Role of ghrelin hormone in the development of alcohol-associated liver disease

Sundararajan Mahalingam, Ramesh Bellamkonda, Kusum K. Kharbanda, Madan Kumar Arumugam, Vikas Kumar, Carol A. Casey, Lorenzo Leggio, Karuna Rasineni

Research output: Contribution to journalArticlepeer-review

Abstract

Fatty liver is the earliest response of the liver to excessive alcohol consumption. Previously we identified that chronic alcohol administration increases levels of stomach-derived hormone, ghrelin, which by reducing circulating insulin levels, ultimately contributes to the development of alcohol-associated liver disease (ALD). In addition, ghrelin directly promotes fat accumulation in hepatocytes by enhancing de novo lipogenesis. Other than promoting ALD, ghrelin is known to increase alcohol craving and intake. In this study, we used a ghrelin receptor (GHSR) knockout (KO) rat model to characterize the specific contribution of ghrelin in the development of ALD with emphasis on energy homeostasis. Male Wistar wild type (WT) and GHSR-KO rats were pair-fed the Lieber-DeCarli control or ethanol diet for 6 weeks. At the end of the feeding period, glucose tolerance test was conducted, and tissue samples were collected. We observed reduced alcohol intake by GHSR-KOs compared to a previous study where WT rats were fed ethanol diet ad libitum. Further, when the WTs were pair-fed to GHSR-KOs, the KO rats exhibited resistance to develop ALD through improving insulin secretion/sensitivity to reduce adipose lipolysis and hepatic fatty acid uptake/synthesis and increase fatty acid oxidation. Furthermore, proteomic data revealed that ethanol-fed KO exhibit less alcohol-induced mitochondrial dysfunction and oxidative stress than WT rats. Proteomic data also confirmed that the ethanol-fed KOs are insulin sensitive and are resistant to hepatic steatosis development compared to WT rats. Together, these data confirm that inhibiting ghrelin action prevent alcohol-induced liver and adipose dysfunction independent of reducing alcohol intake.

Original languageEnglish (US)
Article number116595
JournalBiomedicine and Pharmacotherapy
Volume174
DOIs
StatePublished - May 2024

Keywords

  • Chronic alcohol
  • Fatty liver disease
  • GHSR
  • Ghrelin
  • Gut peptides
  • Organ crosstalk

ASJC Scopus subject areas

  • Pharmacology

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