Investigation of the mechanisms underlying the protective effect of Glucagon-Like Peptide-1 Receptor agonists on Non-alcoholic Fatty Liver Disease in mice

Project: Experimental Development/Translation Research

Project Details

Abstract

Non-alcoholic Fatty Liver Disease (NAFLD) affects ~25% of the global population and involves hepatic fat accumulation independent of alcohol, virus, and medications . It's increasingly linked to liver transplantation and elevated risks of T2D, CKD, and CVD, causing higher morbidity and mortality. With the ongoing obesity epidemic driving NAFLD, urgent treatments are needed. To date, no approved NAFLD treatments exist. Lifestyle modifications achieving >5% weight loss are the only successful intervention. Yet, patients struggle to sustain weight loss, highlighting the need for effective pharmacotherapy . Glucagon-Like Peptide-1 Receptor agonists (GLP-1RAs), approved for T2D, have shown beneficial impact on NAFLD in humans. However, the mechanisms behind this protection are controversial. Studies propose weight loss or direct hepatic GLP-1 receptor activation. In vitro and in vivo studies show that GLP-1RAs regulate lipid metabolism genes via different pathways, reducing lipid accumulation. Also, GLP-1RAs suppress hepatic glucose production regardless of insulin and glucagon, and reduce hepatic triglycerides and liver enzymes in T2D patients, independent of weight. Thus, to develop novel and safe therapies for NAFLD and identify new drug targets, understanding the mechanisms behind GLP-1RAs' benefits is crucial. We hypothesize that GLP-1RAs binding to hepatic GLP-1R triggers downstream pathways, reducing hepatic fat and improving NAFLD. To investigate the signaling pathways underlying the GLP-1RA-induced NAFLD improvement, we aim to use a multipronged approach combining molecular, cellular, and omics techniques to achieve the following objectives in a non-obese NAFLD mouse model: • Identify differentially expressed metabolites and proteins and their associated metabolic pathways in the liver and plasma of healthy, NAFLD, and Liraglutide-treated NAFLD mice. • Identify differentially expressed long noncoding RNAs and microRNAs in the liver and plasma of healthy, NAFLD, and Liraglutide-treated NAFLD mice. • Conduct functional studies to elucidate the role of the top differentially expressed molecules. Innovation: This study combines multi-omics, cellular, and molecular techniques, and a non-obese NAFLD mouse model, to isolate direct hepatic GLP-1R activation, to uncover GLP-1RAs' protective signaling pathways in NAFLD, regardless of weight loss. Integrating omics data aims to comprehend molecular systems and biomolecule interrelationships in response to GLP-1RAs. Outcome: By deciphering GLP-1RAs' protective mechanisms on NAFLD, irrespective of weight loss, we expect important publications and patents for novel therapeutics and drug targets. Impact: The study's findings will directly impact NAFLD treatment, prevention, and associated comorbidities (CVD, T2D, CKD), with potential for substantial public health impact.

Submitting Institute Name

Hamad Bin Khalifa University (HBKU)
Sponsor's Award NumberARG01-0521-230245
Proposal IDEX-QNRF-ARG-62
StatusActive
Effective start/end date1/04/241/04/27

Collaborative partners

Primary Theme

  • None

Primary Subtheme

  • None

Secondary Theme

  • None

Secondary Subtheme

  • None

Keywords

  • Non-alcoholli fatty liver disease,Steatosis,Diabetes,glucagon-like peptide-1 agonists,obesity
  • None

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