LRH-1 NUTRIGENOMICS: The Provision of Lauric Acid Results in the Endogenous Production of the Liver Receptor Homolog-1 Ligand, Dilauroylphosphatidylcholine, and LRH-1 Transactivation

Klatt, K. C.; Zhang, S.; Malysheva, O. V.; Sun, Z.; Dong, B.; Brenna, J. T.; Moore, D. D.; Roberson, M. S.; Caudill, M. A.

doi:10.1101/2021.02.01.429240

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bioRxiv · 10.1101/2021.02.01.429240

LRH-1 NUTRIGENOMICS: The Provision of Lauric Acid Results in the Endogenous Production of the Liver Receptor Homolog-1 Ligand, Dilauroylphosphatidylcholine, and LRH-1 Transactivation

Klatt, K. C.·Zhang, S.·Malysheva, O. V.·Sun, Z.·Dong, B.·Brenna, J. T.·Moore, D. D.·Roberson, M. S.·Caudill, M. A.

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Abstract

BackgroundThe unusual phosphatidylcholine species, dilauroylphosphatidylcholine (DLPC), has been reported to bind and activate the orphan nuclear receptor, liver receptor homolog-1 (LRH-1). To date, DLPC has not been reported endogenously in metabolomic databases. ObjectiveHerein, we test the hypothesis that the provision of the acyl constituent of DLPC, lauric acid (C12:0), a saturated fatty acid rich in tropical oils such as coconut oil, will 1) result in endogenous DLPC production and 2) enhance LRH-1 transcriptional activity. MethodsWe measured DLPC following provision of C12:0 to HepG2 cells, C57/BL6J mice, and to healthy human participants in an acute, randomized, controlled cross-over trial. LRH-1fl/fl and LRH-1fl/fl Albumin-Cre mice were used in ex vivo and in vivo approaches. to assess the impact of C12:0 on LRH-1 target gene expression. 1-13C-lauric acid and methyl-d9-choline were used to assess DLPC production dynamics. ResultsDLPC was not observed in any C12:0-free approach. Provision of C12:0 in the culture media or to C57/BL6J mice resulted in the rapid production of DLPC, including DLPCs presence in multiple LRH-1 expressing tissues. Coconut oil-fed human participants exhibited DLPC in postprandial serum samples. Ex vivo and in vivo C12:0 provision resulted in increased mRNA expression of LRH-1 target genes, an effect that was not observed in hepatic knockout mice. Methyl-d9-choline administration revealed a complex reliance on CDP-choline-derived DLPC. ConclusionC12:0 provision results in endogenous production of the LRH-1 ligand, DLPC, and LRH-1 transcriptional activation phenotypes. Our findings highlight pleiotropic effects of lauric acid, a common hypercholesterolemic dietary saturated fatty acid, secondary to LRH-1 agonism.

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Klatt, K. C., Zhang, S., Malysheva, O. V., Sun, Z., Dong, B., Brenna, J. T., Moore, D. D., Roberson, M. S., Caudill, M. A.. 2021-02-02. LRH-1 NUTRIGENOMICS: The Provision of Lauric Acid Results in the Endogenous Production of the Liver Receptor Homolog-1 Ligand, Dilauroylphosphatidylcholine, and LRH-1 Transactivation. https://doi.org/10.1101/2021.02.01.429240

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