# Impaired VLDL secretion, progression and reversal of hepatic fibrogenesis

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $522,202

## Abstract

PROJECT SUMMARY/ABSTRACT
The major OBJECTIVES in this application are to understand the mechanisms and pathways by which
impaired hepatic VLDL secretion promotes fibrosis and HCC. Our proposal is SIGNIFICANT because of the
unmet need for a more nuanced approach to identify subsets of NAFLD where a more tailored approach might
inform strategies for prevention and reversal of NASH/fibrosis and HCC. The BACKGROUND to this proposal
is that genetic defects (APOB, APOC3, 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 is that elucidating pathways whereby impaired hepatic
VLDL secretion promotes fibrosis and HCC will identify novel, druggable pathways for fibrosis reversal and
HCC prevention in a metabolic subset of NAFLD/NASH. Our proposal is supported by KEY PRELIMINARY
DATA including: (AIM 1) CDK4 activation as a mediator of fibrogenic injury with impaired hepatic VLDL
secretion following liver-specific microsomal triglyceride transfer protein (Mttp) deletion (Mttp-LKO). We also
find increased genotoxic HCC in Mttp-LKO mice and will pursue the underlying mechanisms involved. (AIM 2).
We have developed novel tissue-specific Tm6sf2 knockout mice to examine the metabolic and fibrogenic
pathways associated with both loss of function and conditional (WT and E167K) rescue, to discern
mechanisms of fibrosis and tumorigenesis with impaired VLDL secretion resulting from liver-specific Tm6sf2
deletion, compared to mice with Mttp deletion. The AIMS of this proposal are: AIM 1. What pathways and
mediators promote fibrosis and HCC with impaired hepatic VLDL secretion and how are these pathways
modified by altered lipid droplet (LD) turnover? Aim 1 builds on the findings with CDK4 activation pathways
and will identify lipidomic mediators of fibrogenesis as well as examining strategies for modifying LD turnover
to mitigate the development of fibrosis and HCC. AIM 2. How does liver specific Tm6sf2 (Tm6-LKO) deletion,
and rescue, alter hepatic lipid homeostasis and how do these adaptations influence hepatic fibrogenic injury
and HCC? Aim 2 asks how LD formation, turnover and FA utilization for VLDL secretion is altered in Tm6-LKO
mice and with what implications for fibrosis and HCC. We also ask how those pathways differ from those
elucidated with Mttp deletion and, further, how AAV8-mediated rescue with either wild-type (E167) or mutant
(K167) Tm6sf2 modifies those metabolic phenotypes and with what impact for hepatic fibrogenesis and HCC in
Tm6 LKO mice. Taken together, we address a CRITICAL KNOWLEDGE GAP by exploring novel pathways of
fibrogenic injury and HCC, focusing on defective VLDL secretion as a nexus point directly relevant to a subset
of genetic and acquired etiologies of NAFLD...

## Key facts

- **NIH application ID:** 10151606
- **Project number:** 5R01DK119437-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Nicholas O. Davidson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $522,202
- **Award type:** 5
- **Project period:** 2019-07-16 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10151606

## Citation

> US National Institutes of Health, RePORTER application 10151606, Impaired VLDL secretion, progression and reversal of hepatic fibrogenesis (5R01DK119437-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10151606. Licensed CC0.

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