"MiR-7 controls cholesterol biosynthesis through posttranscriptional regulation of DHCR24 expression"
Por:
Frutos, MFD, Pardo-Marques, V, Torrecilla-Parra, M, Rada, P, Perez-Garcia, A, Martin-Martin, Y, de la Pena, G, Gomez, A, Toledano-Zaragoza, A, Gomez-Coronado, D, Casarejos, MJ, Solis, JM, Rotllan, N, Pastor, O, Ledesma, MD, Valverde, AM, Busto, R, Ramirez, CM
Publicada:
1 jun 2023
Ahead of Print:
21 abr 2023
Resumen:
Dysregulation of cholesterol homeostasis is associated with several pathologies including cardiovascular diseases and neurological disorders such as Alzheimer's disease (AD). MicroRNAs (miRNAs) have emerged as key post-transcriptional regulators of cholesterol metabolism. We previously established the role of miR-7 in regulating insulin resistance and amyloidosis, which represents a common pathological feature between type 2 diabetes and AD. We show here an additional metabolic function of miR-7 in cholesterol biosynthesis. We found that miR-7 blocks the last steps of the cholesterol biosynthetic pathway in vitro by targeting relevant genes including DHCR24 and SC5D posttranscriptionally. Intracranial infusion of miR-7 on an adeno-associated viral vector reduced the expression of DHCR24 in the brain of wild-type mice, supporting in vivo miR-7 targeting. We also found that cholesterol regulates endogenous levels of miR-7 in vitro, correlating with transcriptional regulation through SREBP2 binding to its promoter region. In parallel to SREBP2 inhibition, the levels of miR-7 and hnRNPK (the host gene of miR-7) were concomitantly reduced in brain in a mouse model of Niemann Pick type C1 disease and in murine fatty liver, which are both characterized by intracellular cholesterol accumulation. Taken together, the results establish a novel regulatory feedback loop by which miR-7 modulates cholesterol homeostasis at the posttranscriptional level, an effect that could be exploited for therapeutic interventions against prevalent human diseases.
Filiaciones:
Frutos, MFD:
IMDEA Res Inst Food & Hlth Sci, Madrid, Spain
Pardo-Marques, V:
IMDEA Res Inst Food & Hlth Sci, Madrid, Spain
Torrecilla-Parra, M:
IMDEA Res Inst Food & Hlth Sci, Madrid, Spain
Rada, P:
CSIC, Inst Invest Biomed Alberto Sols, Madrid, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Diabet & Enfermedades Metab, Madrid, Spain
Perez-Garcia, A:
IMDEA Res Inst Food & Hlth Sci, Madrid, Spain
Martin-Martin, Y:
IMDEA Res Inst Food & Hlth Sci, Madrid, Spain
de la Pena, G:
Hosp Univ Ramon Y Cajal, Dept Biochem Res, IRYCIS, Madrid, Spain
Gomez, A:
Hosp Univ Ramon Y Cajal, Dept Neurobiol Res, IRYCIS, Madrid, Spain
Toledano-Zaragoza, A:
Ctr Biol Mol Severo Ochoa CSIC UAM, Dept Mol Neuropathol, Madrid, Spain
Gomez-Coronado, D:
Hosp Univ Ramon Y Cajal, Dept Biochem Res, IRYCIS, Madrid, Spain
Casarejos, MJ:
Hosp Univ Ramon Y Cajal, Dept Neurobiol Res, IRYCIS, Madrid, Spain
Solis, JM:
Hosp Univ Ramon Y Cajal, Dept Neurobiol Res, IRYCIS, Madrid, Spain
Rotllan, N:
Inst Invest Biomed St Pau IIB Sant Pau, Barcelona, Spain
CIBER Diabet & Enfermedades Metab Asociadas CIBERD, Barcelona, Spain
Pastor, O:
Hosp Univ Ramon Y Cajal, Dept Clin Biochem, IRYCIS, Madrid, Spain
Ledesma, MD:
Ctr Biol Mol Severo Ochoa CSIC UAM, Dept Mol Neuropathol, Madrid, Spain
Valverde, AM:
CSIC, Inst Invest Biomed Alberto Sols, Madrid, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Diabet & Enfermedades Metab, Madrid, Spain
Busto, R:
Hosp Univ Ramon Y Cajal, Dept Biochem Res, IRYCIS, Madrid, Spain
Ctra Colmenar Viejo, Madrid 28034, Spain
Ramirez, CM:
IMDEA Res Inst Food & Hlth Sci, Madrid, Spain
Ctra Cantoblanco, Madrid 28049, Spain
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