Oxidative stress and caspase 3/Gsdme-dependent pyroptosis contributes to high fat diet induced-intestinal inflammation and lipotoxicity via Srebp1 cleavage at D444 site by caspase 3

Excessive dietary fat intake was associated with intestinal inflammation and lipotoxicity, but the underlying mechanism remained elusive. In this study, we investigated the effects and mechanisms of dietary fat addition on intestinal inflammation and lipid metabolism by using yellow catfish Pelteobagrus fulvidraco, a freshwater teleost fish of ecological and economic importance. Here, we found that high fat diet (HFD) and fatty acid (FA) incubation induced intestinal lipotoxicity and barrier damage, activated oxidative stress and induced intestinal inflammation by activating cysteinyl aspartate specific proteinase 3 (caspase 3)/ gasdermin E (Gsdme) -dependent pyroptosis; oxidative stress mediated FA-induced pyroptosis, lipogenic metabolism and lipid accumulation; high dietary fat induced full-length sterol regulatory element binding protein 1 (Srebp1) cleavage by caspase 3, which in turn produced the active cleaved forms of Srebp1, and accordingly contributed to lipogenic metabolism and lipid accumulation; D444 was identified as the cleavage site of Srebp1 by caspase 3. Mechanistically, overexpression of the cleaved Srebp1 (Flag-N-Srebp1) by caspase 3 increased the activities of the promoters of lipogenic genes (fatty acid synthase [fas], acetyl CoA carboxylase [acca] and stearoyl-CoA desaturase 1 [scd1]), thereby up-regulating lipogenic metabolism and inducing lipid accumulation. Thus, our study elucidated the novel mechanism of high fat diet (HFD) inducing inflammation and lipotoxicity, and found that oxidative stress and caspase 3/ GsdmE-dependent pyroptosis played important roles in these processes.