UCLA

Cellular lipid requirements are achieved through a combination of biosynthesis and import programs. To date, the molecular mechanisms that regulate whether a cell preferentially scavenges or synthesizes lipids is not well understood, particularly in non-metabolic tissues, such as immune cells. Perturbations in fatty acid and cholesterol homeostasis have been observed in response to a number of viral and microbial infections, leading us to ask if signaling through immune receptors could influence the cellular programs that regulate lipid homeostasis in macrophage. Using mass spectrometry and isotope tracer analysis, we find that activation of Toll-like Receptors (TLRs) can broadly promote a lipid-scavenging program, however, only select TLRs can specifically limit de novo synthesis of both fatty acids and cholesterol. We find that TLR- and virus-mediated production of type I interferon is responsible for inhibition of flux through the lipid biosynthetic program, resulting in a shift in macrophage metabolism to favor lipid import over synthesis. Genetically enforcing this metabolic shift in macrophages is sufficient to render mice resistant to viral challenge, demonstrating the importance of reprogramming the balance of these two metabolic pathways in vivo. Unexpectedly, mechanistic studies reveal that limiting flux through the cholesterol biosynthetic pathway spontaneously engages a type I IFN response in a STING-dependent manner. The upregulation of type I IFNs was traced to a decrease in the pool size of synthesized cholesterol, and replenishing cells with free cholesterol could inhibit STING-mediated production of type I IFNs. Taken together, these data support a model where perturbations in cholesterol biosynthetic flux intrinsically influence the STING signaling cascade and provide a molecular mechanism linking cholesterol homeostasis with type I IFN-mediated inflammation. In sum, these studies delineate a metabolic-inflammatory circuit that links perturbations in cholesterol biosynthesis with activation of innate immunity.