Data_Sheet_1_Loss of ULK1 Attenuates Cholesterogenic Gene Expression in Mammalian Hepatic Cells.docx (54.74 kB)

Data_Sheet_1_Loss of ULK1 Attenuates Cholesterogenic Gene Expression in Mammalian Hepatic Cells.docx

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posted on 30.09.2020, 08:03 by Sangam Rajak, Liliana F. Iannucci, Jin Zhou, B. Anjum, Nelson George, Brijesh K. Singh, Sujoy Ghosh, Paul M. Yen, Rohit A. Sinha

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.

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