Manganese-Induced Oxidative Stress Contributes to Intestinal Lipid Deposition via the Deacetylation of PPAR gamma at K339 by SIRT1

Aims: Excessive manganese (Mn) exposure is toxic, and induces lipid deposition, but the underlying mechanisms remain elusive. Herein, we explored how dietary Mn supplementation affects lipid deposition and metabolism in the intestine of vertebrates using the yellow catfish Pelteobagrus fulvidraco as the model.Results: High-Mn (H-Mn) diet increased intestinal Mn content, promoted lipid accumulation and lipogenesis, and inhibited lipolysis. In addition, it induced oxidative stress, upregulated metal-response element-binding transcription factor-1 (MTF-1), and peroxisome proliferator-activated receptor gamma (PPAR gamma) protein expression in the nucleus, induced PPAR gamma acetylation, and the interaction between PPAR gamma and retinoid X receptor alpha (RXR alpha), while it downregulated sirtuin 1 (SIRT1) expression and activity. Mechanistically, Mn activated the MTF-1/divalent metal transporter 1 (DMT1) pathway, increased Mn accumulation in the mitochondria, and induced oxidative stress. This in turn promoted lipid deposition via deacetylation of PPAR gamma at K339 by SIRT1. Subsequently, PPAR gamma mediated Mn-induced lipid accumulation through transcriptionally activating fatty acid translocase, stearoyl-CoA desaturase 1, and perilipin 2 promoters.Innovation: These studies uncover a previously unknown mechanism by which Mn induces lipid deposition in the intestine via the oxidative stress-SIRT1-PPAR gamma pathway.Conclusion: High dietary Mn intake activates MTF-1/DMT1 and oxidative stress pathways. Oxidative stress-mediated PPAR gamma deacetylation at K339 site contributes to increased lipid accumulation. Our results provided a direct link between Mn and lipid metabolism via the oxidative stress-SIRT1-PPAR gamma axis.