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Loss of ULK1 Attenuates Cholesterogenic Gene Expression in Mammalian Hepatic Cells.

Publication ,  Journal Article
Rajak, S; Iannucci, LF; Zhou, J; Anjum, B; George, N; Singh, BK; Ghosh, S; Yen, PM; Sinha, RA
Published in: Front Cell Dev Biol
September 30, 2020

The hepatic mevalonate (MVA) pathway, responsible for cholesterol biosynthesis, is a therapeutically important metabolic pathway in clinical medicine. Using an unbiased transcriptomics approach, we uncover a novel role of Unc-51 like autophagy activating kinase 1 (ULK1) in regulating the expression of the hepatic de novo cholesterol biosynthesis/MVA pathway genes. Genetic silencing of ULK1 in non-starved mouse (AML-12) and human (HepG2) hepatic cells as well as in mouse liver followed by transcriptome and pathway analysis revealed that the loss of ULK1 expression led to significant down-regulation of genes involved in the MVA/cholesterol biosynthesis pathway. At a mechanistic level, loss of ULK1 led to decreased expression of SREBF2/SREBP2 (sterol regulatory element binding factor 2) via its effects on AKT-FOXO3a signaling and repression of SREBF2 target genes in the MVA pathway. Our findings, therefore, discover ULK1 as a novel regulator of cholesterol biosynthesis and a possible druggable target for controlling cholesterol-associated pathologies.

Duke Scholars

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Published In

Front Cell Dev Biol

DOI

ISSN

2296-634X

Publication Date

September 30, 2020

Volume

8

Start / End Page

523550

Location

Switzerland

Related Subject Headings

  • 32 Biomedical and clinical sciences
  • 31 Biological sciences
 

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Rajak, S., Iannucci, L. F., Zhou, J., Anjum, B., George, N., Singh, B. K., … Sinha, R. A. (2020). Loss of ULK1 Attenuates Cholesterogenic Gene Expression in Mammalian Hepatic Cells. Front Cell Dev Biol, 8, 523550. https://doi.org/10.3389/fcell.2020.523550
Rajak, Sangam, Liliana F. Iannucci, Jin Zhou, B. Anjum, Nelson George, Brijesh K. Singh, Sujoy Ghosh, Paul M. Yen, and Rohit A. Sinha. “Loss of ULK1 Attenuates Cholesterogenic Gene Expression in Mammalian Hepatic Cells.Front Cell Dev Biol 8 (September 30, 2020): 523550. https://doi.org/10.3389/fcell.2020.523550.
Rajak S, Iannucci LF, Zhou J, Anjum B, George N, Singh BK, et al. Loss of ULK1 Attenuates Cholesterogenic Gene Expression in Mammalian Hepatic Cells. Front Cell Dev Biol. 2020 Sep 30;8:523550.
Rajak, Sangam, et al. “Loss of ULK1 Attenuates Cholesterogenic Gene Expression in Mammalian Hepatic Cells.Front Cell Dev Biol, vol. 8, Sept. 2020, p. 523550. Pubmed, doi:10.3389/fcell.2020.523550.
Rajak S, Iannucci LF, Zhou J, Anjum B, George N, Singh BK, Ghosh S, Yen PM, Sinha RA. Loss of ULK1 Attenuates Cholesterogenic Gene Expression in Mammalian Hepatic Cells. Front Cell Dev Biol. 2020 Sep 30;8:523550.

Published In

Front Cell Dev Biol

DOI

ISSN

2296-634X

Publication Date

September 30, 2020

Volume

8

Start / End Page

523550

Location

Switzerland

Related Subject Headings

  • 32 Biomedical and clinical sciences
  • 31 Biological sciences