Induction of Autophagy: A Novel Anti-inflammatory Function of High-Density Lipoprotein

he inverse relationship between plasma highTdensity lipoprotein (HDL) cholesterol levels and the risk for development of atherosclerotic cardiovascular disease has led to extensive studies of HDL and its major apoprotein apolipoprotein A-I (apoA-I) with respect to their antiatherogenic role. The ability of HDL and apoA-I to promote the efflux of cholesterol from cells in peripheral tissues, including macrophages in atherosclerotic plaques, and to transport the cholesterol to the liver for excretion via biliary secretion is considered their major atheroprotective role. However, HDL and apoA-I also have other functions that impact cardiovascular disease and other disorders, including diabetes, autoimmune dysfunction, and neurodegeneration. The activities of HDL are derived from its antioxidant, anti-inflammatory, and antiapoptotic properties. Much of the anti-inflammatory effect of apoA-I and HDL is thought to be mediated by modulation of the cholesterol content of membrane lipid rafts due to their promotion of cholesterol efflux via ATP-binding cassette subfamily A member 1 (ABCA1), ATP-binding cassette subfamily G member 1 (ABCG1), and scavenger receptor class B type I (SR-BI). The article in this issue of Cellular and Molecular Gastroenterology and Hepatology by Gerster et al has demonstrated that HDL also protects the colon from inflammation, providing insight into a novel mechanism by which HDL exerts its anti-inflammatory effect. Using apoA-I knockout and transgenic mouse models, the investigators have demonstrated a protective effect by HDL/apoA-I on colitis induced by dextran sodium sulfate or 2,4,6-trinitrobenzenesulfonic acid. In vitro studies using pharmacologic manipulations or genetic knock down in a colonic epithelial cell line indicate that HDL and apoA-I induce autophagy via inhibition of the mammalian target of rapamycin (mTOR), a negative regulator of autophagy, that leads to the trafficking of phosphorylated IkB kinase (p-IKK) to the autophagosome for degradation and the consequent attenuation of nuclear factor kB (NF-kB)mediated expression of proinflammatory genes. The antiinflammatory role of the induction of autophagy by HDL was further confirmed using mucosal fibroblasts from patients with a Crohn’s disease polymorphism of the autophagy-related gene ATG16L1. Although HDL has been shown to interfere with NF-kBmediated transcription of proinflammatory genes, the molecular mechanisms are not well understood. This study identifies the induction of autophagy by HDL and the recruitment of p-IKK, which is necessary for the activation of NF-kB, to autophagosomes as a novel mechanism mediating the anti-inflammatory function of HDL. The induction of autophagy by HDL is somewhat surprising. Several