1. FNDC4 reduces hepatocyte inflammatory cell death via AMPKα in metabolic dysfunction-associated steatotic liver disease.
- Author
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Neira, Gabriela, Becerril, Sara, Valentí, Víctor, Moncada, Rafael, Catalán, Victoria, Gómez-Ambrosi, Javier, Colina, Inmaculada, Silva, Camilo, Escalada, Javier, Frühbeck, Gema, and Rodríguez, Amaia
- Abstract
The molecular mediators responsible for the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) to steatohepatitis (MASH) have not yet been completely disentangled. We sought to analyze whether FNDC4, an hepatokine and adipokine with anti-inflammatory properties, is involved in TNF-α-induced inflammatory cell death in patients with MASLD. Plasma FNDC4 (n = 168) and hepatic FNDC4 and inflammatory cell death (n = 65) were measured in samples from patients with severe obesity with available liver biopsy-proven MASLD diagnosis. The effect of FNDC4 on TNF-α-induced pyroptosis, apoptosis and necroptosis (PANoptosis) and mitochondrial dysfunction was studied in vitro using human HepG2 hepatocytes. Compared with individuals with normal liver, patients with type 2 diabetes and MASLD exhibited decreased hepatic FNDC4 mRNA and protein levels, which were related to liver inflammation. An overexpression of TNF-α, its receptor TNF-R1 and factors involved in inflammatory cell death was also found in the liver of these patients. FNDC4 -knockdown in HepG2 hepatocytes increased apoptotic cell death, while FNDC4 treatment blunted NLRP3 inflammasome-induced pyroptosis, apoptosis and necroptosis in TNF-α-stimulated hepatocytes. Moreover, FNDC4 improved TNF-α-induced hepatocyte mitochondrial dysfunction by enhancing mitochondrial DNA (mtDNA) copy number and OXPHOS complex subunits I, II, III and V protein expression. Mechanistically, AMP-activated protein kinase α (AMPKα) was required for the FNDC4-mediated inhibition of cell death and increase in mtDNA content. FNDC4 acts as a hepatocyte survival factor favouring mitochondrial homeostasis and decreasing inflammatory cell death via AMPKα. Collectively, our study identifies FNDC4 as an attractive target to prevent hepatocellular damage in patients with MASLD. [Display omitted] • Hepatic FNDC4 expression is decreased in patients with MASLD. • FNDC4 gene silencing promotes hepatocyte apoptosis. • FNDC4 treatment prevents TNF-α-induced hepatocyte inflammatory cell death via AMPKα. • FNDC4 reduces hepatocyte mitochondrial damage improving mitochondrial biogenesis, dynamics and OXPHOS protein expression. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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