Long-term HF–HC–HSD induces inflammasome upregulation and activation as well as upregulation of danger signals. Hepatic mRNA expression of the inflammasome components NLRP3 (a), Pannexin-1 (b), P2X7 (c), ASC (d), and caspase-1 (e), were measured using qPCR at each of the different HF–HC–HSD time points. Activation of inflammatory caspases was evaluated by measurement of caspase-1 activity (f). Cell death was assessed by immunohistochemistry of cleaved PARP (g) on paraffin embedded liver sections. Level of danger signals in the serum, uric acid (h), ATP (i) were determined. Western blot was performed to determine levels of total HMGB1 (j) and immunoprecipitation and western blot for the active form of HMGB1, acetyl-HMGB1 (k). Hepatic mRNA expression of receptors for danger signals, TLR2 (l), TLR4 (m), TLR9 (n) and RAGE (o) were measured using qPCR. Serum endotoxin was measured at 8, 27 and 49 weeks of HF–HC–HSD (p). *p < 0.01, **p = 0.02, ^p = 0.03, #p = 0.04 versus chow fed controls, n = 6–12/group.