Bilirubin, a hepatoprotective agent that activates SIRT1, PGC-1α, and PPAR-α, while inhibiting NF-κB in rats with metabolic-associated fatty liver disease

• Published in: Scientific reports 2024-11, Vol.14 (1), p.29244-22, Article 29244
• Main Authors: Taghizadeh, Motahareh, Maleki, Mohammad Hasan, Vakili, Omid, Tavakoli, Ramin, Zarei, Parvin, Dehghanian, Amirreza, Bordbar, Hossein, Shafiee, Sayed Mohammad
• Format: Article
• Language: English
• Subjects: 631/114; 631/1647; 631/208; 631/337; 631/443; 631/45; 631/80; 631/92; 692/308; 692/4017; 692/4020; Animals; Bilirubin; Bilirubin - metabolism; Diabetes mellitus (non-insulin dependent); Diet, High-Fat - adverse effects; Fatty liver; Gene expression; Genes; Hepatocytes; High fat diet; Humanities and Social Sciences; Inflammation; Interleukin 6; Lipid metabolism; Lipid Metabolism - drug effects; Lipids; Liver; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver diseases; Male; Metabolic associated fatty liver disease; Metabolism; multidisciplinary; NF-kappa B - metabolism; NF-κB; NF-κB protein; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - etiology; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - genetics; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; Peroxisome proliferator-activated receptors; PPAR alpha - metabolism; PPAR-α; Protective Agents - pharmacology; Rats; Rats, Sprague-Dawley; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - drug effects; SIRT1; SIRT1 protein; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; Streptozocin; Tumor necrosis factor-α
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-80119-5

Metabolic-associated fatty liver disease (MAFLD) is a chronic liver disorder characterized by fatty liver disease alongside overweight or obesity and/or type 2 diabetes mellitus (T2DM). Timely intervention is crucial for a potential cure. This study aimed to investigate the effects of bilirubin, an endogenous antioxidant, on lipid metabolism and inflammation in MAFLD. Specifically, it examined bilirubin’s impact on SIRT1, PPAR-α, and NF-κB in the livers of rats with MAFLD induced by a high-fat diet (HFD) and streptozotocin (STZ) administration. Forty eight-week adult male Sprague Dawley rats were divided into five groups (n = 8): Control, HFD-STZ, HFD-S-BR6, HFD-S-BR14, and C-BR14. In the last three groups, bilirubin administration was performed intraperitoneally for 6 and 14 weeks (10 mg/kg/day). We selected the key genes associated with MAFLD and subsequently performed GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses to explore the enriched biological processes and signaling pathways. Hence, the gene expression of SIRT1, PGC-1α, PPAR-α, and inflammatory genes (NF-κB, TNF-α, IL-6, and IL-1β) was measured using Real-time quantitative PCR. Stereological and histopathological alterations of liver structure as well as lipid profile, biochemical indices, and liver indices, were also assessed among different groups. The enrichment analysis identified that several signaling pathways and biological processes might be related to MAFLD. Bilirubin-treated rats contained higher PPAR-α, PGC-1α, and SIRT1 expression levels by approximately 5.7-, 2.1-, and 2.2-fold, respectively, compared to the HFD-receiving rats (p