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Endogenous Sterol Intermediates of the Mevalonate Pathway Regulate HMGCR Degradation and SREBP-2 Processing

Endogenous Sterol Intermediates of the Mevalonate Pathway Regulate HMGCR Degradation and SREBP-2 Processing

Liang Chen, Mei-Yan Ma, Ming Sun, Lu-Yi Jiang, Xue-Tong Zhao, Xian-Xiu Fang, Sin Man Lam, Guang-Hou Shui, Jie Luo, Xiong-Jie Shi, Bao-Liang Song

J Lipid Res. 2019 Oct;60(10):1765-1775.

PMID: 31455613

Abstract:

Sterol-regulated HMG-CoA reductase (HMGCR) degradation and SREBP-2 cleavage are two major feedback regulatory mechanisms governing cholesterol biosynthesis. Reportedly, lanosterol selectively stimulates HMGCR degradation, and cholesterol is a specific regulator of SREBP-2 cleavage. However, it is unclear whether other endogenously generated sterols regulate these events. Here, we investigated the sterol intermediates from the mevalonate pathway of cholesterol biosynthesis using a CRISPR/Cas9-mediated genetic engineering approach. With a constructed HeLa cell line expressing the mevalonate transporter, we individually deleted genes encoding major enzymes in the mevalonate pathway, used lipidomics to measure sterol intermediates, and examined HMGCR and SREBP-2 statuses. We found that the C4-dimethylated sterol intermediates, including lanosterol, 24,25-dihydrolanosterol, follicular fluid meiosis activating sterol, testis meiosis activating sterol, and dihydro-testis meiosis activating sterol, were significantly upregulated upon mevalonate loading. These intermediates augmented both degradation of HMGCR and inhibition of SREBP-2 cleavage. The accumulated lanosterol induced rapid degradation of HMGCR, but did not inhibit SREBP-2 cleavage. The newly synthesized cholesterol from the mevalonate pathway is dispensable for inhibiting SREBP-2 cleavage. Together, these results suggest that lanosterol is a bona fide endogenous regulator that specifically promotes HMGCR degradation, and that other C4-dimethylated sterol intermediates may regulate both HMGCR degradation and SREBP-2 cleavage.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP79630	Lanosterol		79-63-0	Price

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