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Modulation of lanosterol synthase drives 24,25-epoxysterol synthesis and oligodendrocyte formation.

ABSTRACT: Small molecules that promote the formation of new myelinating oligodendrocytes from oligodendrocyte progenitor cells (OPCs) are potential therapeutics for demyelinating diseases. We recently established inhibition of specific cholesterol biosynthesis enzymes and resulting accumulation of 8,9-unsaturated sterols as a unifying mechanism through which many such molecules act. To identify more potent sterol enhancers of oligodendrocyte formation, we synthesized a collection of 8,9-unsaturated sterol derivatives and found that 24,25-epoxylanosterol potently promoted oligodendrocyte formation. In OPCs, 24,25-epoxylanosterol was metabolized to 24,25-epoxycholesterol via the epoxycholesterol shunt pathway. Increasing flux through the epoxycholesterol shunt using genetic manipulation or small-molecule inhibition of lanosterol synthase (LSS) increased endogenous 24,25-epoxycholesterol levels and OPC differentiation. Notably, exogenously supplied 24,25-epoxycholesterol promoted oligodendrocyte formation despite lacking an 8,9-unsaturation. This work highlights epoxycholesterol shunt usage, controlled by inhibitors of LSS, as a target to promote oligodendrocyte formation. Additionally, sterols beyond the 8,9-unsaturated sterols, including 24,25-epoxycholesterol, drive oligodendrocyte formation.

SUBMITTER: Hubler Z

PROVIDER: S-EPMC8217109 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Modulation of lanosterol synthase drives 24,25-epoxysterol synthesis and oligodendrocyte formation.

Hubler Zita Z Friedrich Ryan M RM Sax Joel L JL Allimuthu Dharmaraja D Gao Farrah F Rivera-León Adrianna M AM Pleshinger Matthew J MJ Bederman Ilya I Adams Drew J DJ

Cell chemical biology 20210225 6

Small molecules that promote the formation of new myelinating oligodendrocytes from oligodendrocyte progenitor cells (OPCs) are potential therapeutics for demyelinating diseases. We recently established inhibition of specific cholesterol biosynthesis enzymes and resulting accumulation of 8,9-unsaturated sterols as a unifying mechanism through which many such molecules act. To identify more potent sterol enhancers of oligodendrocyte formation, we synthesized a collection of 8,9-unsaturated sterol ...[more]

PMID: 33636107

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Project description:UV-B radiation may be an important risk factor in cataract etiology. After exposure to UV-B radiation, cells show imbalances in the repair of DNA damage, which induce changes in the levels of certain proteins, including alpha-crystallin, which is the most abundant protein in the lens and crucial for the maintenance of lens transparency. Lanosterol synthase (LSS), an essential rate-limiting enzyme in cholesterol biosynthesis, might play significant roles in oxidative stress and in the maintenance of lens transparency. However, the roles of LSS in UV-B-induced apoptosis are not well understood. Therefore, we irradiated female Sprague-Dawley rats with ultraviolet radiation to establish an animal model for exploring the variations in LSS expression during the early stages of UV-B exposure. In addition, we cultured human lens epithelial (HLE) cells that overexpress LSS and exposed them to UV-B radiation to explore the function of increased LSS expression in UV-B-induced apoptosis. The data demonstrated that UV-B exposure induced oxidative stress and apoptosis in rat lens epithelial cells and that irradiance exposure increased the level of lenticular damage. Additionally, UV-B exposure decreased the alpha-crystallin content and increased the expressions of Bax and cleaved caspase-3 compared with the control levels. After exposure to UV-B, the apoptosis-related index of HLE cells overexpressing LSS was lower than that of the control cells. Furthermore, ROS overproduction might activate the sirtuin 1 (Sirt1) pathway, which induced protein expressions of sterol regulatory element-binding transcription factor 2 (SREBF2), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), and LSS. However, the specific mechanism of the Sirt1 pathway needed to be further studied. In summary, UV-B exposure induced oxidative injury and resulted in crystallin denaturation and apoptosis in lens epithelial cells, and LSS might play a protective role during the early stages of this process and could be an important target in the cataract prevention.

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Modulation of lanosterol synthase drives 24,25-epoxysterol synthesis and oligodendrocyte formation.

Publications

Modulation of lanosterol synthase drives 24,25-epoxysterol synthesis and oligodendrocyte formation.

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