Molecular Signaling Laboratory, School of Pharmacy, University of Wyoming, Wyoming; Central Wyoming College, Riverton, Wyoming
High fat diet (HFD)-induced liver insult leads to progressive accumulation of fat in the liver causing non-alcoholic fatty liver disease (NAFLD). Currently, therapeutic options to treat NAFLD are limited. Therefore, it is very important to develop a novel strategy to counter NAFLD.
Recent research suggests that transient receptor potential vanilloid 1 (TRPV1; capsaicin receptor) protein is implicated in the prevention of NAFLD. We evaluated the novel mechanism by which TRPV1 activation by capsaicin coupled to sirtuin-1 (SiRT-1; a sensor of cellular metabolism) expression/activation to prevent NAFLD. We hypothesized that capsaicin-stimulated Ca2+ influx via TRPV1 stimulated SiRT-1 phosphorylation and activation by stimulating protein kinases.
We fed wild type and TRPV1-/- mice either normal chow diet, HFD or HFD + capsaicin (CAP-0.01%) for 32 weeks and determined the expression of TRPV1, SiRT-1 and cellular protein kinases that activate SiRT-1 in livers isolated from these mice. Alternatively, we used TRPV1 stably expressing HEK293 cells and determined the expression and phosphorylation state of SiRT-1 as well as SiRT-1/PPAR interaction.
HFD suppressed TRPV1 expression in liver and CAP prevented this. Also, CAP increased SiRT-1/ PPAR interaction in the liver of wild type mice. In HEKTRPV1 cells, CAP-stimulated Ca2+ influx via TRPV1 activated Ca2+/calmodulin-dependent protein kinase II (CaMKII), which in-turn, activated 5â€™-adenosine monophosphate activated kinase (AMPK), leading to SiRT-1 activation. These effects were prevented by capsazepine (TRPV1 antagonist), BAPTA-AM (cell permeable Ca2+ chelator) or KN62 (CaMKII inhibitor) pretreatment. CAP also increased the expression of fork-head box 1 (FOXO1), a transcription factor that is deacetylated by SiRT-1 and prevents lipogenesis.
Our data suggest that TRPV1 activation stimulates SiRT-1/ PPAR interaction and increases SiRT-1-dependent FOXO1 expression to prevent NAFLD.