# Impaired VLDL secretion in progression of NAFLD and NASH in mice and humans

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $568,310

## Abstract

PROJECT SUMMARY/ABSTRACT
The major OBJECTIVES in this application are to expand understanding of mediators of fibrogenic injury
and HCC development associated with impaired VLDL secretion in both mice and humans. Our proposal
is SIGNIFICANT because of the unmet need to identify subsets of patients with NAFLD whose disease will
progress and where a more tailored approach might inform therapeutic strategies for prevention and reversal of
NASH/fibrosis and the development of HCC. The BACKGROUND is that genetic defects (APOB, MTTP,
TM6SF2) that impair hepatic VLDL secretion cause hepatic steatosis and progress to NASH with fibrosis and
HCC, even without obesity or insulin resistance. In addition, VLDL secretion is relatively (ie paradoxically)
impaired in a subset of insulin-resistant, NAFLD patients. Accordingly, our overall SCIENTIFIC PREMISE is that
identifying shared pathways in genetically modified mouse models and in metabolic subset of patients
with NASH and impaired hepatic VLDL secretion will identify druggable targets for fibrosis reversal and
prevention of HCC. Our proposal is supported by KEY PRELIMINARY DATA including: (AIM 1) Liver-specific
Tm6sf2 knockout mice (Tm6-LKO), phenocopies the loss-of-function human TM6SF2 (E167K) variant
rs58542926 with defective VLDL secretion, hepatic steatosis, fibrosis and increased HCC. We generated
Tm6sf2 variant knockin (K167K) mice to examine hepatic VLDL and intestinal chylomicron secretion. We
generated variant knockin HepG2 cells and iPS-derived hepatocyte-like cell lines to study the loss-of-function
variant in human VLDL assembly. (AIM 2). Liver-specific microsomal triglyceride transfer protein knockout mice
(Mttp-LKO) mice crossed into Fabp1–/– mice (ML-DKO) mice exhibit reduced steatosis and decreased fibrosis,
yet paradoxically increased HCC. By contrast Mttp-LKO mice crossed into liver-specific DGAT2 knockout mice
are protected against HCC. We identified a metabolomic signature in patients with NAFLD/NASH that aligns
with impaired VLDL secretion and will examine patients with NASH-HCC. The AIMS of this proposal are: AIM 1.
How does how the Tm6sf2 variant alter APOB lipidation and regulate hepatic and intestinal VLDL/chylomicron
assembly and secretion? How does the K167K variant influence the development of fibrosis and HCC? How
are these pathways in mouse VLDL assembly and secretion replicated in representative human hepatocyte-like
cell lines (HepG2, iPS-derived hepatocyte-like cells)? AIM 2. How do modifiers of DNL and LD turnover modify
signaling pathways in mice with impaired VLDL secretion (Mttp-LKO) that either promote (Fabp1-dependent) or
mitigate (Dgat2-dependent) HCC development? We will examine how pathways identified in mice with impaired
VLDL secretion and either increased or decreased HCC susceptibility align with transcriptomic signatures in liver
of patients with NASH-HCC and a metabotype of impaired VLDL secretion. Taken together, we address a
CRITICAL KNOWLEDGE GAP by explor...

## Key facts

- **NIH application ID:** 10881216
- **Project number:** 2R01DK119437-05A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Nicholas O. Davidson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $568,310
- **Award type:** 2
- **Project period:** 2019-07-16 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881216

## Citation

> US National Institutes of Health, RePORTER application 10881216, Impaired VLDL secretion in progression of NAFLD and NASH in mice and humans (2R01DK119437-05A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10881216. Licensed CC0.

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