Molecular Basis of Preventive EŠects of Habitual CoŠee Intake against Chronic Diseases

Abstract

Epidemiological studies have shown that coŠee consumption may be associated with a lower risk of developing several chronic disorders. To elucidate the molecular mechanism of the eŠects of coŠee, we analyzed molecular response upon exposure to coŠee extract using cellular and animal models of these diseases. As obesity is recognized as a major risk factor for these chronic diseases, we investigated the eŠect of coŠee on adipogenesis using mouse preadipocyte 3T3-L1 cells. We found that coŠee induced proteasomal degradation of IRS-1, leading to reduction of PPARg expression, a master transcription factor for adipogenesis. Reduction in weight as well as in IRS-1 expression was detected in the fat tissues of the high fat-diet-fed mice when reared with 60％ coŠee for 7 weeks. As for Alzheimer's disease, we analyzed the eŠect of coŠee on amyloid b (Ab) production in human neuronal SH-SY5Y cells. We found a 20％ reduction in Ab production when treated with 2.5％ coŠee for 2 d. This reduction was due to proteasomal degradation of BACE1 (bsecretase), which was activated by protein kinase A. In addition, coŠee ameliorates LPS-induced inflammatory responses in RAW264.7 macrophages by reducing NFkB activity and Nrf2 activation. Roasted coŠee prevents selenite-induced cataractogenesis by ameliorating antioxidant loss. Pyrocatechol, a component of roasted coŠee, also reduced Ab production and exhibits anti-inflammatory eŠects by a similar mechanism as coŠee. Our results suggest that roasting coŠee beans to generate pyrocatechol is necessary for the preventive eŠects of coŠee intake on the chronic diseases.