# Regulation of Hepatic Phosphatidylcholine Synthesis by mTORC1

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2022 · $46,752

## Abstract

PROJECT SUMMARY
Non-alcoholic fatty liver disease (NAFLD) is a disease of altered lipid metabolism characterized by the
accumulation of fat in the liver. The prevalence of NAFLD is closely correlated with obesity, insulin resistance,
and type 2 diabetes mellitus. NALF can progress to a more severe form of liver disease, known as non-alcoholic
steatohepatitis, hallmarked by inflammation and fibrosis of the liver. Despite the severity of these diseases, there
are currently no FDA approved treatments for NAFLD and NASH, highlighting the critical need to elucidate the
mechanism underlying these diseases to develop new therapies. In the liver, the anabolic hormone insulin
regulates hepatic lipid homeostasis by promoting triacylglyceride (TAG) synthesis, suppressing fatty acid
breakdown, and promoting TAG export via very low-density lipoproteins (VLDL). VLDL-TAG secretion from the
liver is controlled by the biosynthesis of phosphatidylcholine (PC), the main phospholipid coating lipoproteins.
Defects in PC synthesis in human and rodent models are linked to decreased VLDL-TAG secretion and ultimately,
NAFL. Our lab recently demonstrated that downstream of insulin signaling in mice, the mechanistic target of
rapamycin complex 1 (mTORC1) controls VLDL-TAG secretion through regulation of CCTα, the rate-limiting
enzyme in PC synthesis. Therefore, the goals of this study are (1) to elucidate the relationship between mTORC1
and CCTα protein, and (2) to evaluate their subsequent control of hepatic phospholipid synthesis and lipid
homeostasis in vivo. Based on published phosphoproteomic studies, I hypothesize that mTORC1 directly
phosphorylates CCTα at Serine-315, and this phosphorylation prevents ubiquitination and subsequent
degradation of CCTα protein. In my preliminary data, I identify a mTORC1-dependent phosphorylation of CCTα
at Serine-315 as a critical step in controlling CCTα activity and this phosphorylation regulates total CCTα protein
content. Thus, I will test whether CCTα is directly phosphorylated by mTORC1 and establish the mechanism
through which mTORC1 regulates CCTα stability and activity. Furthermore, I will test the effects of CCTα
phosphorylation at Serine-315 in vivo, by utilizing adeno-associated virus constructs carry CCTα phosphorylation
mutants. On the basis of my preliminary data revealing CCTα phosphomimetic mutant at Ser315 (S315D) has
increased CCTα activity, I hypothesize that CCTα phosphomimetic mutant, S315D, enhances PC synthesis and
TAG secretion in vivo in mice. Lastly, I will test whether CCTα S315D mutant is sufficient to prevent NASH in
mice fed a high fat, low methionine, choline deficient diet, a commonly used NASH-inducing diet. Altogether,
findings from this study will identify a novel role of mTORC1 in regulating hepatic PC synthesis and TAG
secretion, which may be beneficial for the development of new therapies for NAFLD and NASH.

## Key facts

- **NIH application ID:** 10508492
- **Project number:** 5F31DK128876-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Kahealani Uehara
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 5
- **Project period:** 2021-04-25 → 2024-04-24

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10508492

## Citation

> US National Institutes of Health, RePORTER application 10508492, Regulation of Hepatic Phosphatidylcholine Synthesis by mTORC1 (5F31DK128876-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10508492. Licensed CC0.

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