Fig 2.
Metabolic fluxes, NLRP3 and IL-1β. Hyperlipidemia in the form of saturated fatty acids such as palmitate, has been shown to activate the NLRP3 inflammasome leading to caspase-1 activation and the processing of pro- IL-1β. Impaired mitochondrial metabolism, including decreased β-oxidation of fatty acids, could promote this process, as will production of reactive oxygen species. Activation of TLR4 by LPS or minimally modified oxidized LDL promotes glycolysis via induction of enzymes such as uPFK2 leading to enhanced ATP production and nucleotide biosynthesis via the pentose phosphate pathway. Purines including uric acid, could be over-produced via this process leading to NLRP3 inflammasome activation. IL-1β will give rise to insulin resistance, causing enhanced IAPP production, which in turn will further activate NLRP3. Insulin resistance in liver and muscle could spare glucose for macrophages. See text for details.