AICAR Ameliorates Non-Alcoholic Fatty Liver Disease via Modulation of the HGF/NF-κB/SNARK Signaling Pathway and Restores Mitochondrial and Endoplasmic Reticular Impairments in High-Fat Diet-Fed Rats.

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a global health problem characterized by altered lipid and redox homeostasis, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. The AMP-dependent kinase (AMPK) agonist 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) has been shown to improve the outcome of NAFLD in the context of AMPK activation, yet the underlying molecular mechanism remains obscure. This study investigated the potential mechanism(s) of AICAR to attenuate NAFLD by exploring AICAR's effects on the HGF/NF-κB/SNARK axis and downstream effectors as well as mitochondrial and ER derangements. High-fat diet (HFD)-fed male Wistar rats were given intraperitoneal AICAR at 0.7 mg/g body weight or left untreated for 8 weeks. In vitro steatosis was also examined. ELISA, Western blotting, immunohistochemistry and RT-PCR were used to explore AICAR's effects. NAFLD was confirmed by steatosis score, dyslipidemia, altered glycemic, and redox status. HGF/NF-κB/SNARK was downregulated in HFD-fed rats receiving AICAR with improved hepatic steatosis and reduced inflammatory cytokines and oxidative stress. Aside from AMPK dominance, AICAR improved hepatic fatty acid oxidation and alleviated the ER stress response. In addition, it restored mitochondrial homeostasis by modulating Sirtuin 2 and mitochondrial quality gene expression. Our results provide a new mechanistic insight into the prophylactic role of AICAR in the prevention of NAFLD and its complications.

• Authors: Doaa Hussein Zineldeen, Nahid Mohamed Tahoon, Naglaa Ibrahim Sarhan
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 24 Issue 4 (Feb 08 2023) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 36834782 (Publication Type: Journal Article)

Chemical References

• AICA ribonucleotide
• AMP-Activated Protein Kinases
• NF-kappa B
• Hgf protein, rat
• Nuak2 protein, rat

Topics

• Animals
• Male
• Rats
• AMP-Activated Protein Kinases (metabolism)
• Diet, High-Fat
• Lipid Metabolism
• Liver (metabolism)
• Mitochondria (metabolism)
• NF-kappa B (metabolism)
• Non-alcoholic Fatty Liver Disease (metabolism)
• Rats, Wistar
• Signal Transduction