Cholesterol synthesis enzyme SC4MOL is fine-tuned by sterols and targeted for degradation by the E3 ligase MARCHF6

Qian, Lydia; Scott, Nicola A.; Capell-Hattam, Isabelle M.; Draper, Eliza A.; Fenton, Nicole; Luu, Winnie; Sharpe, Laura J.; Brown, Andrew

doi:10.1016/j.jlr.2023.100362

Cited by 11 publications

(2 citation statements)

References 56 publications

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“…Levels of sterol pathway intermediates can affect the expression of enzymes [ 36 , 37 , 38 , 39 ]. Since 7-DHC was the most increased metabolite as a result of ARI+TRZ polypharmacy, we decided to evaluate the protein levels of the DHCR7 enzyme.…”

Section: Resultsmentioning

confidence: 99%

Chronic Aripiprazole and Trazodone Polypharmacy Effects on Systemic and Brain Cholesterol Biosynthesis

Korade,

Anderson,

Balog

et al. 2023

Biomolecules

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The concurrent use of several medications is a common practice in the treatment of complex psychiatric conditions. One such commonly used combination is aripiprazole (ARI), an antipsychotic, and trazodone (TRZ), an antidepressant. In addition to their effects on dopamine and serotonin systems, both of these compounds are inhibitors of the 7-dehydrocholesterol reductase (DHCR7) enzyme. To evaluate the systemic and nervous system distribution of ARI and TRZ and their effects on cholesterol biosynthesis, adult mice were treated with both ARI and TRZ for 21 days. The parent drugs, their metabolites, and sterols were analyzed in the brain and various organs of mice using LC-MS/MS. The analyses revealed that ARI, TRZ, and their metabolites were readily detectable in the brain and organs, leading to changes in the sterol profile. The levels of medications, their metabolites, and sterols differed across tissues with notable sex differences. Female mice showed higher turnover of ARI and more cholesterol clearance in the brain, with several post-lanosterol intermediates significantly altered. In addition to interfering with sterol biosynthesis, ARI and TRZ exposure led to decreased ionized calcium-binding adaptor molecule 1 (IBA1) and increased DHCR7 protein expression in the cortex. Changes in sterol profile have been also identified in the spleen, liver, and serum, underscoring the systemic effect of ARI and TRZ on sterol biosynthesis. Long-term use of concurrent ARI and TRZ warrants further studies to fully evaluate the lasting consequences of altered sterol biosynthesis on the whole body.

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Section: Resultsmentioning

confidence: 99%

Chronic Aripiprazole and Trazodone Polypharmacy Effects on Systemic and Brain Cholesterol Biosynthesis

Korade,

Anderson,

Balog

et al. 2023

Biomolecules

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show abstract

“…[28] The repertoire of known substrates is growing, but notable amongst these are targets involved in metabolism, especially lipid metabolism. [8] MARCHF6 degrades at least six enzymes involved in cholesterol biosynthesis [29][30][31][32] and is itself stabilized by cholesterol. [33] Remarkably, MARCHF6 is the only mammalian E3 ubiquitin ligase known to target multiple points within the same metabolic pathway, [8] and as such, highlights the exquisite multilayered control of cholesterol biosynthesis.…”

Section: Marchf6: a Major Controller Of Cholesterol Biosynthesismentioning

confidence: 99%

A paREDOX in the control of cholesterol biosynthesis

Fenton,

Qian,

Paine

et al. 2024

BioEssays

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Sterols and the reductant nicotinamide adenine dinucleotide phosphate (NADPH), essential for eukaryotic life, arose because of, and as an adaptation to, rising levels of molecular oxygen (O2). Hence, the NADPH and O2‐intensive process of sterol biosynthesis is inextricably linked to redox status. In mammals, cholesterol biosynthesis is exquisitely regulated post‐translationally by multiple E3 ubiquitin ligases, with membrane associated Really Interesting New Gene (RING) C3HC4 finger 6 (MARCHF6) degrading at least six enzymes in the pathway. Intriguingly, all these MARCHF6‐dependent enzymes require NADPH. Moreover, MARCHF6 is activated by NADPH, although what this means for control of cholesterol synthesis is unclear. Indeed, this presents a paradox for how NADPH regulates this vital pathway, since NADPH is a cofactor in cholesterol biosynthesis and yet, low levels of NADPH should spare cholesterol biosynthesis enzymes targeted by MARCHF6 by reducing its activity. We speculate MARCHF6 helps mammalian cells adapt to oxidative stress (signified by low NADPH levels) by reducing degradation of cholesterogenic enzymes, thereby maintaining synthesis of protective cholesterol.

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As a matter of fat: Emerging roles of lipid‐sensitive E3 ubiquitin ligases

Gawden‐Bone,

Lehner,

Volkmar

2023

BioEssays

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The dynamic structure and composition of lipid membranes need to be tightly regulated to control the vast array of cellular processes from cell and organelle morphology to protein‐protein interactions and signal transduction pathways. To maintain membrane integrity, sense‐and‐response systems monitor and adjust membrane lipid composition to the ever‐changing cellular environment, but only a relatively small number of control systems have been described. Here, we explore the emerging role of the ubiquitin‐proteasome system in monitoring and maintaining membrane lipid composition. We focus on the ER‐resident RNF145 E3 ubiquitin ligase, its role in regulating adiponectin receptor 2 (ADIPOR2), its lipid hydrolase substrate, and the broader implications for understanding the homeostatic processes that fine‐tune cellular membrane composition.

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Cholesterol synthesis enzyme SC4MOL is fine-tuned by sterols and targeted for degradation by the E3 ligase MARCHF6

Cited by 11 publications

References 56 publications

Chronic Aripiprazole and Trazodone Polypharmacy Effects on Systemic and Brain Cholesterol Biosynthesis

Chronic Aripiprazole and Trazodone Polypharmacy Effects on Systemic and Brain Cholesterol Biosynthesis

A paREDOX in the control of cholesterol biosynthesis

As a matter of fat: Emerging roles of lipid‐sensitive E3 ubiquitin ligases

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