# Novel mechanism based treatment to improve tissue injury in alcoholic hepatitis

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $557,780

## Abstract

Abstract
Despite poor clinical outcomes there has been very limited response to therapies targeting hepatic inflammatory
response especially in patients with malnutrition. Sarcopenia or skeletal muscle loss is a major component of
malnutrition in AH and adversely affects clinical outcomes in these patients. Potential mechanisms by which
sarcopenia can aggravate AH include reduced skeletal muscle metabolism of ethanol and impaired ammonia
disposal due to decreased hepatic ureagenesis promoting ammonia induced hepatotoxicity. Even though
targeting sarcopenia is an innovative approach with a mechanistic rationale to improve outcomes in patients with
AH, this is not part of the therapeutic strategy in the ongoing NIAAA funded AlcHep network. Our published and
preliminary data show dysregulated skeletal muscle protein homeostasis or proteostasis in response to ethanol
in myotubes, mouse models, and human patients with alcoholic liver disease including AH. We also observed
that ethanol exposure increases the skeletal muscle sensitivity to lipopolysaccharide (LPS) that results in
impaired protein synthesis and increased autophagy and consequent sarcopenia. Interestingly, expression of
canonical LPS receptor, TLR4, is increased in myotubes and in muscles from mice exposed to ethanol and
patients with alcoholic liver disease. Consistently, P65NFkB, a downstream target of TLR4, is activated with
increased. Expression of myostatin, a TGFβ superfamily member, a known transcriptional target of P65NFkB
and negative regulator of skeletal muscle protein synthesis is also increased with LPS and ethanol. Interestingly,
low molecular weight hyaluronic acid, especially fragments 35Kd and lower (HA35) have been reported to inhibit
or modulate TLR4 signaling via specific receptors in a context specific manner. We made a novel observation
that HA35 reversed ethanol and LPS induced reduction in myotube diameter, impaired proteostasis and signaling
perturbations in both myotubes and mice exposed to ethanol. We will use HA35 initially in myotubes exposed to
ethanol and mice chronically fed ethanol with binge (Gao model) that has significant sarcopenia and liver injury
similar to that in human AH. In these preclinical studies, we will determine the molecular mechanisms by which
HA35 reverses sarcopenia in AH. We will study the tissue responses to HA35 in ethanol-fed mice including
skeletal muscle protein synthesis and breakdown and signaling responses. We will translate our preliminary and
preclinical data into clinical application by treating human subjects with HA35, a food supplement, following acute
ethanol exposure. We will also test if HA35 is beneficial in patients with moderate AH, a group of patients for
whom there are currently no therapies available despite significant muscle loss and there are no ongoing clinical
trials in moderate AH in the Alchep network. A data coordinating center will assist with these human studies.
These studies will permit rapid therapeu...

## Key facts

- **NIH application ID:** 10071359
- **Project number:** 1R01AA028190-01A1
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Srinivasan Dasarathy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $557,780
- **Award type:** 1
- **Project period:** 2020-09-25 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071359

## Citation

> US National Institutes of Health, RePORTER application 10071359, Novel mechanism based treatment to improve tissue injury in alcoholic hepatitis (1R01AA028190-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10071359. Licensed CC0.

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