# Role of alcohol-induced ghrelin in modulating organ crosstalk to promote the development of fatty liver disease

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2022 · $339,215

## Abstract

ABSTRACT:
Fatty liver (steatosis), characterized by an accumulation of lipids in hepatocytes, is one of the earliest pathological
changes in the progression of alcohol-associated fatty liver disease (AFLD). Pathophysiological mechanisms
involved during development of AFLD are complex and multifactorial, including gut, pancreas and adipose tissue
dysfunctions that reportedly affect liver pathology. Accumulating evidence has demonstrated that the crosstalk
between these organs are regulated by peptide hormones. Especially relevant to this proposal is the growing
interest in understanding the role of gut hormones in organ interactions and in the development of AFLD.
Among all the gastrointestinal hormones, the stomach-derived ghrelin is the one of the hormones that
significantly increases with chronic alcohol exposure in humans and experimental animal models. In our recent
studies, we demonstrated that an alcohol-induced increase in serum ghrelin levels impairs insulin secretion from
pancreatic β-cells. The consequent reduction in the circulating insulin levels promotes adipose lipolysis and
mobilization of fatty acids to the liver to ultimately contribute to hepatic steatosis. Concomitantly, chronic alcohol
treatment to rats increases serum levels of the gut hormone, glucagon-like peptide-1 (GLP-1) while decreasing
liver-expressed antimicrobial peptide-2 (LEAP-2) and adiponectin levels. Interestingly, these pathological
changes were not altered in ethanol-fed ghrelin receptor knockout (GHS-R KO) rats, which were also resistant
to steatosis development. Collectively, these results indicate a fundamental role of an alcohol-induced ghrelin
increase in affecting multiple organs, such as the gut and adipose to modulate GLP-1, insulin, adiponectin and
LEAP-2 activity/levels, to ultimately lead to the development of AFLD.
To study these effects, we present the following hypothesis: Alcohol-induced increase in serum ghrelin levels
directly (i) inhibits GLP-1 hormone-mediated energy metabolism in hepatocytes and (ii) modulates
adipose metabolism to increase adipose lipolysis and decrease adiponectin secretion, both of which
contribute to hepatic steatosis. Furthermore, ghrelin also enhances its effects by lowering the levels of
LEAP-2, recently discovered endogenous ghrelin antagonist peptide that reduces the ghrelin receptor
(GHS-R) mediated signal transduction.
We will utilize a variety of state-of-the art technologies and innovative biological concepts to explore our
hypothesis in three specific aims: 1) Characterize the role of ghrelin in modulating the gut-derived GLP-1
hormone-mediated gut-liver crosstalk during the development of AFLD; 2) Characterize the specific contribution
of ghrelin in modulating the adipose-liver axis in the development of ALFD; and 3) Examine the effect of alcohol-
induced ghrelin increase on LEAP-2 expression and characterize its role in modulating hepatic steatosis.
Successful completion of the proposed studies will aid mech...

## Key facts

- **NIH application ID:** 10428677
- **Project number:** 5R01AA028504-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Karuna Rasineni
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $339,215
- **Award type:** 5
- **Project period:** 2021-06-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428677

## Citation

> US National Institutes of Health, RePORTER application 10428677, Role of alcohol-induced ghrelin in modulating organ crosstalk to promote the development of fatty liver disease (5R01AA028504-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10428677. Licensed CC0.

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