# Molecular Mechanisms of Nonalcoholic Fatty Liver Disease

> **NIH VA I01** · JESSE BROWN VA MEDICAL CENTER · 2020 · —

## Abstract

Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, is
rapidly becoming a major public health crisis in the United States paralleling the epidemic of obesity and
diabetes. It has been speculated that the burden of NAFLD among the Veteran population is poised to exceed
that of the general US population. The number of Veterans diagnosed with NAFLD increased nearly 3-fold
from 2003 to 2011 with the steepest rise among Veterans under 45 years of age. Furthermore, Veterans with
NAFLD have a higher prevalence of risk factors associated with progression to cirrhosis. Unfortunately there is
no definitive pharmacologic therapy to prevent or treat NAFLD owing to the fact that the fundamental
pathogenesis of this disorder is incompletely understood. In the current proposal we identify plasminogen
activator inhibitor 1 (PAI-1) as a novel therapeutic target for NAFLD. PAI-1, best characterized as a regulator of
the fibrinolytic cascade, is increasingly recognized as a mediator of metabolic diseases such obesity and
diabetes. Patients with NAFLD have significantly elevated circulating PAI-1 levels and the degree of elevation
closely correlates with the severity of liver disease. Despite this strong association, it remains unknown
whether PAI-1 functions in the pathogenesis of NAFLD or whether pharmacologic inhibition of PAI-1 may have
therapeutic potential. We have generated compelling preliminary data demonstrating that genetic deletion or
pharmacologic inhibition of PAI-1 protects against the development of hepatic steatosis in mice. In the current
proposal we assert that PAI-1 has a fundamental mechanistic role in the progression of NAFLD and inhibiting
PAI-1 will be an effective therapeutic strategy to reverse NAFLD in mice. In Specific Aim 1 we will firmly
establish the role of PAI-1 in NAFLD progression and investigate the therapeutic potential of a novel small
molecule PAI-1 inhibitor in a murine dietary model of nonalcoholic steatohepatitis (NASH). To determine the
role of PAI-1 in progressive NASH (characterized by hepatic inflammation and fibrosis) mice bearing a global
deletion of Pai-1 will be challenged with a high-fat, high-fructose corn syrup (a.k.a “fast-food diet”). To
determine whether inhibiting PAI-1 effectively prevents NASH progression, wild-type C57Bl/6 mice will be fed a
fast-food diet supplemented with TM5441, a novel, orally-active, highly-specific small molecular inhibitor of
PAI-1. To determine whether pharmacologic inhibition of PAI-1 reverses existing NAFLD, TM5441 will be
administered to mice with experimentally induced NAFLD. We hypothesize that 1) Pai-1 deletion or PAI-1
inhibition will protect against fast-food diet-induced steatohepatitis and fibrosis and 2) pharmacologic inhibition
of PAI-1 using TM5441 will effectively reduce existing steatosis in mice. In Specific Aim 2 we will determine the
function of adipose-derived Pai-1 in the development of murine NAFLD and obesity. Adipose ...

## Key facts

- **NIH application ID:** 9933790
- **Project number:** 5I01BX003854-04
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** ANNE S HENKEL
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933790

## Citation

> US National Institutes of Health, RePORTER application 9933790, Molecular Mechanisms of Nonalcoholic Fatty Liver Disease (5I01BX003854-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9933790. Licensed CC0.

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