# Investigating folliculin as a regulator of VLDL-TG secretion in non-alcoholic fatty liver disease and steatohepatitis

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2024 · $51,974

## Abstract

Abstract
Non-alcoholic fatty liver disease (NAFLD) is a rapidly emerging public health risk. Approximately 35% of
Americans have NAFLD, and if left untreated, NAFLD can progress to non-alcoholic steatohepatitis (NASH),
cirrhosis, and hepatocellular carcinoma. Although obesity and Type II diabetes have emerged as risk factors,
disease pathogenesis is poorly understood. Accordingly, there are no FDA-approved pharmacotherapies
currently available for patients with NAFLD/NASH. An ideal therapeutic would target multiple hepatic lipid
homeostatic processes, including de novo lipogenesis (DNL), fatty acid oxidation (FAO), and very-low-density
lipoprotein (VLDL)-triglyceride (TG) secretion, as attempts to modulate a single lipid homeostatic process have
often led to undesirable compensation from the remaining pathways. Our lab has identified the protein folliculin
(FLCN) as a potential therapeutic target. Mice with hepatic deletion of FLCN are robustly protected against
steatosis when challenged with NAFLD-inducing diets via an FLCN-mTORC1-TFE3 signaling axis. TFE3
suppresses DNL and induces genes involved in FAO to decrease hepatic TG content in FLCN-null livers. Given
that VLDL-TG secretion is heavily regulated by TG availability, we expected to see a compensatory decrease in
VLDL-TG secretion rate in FLCN-null mice. Strikingly, however, we saw marked upregulation of VLDL-TG
secretion in FLCN deficient mice, which makes FLCN even more appealing as a therapeutic target. I hypothesize
that upregulated VLDL-TG secretion is critical to the robust protection against steatosis afforded by liver deletion
of FLCN, and that activated TFE3 is necessary and sufficient for VLDL-TG secretion. To test this, I will generate
FLCN knockout (KO), TFE3 KO, and FLCN/TFE3 double knockout (DKO) mice and assess VLDL-TG secretion
rates. I will overexpress constitutively active TFE3 in wild-type mice to test if TFE3 is sufficient for VLDL-TG
secretion. My preliminary data further lead me to hypothesize that the upregulated VLDL-TG secretion in FLCN-
null livers is mediated by TFE3-dependent transcriptional activation of CTP:phosphocholine cytidylyltransferase
alpha (CCTa). CCTa is the rate-limiting enzyme in the synthesis of phosphatidylcholine, a critical necessary
component for VLDL-TG secretion. My preliminary data show increased CCTa mRNA and protein levels in FLCN
knockout mice. I will generate FLCN KO, CCTa KO, FLCN/CCTa DKO mice. I will assess their susceptibility to
NAFLD/NASH and perform VLDL-TG secretion assays. Completion of this work would provide insight into the
regulation of hepatic lipid homeostatic processes affected in NAFLD/NASH, as well as demonstrate FLCN to be
a promising therapeutic target for treatment.

## Key facts

- **NIH application ID:** 10808892
- **Project number:** 5F31DK135277-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Chelsea Thorsheim
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $51,974
- **Award type:** 5
- **Project period:** 2023-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10808892

## Citation

> US National Institutes of Health, RePORTER application 10808892, Investigating folliculin as a regulator of VLDL-TG secretion in non-alcoholic fatty liver disease and steatohepatitis (5F31DK135277-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10808892. Licensed CC0.

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