Curcumin inhibits the proteolytic process of SREBP-2 by first inhibiting the expression of S1P rather than directly inhibiting SREBP-2 expression.

Many studies have demonstrated that curcumin can downregulate mRNA levels of sterol regulatory element-binding proteins (SREBP-2); however, our study did not find similar results. This study was designed to demonstrate that curcumin inhibits the proteolytic process of SREBP-2 by first inhibiting the expression of membrane-bound transcription factor site-1 protease (S1P) rather than directly inhibiting SREBP-2 expression. After curcumin treatment, Caco-2 cells were collected to observe the dose- and time-dependent dynamics of precursor and mature SREBP-2, transcription factor-specific protein 1 (SP-1), and SREBP cleavage-activating protein (SCAP). After curcumin treatment, SREBP-2 distribution was detected in the cells and S1P protein expression was examined. Curcumin could downregulate mRNA levels of SREBP2, SP-1 and SCAP, but it did not simultaneously downregulate the expression of precursor SREBP-2 (pSREBP-2) and SCAP. Curcumin can inhibit the proteolytic process of SREBP-2, reduce the production of mature SREBP-2 (mSREBP-2), and change the cellular distribution of SREBP-2. The inhibitory effect of curcumin on SP-1 protein expression is short-acting. Curcumin could downregulate the mRNA and protein expression of S1P, but has no obvious inhibitory effect on the mRNA and protein expression of S2P (site-2 protease). Curcumin can inhibit the SREBP-2 proteolytic process to reduce mSREBP-2 which functions as a transcription factor, affecting the regulation of cholesterol metabolism-related genes. Curcumin does not directly inhibit the expression of mSREBP-2 protein, and it has no such inhibitory effect for at least a short period of time, although curcumin does reduce the amount of mSREBP-2 protein. S1P is a key protease in the hydrolysis of pSREBP-2 into mSREBP-2. Therefore, curcumin may decrease the amount of mSREBP-2 by directly inhibiting the expression of S1P mRNA and protein.