# Role of non-genomic regulation of mitochondrial trifunctional protein in NAFLD

> **NIH VA I01** · HARRY S. TRUMAN MEMORIAL VA HOSPITAL · 2022 · —

## Abstract

Nonalcoholic fatty liver disease (NAFLD) is characterized by increased deposition of fat in the liver that may
progress to inflammation, hepatocellular carcinoma, and liver failure. NAFLD is closely linked to type 2
diabetes mellitus and obesity. It remains a major public health problem with little progress made on its
treatment. Disturbingly, NAFLD appears to be more common in the military and Veteran population compared
with the general US population. Thus, efforts to understand the underlying mechanisms that contribute to
NAFLD will provide valuable insight into developing therapeutic options for our Veteran population.
Mitochondrial dysfunction plays a crucial role in the development of NAFLD, however, little is known about how
to treat mitochondrial dysfunction and rescue the associated NAFLD. Mitochondrial trifunctional protein (MTP)
is the major enzymatic complex in mitochondrial fatty acid oxidation (FAO) that consists of 4 α and 4β subunits
carrying three enzymatic activities breaks down fatty acids in the mitochondria. A key unanswered question is
whether regulation of MTP modulates NAFLD. In a reported mouse model with an MTP defect, mice
heterozygous for the defect (MTP+/-) develop mitochondrial dysfunction and are susceptible to NAFLD.
Determining the mechanisms involved in regulating MTP in this mouse model is critical to the understanding of
the role of mitochondria in development and rescue of NAFLD. The hypothesis in this application is that
increasing the assembly of the MTP complex increases its stability, which leads to improvement in
mitochondrial fatty acid oxidation (FAO) and rescue of NAFLD. The proposal in this application is that both the
NAD+-dependent SIRT3 and the triiodothyronine (T3) hormone improve MTP stability by nongenomic
mechanisms through enhancement of the MTP complex assembly. The preliminary data strongly support the
hypothesis. First, mitochondrial FAO, MTP and SIRT3 levels were reduced in liver samples obtained from
human subjects with NAFLD. Second, overexpression of SIRT3 in the MTP+/- mice reduced the acetylation of
MTP compared to controls, increased mitochondrial FAO, and reduced steatosis and inflammatory markers in
the liver. Third, in vitro studies in cultured cells demonstrate that MTP stability and its levels were increased by
T3 treatment. To examine this hypothesis, we will use human liver samples obtained from a Veteran patient
population and the MTP mouse model to conduct ex vivo, in vivo, and in vitro studies towards the following
specific aims: 1) To define the relationship between hepatic MTP-α levels, SIRT3 levels, mitochondrial FAO
and disease severity in human liver samples obtained from Veteran population. 2) To determine the underlying
mechanisms of increased MTP levels by SIRT3 overexpression in mice. 3) To test whether T3 rescues NAFLD
in the MTP mouse model and whether it improves hepatic mitochondrial FAO by increasing MTP stability
through interaction with mitochondrial shorten...

## Key facts

- **NIH application ID:** 10292920
- **Project number:** 5I01BX004710-03
- **Recipient organization:** HARRY S. TRUMAN MEMORIAL VA HOSPITAL
- **Principal Investigator:** JAMAL A IBDAH
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10292920

## Citation

> US National Institutes of Health, RePORTER application 10292920, Role of non-genomic regulation of mitochondrial trifunctional protein in NAFLD (5I01BX004710-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10292920. Licensed CC0.

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