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. 2022 Apr 29;9:879355. doi: 10.3389/fcvm.2022.879355

Figure 1.

Figure 1

Effects of Glucose/insulin on cholesterol metabolism. Glucose provides Acetyl-CoA for cholesterol biosynthesis. Glucose/insulin also enhances cholesterol biosynthesis by stabilizing HMGCR and increasing HMGCR expression. Glucose or insulin activates mTORC1 by repressing AMPK or stimulating insulin-mediated PI3K/AKT signaling pathway, respectively. The USP20 phosphorylated by mTORC1 prevents HMGCR from being degraded by GP78. PI3K/Akt signaling pathway also stabilizes HMGCR via inhibiting the recruitment of E3 ligase TRC8. The upregulated mTORC1 can promote the translocation of SREBP2 from ER to the Golgi apparatus, where nSREBP2 is produced sequentially by the S1P and S2P. nSREBP2 translocates into the nucleus and binds to SRE sequences to stimulate HMGCR expression. Meanwhile, PI3K/Akt signaling pathway upregulates HMGCR via promoting SREBP–SCAP complex to migrate into the Golgi. Besides, glucose and its metabolites inhibit cholesterol uptake by activating ChREBP, which enters the nucleus to augment human PCSK9 expression, thereby increasing PCSK9-induced LDLR degradation. Moreover, elevated circulating glucose levels can enhance enterocyte NPC1L1 expression via some unknown mechanisms, thereby strengthening intestinal absorption of cholesterol.