SUMMARY We investigated the role of autophagy in atherosclerosis. During plaque formation in mice, autophagic markers co-localized predominantly with macrophages (mϕ). Atherosclerotic aortas had elevated levels of p62, suggesting that dysfunctional autophagy is characteristic of plaques. To determine if autophagy directly influences atherogenesis, we characterized Beclin-1 heterozygous-null and mϕ-specific ATG5-null (ATG5-mϕKO) mice, commonly used models of autophagy haploinsufficiency and deficiency, respectively. Haploinsufficent Beclin-1 mice had no atherosclerotic phenotype, but ATG5-mϕKO mice had increased plaques suggesting an essential role for basal levels of autophagy in atheroprotection. Defective autophagy is associated with pro-atherogenic inflammasome activation. Classic inflammasome markers were robustly induced in ATG5-null mϕ, especially when co-incubated with cholesterol crystals. Moreover, cholesterol crystals appear to be increased in ATG5-mϕKO plaques, suggesting a potentially vicious cycle of crystal formation and inflammasome activation in autophagy-deficient plaques. These results show that autophagy becomes dysfunctional in atherosclerosis and its deficiency promotes atherosclerosis in part through inflammasome hyperactivation.

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Hypertension and diabetes are common side effects of glucocorticoid treatment. To determine whether peroxisome proliferator-activated receptor-alpha (PPAR-alpha) mediates these sequelae, mice deficient in low-density lipoprotein receptor (Ldlr-/-), with (Ppara+/+) or without (Ppara-/-) PPAR-alpha, were treated chronically with dexamethasone. Ppara+/+, but not Ppara-/-, mice developed hyperglycemia, hyperinsulinemia and hypertension. Similar effects on glucose metabolism were seen in a different model using C57BL/6 mice. Hepatic gluconeogenic gene expression was increased and insulin-mediated suppression of endogenous glucose production was less effective in dexamethasone-treated Ppara+/+ mice. Adenoviral reconstitution of PPAR-alpha in the livers of nondiabetic, normotensive, dexamethasone-treated Ppara-/- mice induced hyperglycemia, hyperinsulinemia and increased gluconeogenic gene expression. It also increased blood pressure, renin activity, sympathetic nervous activity and renal sodium retention. Human hepatocytes treated with dexamethasone and the PPAR-alpha agonist Wy14,643 induced PPARA and gluconeogenic gene expression. These results identify hepatic activation of PPAR-alpha as a mechanism underlying glucocorticoid-induced insulin resistance.

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The transcription regulator YAP controls organ size by regulating cell growth, proliferation and apoptosis. However, whether YAP has a role in innate antiviral immunity is largely unknown. Here we found that YAP negatively regulated an antiviral immune response. YAP deficiency resulted in enhanced innate immunity, a diminished viral load, and morbidity in vivo. YAP blocked dimerization of the transcription factor IRF3 and impeded translocation of IRF3 to the nucleus after viral infection. Notably, virus-activated kinase IKKɛ phosphorylated YAP at Ser403 and thereby triggered degradation of YAP in lysosomes and, consequently, relief of YAP-mediated inhibition of the cellular antiviral response. These findings not only establish YAP as a modulator of the activation of IRF3 but also identify a previously unknown regulatory mechanism independent of the kinases Hippo and LATS via which YAP is controlled by the innate immune pathway.