# Low Dose Thyroid Hormone, Mitochondrial Fatty Acid Oxidation, and Treatment of Nonalcoholic Steatohepatitis (NASH)

> **NIH VA I01** · HARRY S. TRUMAN MEMORIAL VA HOSPITAL · 2024 · —

## Abstract

Nonalcoholic steatohepatitis (NASH) is an aggressive part of the pathological spectrum of nonalcoholic fatty
liver disease (NAFLD) that has evolved into a world-wide epidemic and is the most common chronic liver
disease in the United States. NASH is strongly linked to obesity, and type 2 diabetes mellitus and may
progress to cirrhosis and liver cancer. Disturbingly, prevalence rates of NASH appear to be greater in the
Veteran population compared with the general US population. Thus, the burden of NASH is substantial to
Veterans. Despite the recognition of NASH as a major public health problem, only lifestyle modifications aimed
at increasing physical activity and reducing caloric intake are currently recommended as treatments with
limited success. Thus, there is a great need for effective therapy of NASH. The goal of this study is to test
whether low dose thyroid hormone administered to Veterans with biopsy-proven NASH, at a titrated dose that
will maintain thyroid function within normal range, can result in histological improvement of NASH, measured
by significant reduction in nonalcoholic fatty liver disease score (NAS). The hypothesis is that low dose thyroid
hormone causes histological improvement in NASH by increasing mitochondrial FAO in the liver mediated by
an increase in mitochondrial trifunctional protein (MTP), the key enzyme in FAO cycle. The preliminary clinical
studies in human subjects, including Veterans, support reduced FAO in NASH. In addition, preclinical in vivo
animal studies and in vitro cell culture studies support that low dose thyroid hormone can effectively increase
mitochondrial fatty acid oxidation and rescue NAFLD. In a randomized double-blinded placebo-controlled
clinical trial, Veterans with normal thyroid levels and biopsy-proven NASH will be recruited and randomized to
receive 52 weeks of either active treatment (low dose levothyroxine) or placebo control to accomplish the
following Specific Aims. 1) To determine the efficacy of low dose thyroid hormone in improving NASH
histological features. To accomplish this aim, NAS will be measured in pre- and post-liver biopsy samples. 2)
To determine the effect of low dose thyroid hormone on mitochondrial FAO, MTP, and mitochondrial health
markers in the liver compared to control. To accomplish this aim, mitochondrial FAO and the expression of
genes supporting mitochondrial health will be measured in the pre- and post-liver biopsy samples. The primary
clinical outcome is histological improvement in NASH measured by improvement in NAS and the secondary
clinical outcome is improvement in fibrosis stage. The mechanistic outcomes include improvements in
mitochondrial FAO, MTP, and quality markers. This project will be conducted in two stages. In stage 1 (proof-
of-concept, 2 years), 32 Veterans with biopsy-proven NASH will be recruited and randomized to either the
active treatment or placebo groups (16/group). At the end of the second year, interim analysis will be
performed b...

## Key facts

- **NIH application ID:** 10909792
- **Project number:** 5I01CX002436-02
- **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:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2023-04-01 → 2029-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909792

## Citation

> US National Institutes of Health, RePORTER application 10909792, Low Dose Thyroid Hormone, Mitochondrial Fatty Acid Oxidation, and Treatment of Nonalcoholic Steatohepatitis (NASH) (5I01CX002436-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10909792. Licensed CC0.

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