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Endogenous sterol intermediates of the mevalonate pathway regulate HMGCR degradation and SREBP-2 processing.

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.

SUBMITTER: Chen L

PROVIDER: S-EPMC6795084 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Endogenous sterol intermediates of the mevalonate pathway regulate HMGCR degradation and SREBP-2 processing.

Chen Liang L Ma Mei-Yan MY Sun Ming M Jiang Lu-Yi LY Zhao Xue-Tong XT Fang Xian-Xiu XX Man Lam Sin S Shui Guang-Hou GH Luo Jie J Shi Xiong-Jie XJ Song Bao-Liang BL

Journal of lipid research 20190827 10

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-med ...[more]

PMID: 31455613

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Dataset Information

Endogenous sterol intermediates of the mevalonate pathway regulate HMGCR degradation and SREBP-2 processing.

Publications

Endogenous sterol intermediates of the mevalonate pathway regulate HMGCR degradation and SREBP-2 processing.

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