor*innen der Med Uni Graz
Wagner Martin
Co-Autor*innen der Med Uni Graz
Panzitt Katrin
Zaufel Alex
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Abstract:
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).
Find related publications in this database (using NLM MeSH Indexing)
Animals - administration & dosage
Liver - metabolism
Male - administration & dosage
Methylation - administration & dosage
Mice - administration & dosage
Mice, Knockout - administration & dosage
Receptors, Cytoplasmic and Nuclear - physiology

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