Monascin and AITC attenuate methylglyoxal-induced PPARγ phosphorylation and degradation through inhibition of the oxidative stress/PKC pathway depending on Nrf2 activation.

Abstract

Abnormal cellular accumulation of the dicarbonyl metabolite methylglyoxal (MG) results in cell damage, inflammation, and oxidative stress. It is also associated with increased protein linkage to form advanced glycation end products (AGEs) or induce DNA strand breaks. The association between peroxisome proliferator-activated receptor-γ (PPARγ) and nuclear factor-erythroid 2-related factor 2 (Nrf2) is unclear. This study investigated Nrf2 activator protection against PPARγ phosphorylation and degradation to maintain pancreatic function. MG was used at a noncytotoxic concentration (200 μM) to induce protein kinase C (PKC) and PPARγ phosphorylation in pancreatic RINm5F cells. For in vivo studies, MG (60 mg/kg bw) was intraperitoneally (IP) injected into Balb/C mice for 28 d to induce pancreas damage, at which point we investigated the effect of monascin protection (PPARγ and Nrf2 activator), rosiglitazone (PPARγ activator), allyl isothiocyanate (AITC; Nrf2 activator), or N-acetylcysteine (NAC) on pancreatic function. The in vitro and in vivo results indicated that MG leads to marked PPARγ phosphorylation (serine 82); this effect led to reduction in pancreatic and duodenal homeobox-1 (PDX-1), glucokinase (GCK), and insulin expression. However, monascin and rosiglitazone may protect PPARγ degradation by elevating PDX-1, GCK, and as a result, insulin expression. Monascin and AITC can attenuate PKC activation to suppress PPARγ phosphorylation caused by oxidative stress through the Nrf2 pathway. Similarly, the N-acetylcysteine (NAC) antioxidant also improved oxidative stress and pancreatic function. This study examined whether MG caused impairment of PDX-1, GCK, and insulin through PPARγ phosphorylation and degradation. MG and AGE accumulation improved on Nrf2 activation, thereby protecting against pancreas damage. Taken together, PPARγ activation maintained pancreatic PDX-1, GCK, and insulin expression levels to regulate blood glucose levels.

• Authors: Wei-Hsuan Hsu, Bao-Hong Lee, Chih-Heng Li, Ya-Wen Hsu, Tzu-Ming Pan
• Journal: Journal of agricultural and food chemistry (J Agric Food Chem) Vol. 61 Issue 25 Pg. 5996-6006 (Jun 26 2013) ISSN: 1520-5118 [Electronic] United States
• PMID: 23731245 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Heterocyclic Compounds, 3-Ring
• Isothiocyanates
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• PPAR gamma
• Pyruvaldehyde
• allyl isothiocyanate
• Protein Kinase C
• monascin

Topics

• Animals
• Heterocyclic Compounds, 3-Ring (pharmacology)
• Isothiocyanates (pharmacology)
• Mice
• Mice, Inbred BALB C
• NF-E2-Related Factor 2 (genetics, metabolism)
• Oxidative Stress (drug effects)
• PPAR gamma (genetics, metabolism)
• Phosphorylation (drug effects)
• Protein Kinase C (genetics, metabolism)
• Proteolysis (drug effects)
• Pyruvaldehyde (pharmacology)