Fig. 7

Figure 7. Model for lipoprotein regulation of HIF and SREBP. Left, lipoproteins are directed to lysosomes through receptor-mediated endocytosis, where free cholesterol and fatty acids are released by LAL-catalyzed hydrolysis. Released cholesterol blocks SREBP activation, and fatty acids prevent ROS production from mitochondria. PHD remains active and hydroxylates prolyl residues on HIFα, which leads to its rapid degradation. Middle, in the absence of lipoproteins, cells are deprived of cholesterol and fatty acids, resulting in SREBP activation and mitochondrial stress. Mitochondrial-ROS production increases, thereby inactivating PHD and stabilizing HIFα. Right, upon LAL inhibition, cholesterol and fatty acids from cholesteryl esters and triglycerides are unavailable. Decreased cholesterol supply activates SREBP, and decreased fatty acid supply results in mitochondrial stress. As with lipoprotein depletion, stressed mitochondria produce ROS, which inactivates PHD and stabilizes HIFα. Organelles are not to scale.