Identification of metabolic regulators of hepatic phosphatidylcholine synthesis
NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases
About This Grant
Abstract Hepatic phosphatidylcholine (PC) metabolism is essential for maintaining lipid homeostasis, as PCs are required for very-low-density lipoprotein (VLDL) secretion and protection against hepatic fat accumulation. Disruptions in PC synthesis are linked to metabolic dysfunction-associated fatty liver disease (MAFLD), a condition affecting over 25% of the U.S. population. However, the genetic regulation of PC metabolism in response to metabolic stress, and its relevance to MAFLD prevention and progression, remain poorly understood. Our preliminary data reveal that the transmembrane oxidoreductase VKORC1L1 regulates hepatic PC levels through a function independent of its enzymatic activity. Furthermore, loss of hepatic Vkorc1l1 in mice decreases PC levels, reduces VLDL secretion, and promotes hepatic fat accumulation. Lastly, human genetic data indicate a potential link between VKORC1L1 variants and liver steatosis, suggesting a role in MAFLD progression. Hepatic PC levels are regulated through three primary pathways: de novo synthesis from choline via the Kennedy pathway, methylation of phosphatidylethanolamine (PE), and the salvage of exogenous lipids. We aim to define the role of VKORC1L1 in hepatic PC metabolism and MAFLD by addressing three key questions. First, we will determine whether VKORC1L1 is necessary and sufficient to regulate PC levels and mitigate MAFLD progression in mouse models under varying dietary conditions, focusing on two MAFLD-relevant nutrients: fat and choline—a precursor for PC synthesis. Using liver-specific Vkorc1l1 knockout and overexpression mice, we will assess its impact on VLDL secretion, hepatic lipid accumulation, and whole-body metabolic health. Second, we will delineate the broader impact of VKORC1L1 on hepatic PC homeostasis by assessing its influence on the three major pathways that maintain PC levels—the Kennedy pathway, PE methylation, and lipid salvage—using isotope-labeled metabolic precursors and phospholipid analytical approaches. Finally, we will investigate the molecular mechanism by which VKORC1L1 influences de novo PC synthesis, building on our preliminary data showing that VKORC1L1 binds to and activates CCTα, the rate-limiting enzyme of the Kennedy pathway. By combining biochemical and structural approaches, including cryo-electron microscopy, we will test whether this interaction is influenced by membrane PC content in cells and mouse liver. By uncovering how VKORC1L1 regulates PC metabolism and VLDL secretion, our study will reveal key molecular mechanisms linking choline and PC deficiency to MAFLD. This is particularly relevant, as low-choline and high-fat diets are prevalent in segments of the U.S. population. Our findings could inform therapeutic strategies targeting VKORC1L1 to restore PC homeostasis and mitigate MAFLD progression—an urgent priority given the widespread prevalence of MAFLD and its considerable variability in severity and treatment response.
Grant Summary
Identification of metabolic regulators of hepatic phosphatidylcholine synthesis is a NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases grant providing up to $676K for university, nonprofit, healthcare org. Applications are due 2029-11-30 (open). Check eligibility and apply with FindGrants.
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How to Apply
Up to $676K
2029-11-30
- 1Confirm your organization is eligible for Identification of metabolic regulators of hepatic phosphatidylcholine synthesis from NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases, checking organization type, location, and any population or project requirements.
- 2Gather the required documents and information, including your organization details, project plan, and budget figures.
- 3Draft your application narrative and budget addressing the funder's priorities and review criteria. FindGrants can draft each section for you to review and edit.
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Identification of metabolic regulators of hepatic phosphatidylcholine synthesis: Frequently Asked Questions
Who is eligible for the Identification of metabolic regulators of hepatic phosphatidylcholine synthesis?
Identification of metabolic regulators of hepatic phosphatidylcholine synthesis is offered by NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases and is generally open to university, nonprofit, healthcare org. It is open to organizations nationwide unless the funder specifies otherwise. Review the specific eligibility terms before applying, since funders set their own requirements around organization type, location, and the population or project being served.
How much funding does the Identification of metabolic regulators of hepatic phosphatidylcholine synthesis provide?
Identification of metabolic regulators of hepatic phosphatidylcholine synthesis provides up to $676K per award from NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases. Actual award sizes depend on the scope of your project, available program funds, and the number of applicants, so build a budget that reflects realistic, allowable costs rather than the maximum figure.
When is the Identification of metabolic regulators of hepatic phosphatidylcholine synthesis deadline?
Applications for Identification of metabolic regulators of hepatic phosphatidylcholine synthesis are due 2029-11-30 (open). Because deadlines can change, verify the date with the funder, NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases, and give yourself enough time to prepare a complete, competitive application before the close date.
How do you apply for the Identification of metabolic regulators of hepatic phosphatidylcholine synthesis?
To apply for Identification of metabolic regulators of hepatic phosphatidylcholine synthesis, confirm your eligibility, gather the required documents, and prepare a narrative and budget that address the funder's priorities. FindGrants guides you step by step and can draft each section, then exports a submission-ready application pack for this grant from NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases.