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Magnesium isoglycyrrhizinate as a hepatoprotective agent possesses immune modulation and anti-inflammation, and treats liver diseases. But its effects on immunological-inflammatory and metabolic profiles for metabolic syndrome with liver injury and underlying potential mechanisms are not fully understood. In this study, magnesium isoglycyrrhizinate alleviated liver inflammation and lipid accumulation in fructose-fed rats with metabolic syndrome. It also suppressed hepatic inflammatory signaling activation by reducing protein levels of phosphorylation of nuclear factor-kappa B p65 (p-NF-κB p65), inhibitor of nuclear factor kappa-B kinase α/β (p-IKKα/β) and inhibitor of NF-κB α (p-IκBα) as well as nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC) and Caspase-1 in rats, being consistent with its reduction of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and IL-6 levels. Furthermore, magnesium isoglycyrrhizinate modulated lipid metabolism-related genes characterized by up-regulating peroxisome proliferator-activated receptor-α (PPAR-α) and carnitine palmitoyl transferase-1 (CPT-1), and down-regulating sensor for fatty acids to control-1 (SREBP-1) and stearoyl-CoA desaturase 1 (SCD-1) in the liver of fructose-fed rats, resulting in the reduction of triglyceride and total cholesterol levels. These effective actions were further confirmed in fructose-exposed BRL-3A and HepG2 cells. The molecular mechanisms underpinning these observations suggest that magnesium isoglycyrrhizinate may inhibit NF-κB/NLRP3 inflammasome activation to reduce immunological-inflammatory response, which in turn may prevent liver lipid metabolic disorder and accumulation under high fructose condition. Thus, blockade of NF-κB/NLRP3 inflammasome activation and lipid metabolism disorder by magnesium isoglycyrrhizinate may be the potential therapeutic approach for improving fructose-induced liver injury with metabolic syndrome in clinic.

Excessive fructose intake is a risk factor for liver oxidative stress injury. Magnesium isoglycyrrhizinate as a hepatoprotective agent is used to treat liver diseases in clinic. However, its antioxidant effects and the underlying potential mechanisms are still not clearly understood. In this study, magnesium isoglycyrrhizinate was found to alleviate liver oxidative stress and inflammatory injury in fructose-fed rats. Magnesium isoglycyrrhizinate suppressed hepatic reactive oxygen species overproduction (0.97 ± 0.04 a.u. versus 1.34 ± 0.07 a.u.) in fructose-fed rats by down-regulating mRNA and protein levels of nicotinamide adenine dinucleotide phosphate oxidase (NOX) 1, NOX2 and NOX4, resulting in reduction of interleukin-1β (IL-1β) levels (1.13 ± 0.09 a.u. versus 1.97 ± 0.12 a.u.). Similarly, magnesium isoglycyrrhizinate reduced reactive oxygen species overproduction (1.07 ± 0.02 a.u. versus 1.35 ± 0.06 a.u.) and IL-1β levels (1.14 ± 0.09 a.u. versus 1.66 ± 0.07 a.u.) in fructose-exposed HepG2 cells. Furthermore, data from treatment of reactive oxygen species inhibitor N-acetyl-L-cysteine or NOXs inhibitor diphenyleneiodonium in fructose-exposed HepG2 cells showed that fructose enhanced NOX1, NOX2 and NOX4 expression to increase reactive oxygen species generation, causing oxidative stress and inflammation, more importantly, these disturbances were significantly attenuated by magnesium isoglycyrrhizinate. The molecular mechanisms underpinning these effects suggest that magnesium isoglycyrrhizinate may inhibit NOX1, NOX2 and NOX4 expression to reduce reactive oxygen species generation, subsequently prevent liver oxidative stress injury under high fructose condition. Thus, the blockade of NOX1, NOX2 and NOX4 expression by magnesium isoglycyrrhizinate may be the potential therapeutic approach for improving fructose-induced liver injury in clinic.