Mechanistic Insights into the Oxidized Low-Density Lipoprotein-Induced Atherosclerosis

Figure 8

Hepatic responses to diet and statins mediated by the SREBP pathway. The figure is reproduced from Goldstein and Brown [35] [under the Creative Commons Attribution License/public domain] “(Reprinted (A Century of Cholesterol and Coronaries: From Plaques to Genes to Statins) with permission from Elsevier (License number 4825791117921)).” (a) Low-cholesterol diet. Proteolytic cleavage of SREBP is increased. The cleaved SREBP enters the nucleus to activate genes controlling cholesterol synthesis (including HMG CoA reductase) and uptake (LDL receptor). nSREBP, nuclear portion of cleaved SREBP. (b) High-cholesterol diet. Proteolytic cleavage of SREBPs is decreased, resulting in decreased nuclear SREBP and decreased activation of target genes. The decrease in LDL receptors produces an increase in plasma LDL. (c) High-cholesterol diet plus statin therapy. Statins inhibit HMG CoA reductase, causing a transient decrease in ER cholesterol. In response, SREBP cleavage is increased, and the resulting nuclear SREBP activates the genes for HMG CoA reductase and LDL receptor. The increased HMG CoA reductase is inhibited by the statin, and the increased LDL receptors lower plasma LDL.

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