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Abstract
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.
Highlights
Cholesterol, at the physiological level, serves as a major constituent of cellular membranes and a precursor for bile and steroid hormone synthesis (Tabas, 2002)
Our results showed significant down-regulation of the cholesterol biosynthesis pathway upon loss of Unc-51 like autophagy activating kinase 1 (ULK1) using the Reactome pathway database (Figure 1B and Supplementary Table S1)
The genes involved in the Reactome cholesterol biosynthesis dataset belong to the broader MVA pathway, which is involved in cholesterol biosynthesis within the hepatocytes (Buhaescu and Izzedine, 2007; Supplementary Table S2)
Summary
Cholesterol, at the physiological level, serves as a major constituent of cellular membranes and a precursor for bile and steroid hormone synthesis (Tabas, 2002). Cholesterol can be synthesized de novo via the mevalonate (MVA) pathway in liver, and may be obtained from food sources (Ye and Debose-Boyd, 2011). Despite the successful use of statin therapy in most of the patients, either alone or in combination with other agents, some individuals may not respond positively to statins (Reiner, 2014) This crisis warrants initiatives to discover novel alternatives and adjunct therapies to counter hypercholesterolemia. While it has been studied mostly in relation to its role in cholesterol synthesis and cardiovascular diseases, the MVA pathway has become a potential therapeutic target for several cancers, autoimmune disorders, atherosclerosis, fatty liver, and Alzheimer’s disease (Buhaescu and Izzedine, 2007)
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