# The role of FIT2 in VLDL assembly, hepatic triglyceride homeostasis, and lipoprotein atherogenicity

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $168,957

## Abstract

This R01 application focuses on the mechanisms that control the generation of very low density lipoproteins
(VLDLs) in liver cells. Prior work from the MPIs, which has resulted in 15 publications, established that a major
mechanism controlling the secretion and circulation of VLDL is the regulated degradation of apolipoprotein
(apoB) in the endoplasmic reticulum (ER). This metabolically orchestrated event requires the ER-associated
degradation (ERAD) pathway, which was named and first elucidated by MPI Brodsky. In contrast, when neutral
lipids (primarily triacylglycerols; TGs) are sufficient, apoB is co-translationally lipidated by MTP, and the nascent
VLDL particles are expanded by lipids sourced from ER-resident lipid droplets (LDs). The re-modelled VLDL
particles are next packaged into COPII vesicles for delivery to the Golgi and then secreted into the medium from
hepatic cells (in vitro) or from liver hepatocytes into the circulation (in vivo). In contrast to these pathways that
control the levels of VLDL, the factors that regulate the concentration and composition of lipids assembled onto
apoB in the ER are poorly characterized. However, recent results generated by the MPIs and colleagues indicate
that an ER-resident membrane protein, FIT2, plays a significant role in controlling TG assembly onto apoB in
vitro and in vivo. Specifically, the preliminary data outlined in this application—which were made possible by the
generation of novel rodent models and engineered VLDL secreting cell lines—strongly suggest that FIT2
regulates both the concentration and composition of apoB-associated lipids, as well as the atherogenicity of
VLDL. Based on these and other new data, the following hypotheses will be tested: 1) FIT2 deficiency will
increase ER membrane lipid content along with the generation of TG-depleted VLDL; 2) FIT2 delivers LDs into
the ER, which are then integrated into VLDL particles in either an MTP-dependent or independent manner; and,
3) the level of FIT2 activity is a previously unappreciated determinant for the severity of fatty liver disease
(NAFLD), steatohepatitis (NASH), and atherosclerosis.
 Because the efficiency of FIT2-mediated loading of TG onto VLDL also impacts hepatic lipid levels in the ER,
FIT2 deficiency may also lead to lipid dysregulation in the ER and toxic stress responses. Moreover, the delivery
of lipid-rich VLDLs could be limited by another ER-associated factor, KLHL12, that helps form specialized VLDL-
resident COPII vesicles. Thus, another hypothesis is that native KLHL12 levels constrain the capacity of FIT2-
supported delivery of VLDL from hepatic cells, thus exacerbating ER stress. Overall, besides dissecting how
FIT2 regulates NASH, NAFLD, VLDL biogenesis, hepatic TG homeostasis, and lipoprotein atherogenicity, the
clinical relevance of this project also includes the integration of transcriptomic data from the recently generated
models with analogous databases obtained from human livers and atherosclerotic...

## Key facts

- **NIH application ID:** 10823239
- **Project number:** 5R01HL168569-02
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** JEFFREY L. BRODSKY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $168,957
- **Award type:** 5
- **Project period:** 2023-04-06 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10823239

## Citation

> US National Institutes of Health, RePORTER application 10823239, The role of FIT2 in VLDL assembly, hepatic triglyceride homeostasis, and lipoprotein atherogenicity (5R01HL168569-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10823239. Licensed CC0.

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