AUTHOR=Rajak Sangam , Iannucci Liliana F. , Zhou Jin , Anjum B. , George Nelson , Singh Brijesh K. , Ghosh Sujoy , Yen Paul M. , Sinha Rohit A. 

TITLE=Loss of ULK1 Attenuates Cholesterogenic Gene Expression in Mammalian Hepatic Cells

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 8 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2020.523550

DOI=10.3389/fcell.2020.523550

ISSN=2296-634X

ABSTRACT=Hepatic mevalonate 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 hepatic de novo cholesterol biosynthesis/mevalonate 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 mevalonate/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 signalling and repression of SREBF2 target genes in the mevalonate pathway. Our findings thus discover ULK1 as a novel regulator of liver cholesterol biosynthesis and a possible druggable target for controlling cholesterol-associated pathologies.