Processed Meat Protein Promoted Inflammation and Hepatic Lipogenesis by Upregulating Nrf2/Keap1 Signaling Pathway in Glrx-Deficient Mice

Oxidative stress may play a critical role in the progression of liver disorders. Increasing interest has been given to the associations among diet, oxidative stress, gut-liver axis, and nonalcoholic fatty liver disease. Here, we investigated the effects of processed meat proteins on biomarkers of lipid homeostasis, hepatic metabolism, antioxidant functions, and gut microbiota composition in glutaredoxin1 deficient (Glrx1-/-) mice. The wild-type (WT) and Glrx1-/- mice were fed a soy protein diet (SPD), a dry-cured pork protein diet (DPD), a braised pork protein diet (BPD), and a cooked pork protein diet (CPD) at a dose of 20% of protein for 3 months. Serum and hepatic total cholesterol, serum endotoxin, hepatic liver droplet %, and antioxidant capacity were significantly increased in the CPD fed WT mice. In addition, CPD fed Glrx1-/- mice significantly increased total cholesterol, triacylglycerol, and pro-inflammatory cytokines which are accompanied by higher steatosis scores, intrahepatic lipid accumulation, and altered gene expression associated with lipid metabolism. Furthermore, hepatic gene expression of Nrf2/keap1 signaling pathway and its downstream signaling targets were determined using RT-qPCR. Glrx1 deficiency increased Nrf2 activity and expression of its target genes (GPx, catalase, SOD1, G6pd, and Bbc3), which was exacerbated by intake of CPD. Metagenomic analyses revealed that Glrx1-/- mice fed meat protein diets had higher abundances of Mucispirillum, Oscillibacter, and Mollicutes but lower abundances of Bacteroidales S24-7 group_norank, Blautia, and Anaerotruncus than their wild-type counterparts. In summary, Glrx1 deficiency induced an increase in serum biomarkers for lipid homeostasis, gut microbiota imbalance, and upregulation of Nrf2/Keap1 and antioxidant defense genes, which was aggravated by cooked meat protein diet.