Long noncoding RNA lncARSR promotes hepatic cholesterol biosynthesis via modulating Akt/SREBP-2/HMGCR pathway

• Published in: Life sciences (1973) Vol. 203; pp. 48 - 53
• Main Authors: Huang, Jiabin, Chen, Shangjun, Cai, Dongliang, Bian, Deqiang, Wang, Fengling
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 15.06.2018; Elsevier BV
• Subjects: 1-Phosphatidylinositol 3-kinase; Adenoviruses; AKT protein; Animals; Arteriosclerosis; Atherosclerosis; Biosynthesis; Case-Control Studies; Cholesterol; Cholesterol - biosynthesis; Cholesterol - genetics; Diet; Fragments; Gene Expression Regulation; Hep G2 Cells; High cholesterol diet; HMG-CoA reductase; Homeostasis; Humans; Hydroxymethylglutaryl CoA Reductases - metabolism; Hydroxymethylglutaryl-CoA reductase; Hypercholesterolemia; Hypercholesterolemia - metabolism; Hypercholesterolemia - pathology; Kinases; Lipid metabolism; Liver; Liver - metabolism; lncARSR; Male; Metabolism; Mice; Mice, Inbred C57BL; Myocardial infarction; Pathogenesis; PI3K/Akt; Proto-Oncogene Proteins c-akt - metabolism; Ribonucleic acid; RNA; RNA, Long Noncoding - genetics; SREBP-2; Sterol Regulatory Element Binding Protein 2 - metabolism; Sterol regulatory element-binding protein; Stroke; Therapeutic applications; HMG-CoA reductase; lncARSR; Cholesterol; SREBP-2; PI3K/Akt
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2018.04.028

Disruption of cholesterol homeostasis has been identified as a major factor in the pathogenesis of atherosclerosis, myocardial infarction, and strokes. Long noncoding RNAs (lncRNAs) have emerged as critical players in cellular cholesterol metabolism, but their functions are still largely unknown. C57BL6/j mice were fed with high cholesterol diet (containing 4% cholesterol) or chow diet. Adenoviruses-lncARSR and lncARSR shRNA were used to overexpress or knockdown lncARSR expression. The expression of lncARSR were increased both in patients with hypercholesterolemia and mice with high cholesterol diet feeding. Overexpression of lncARSR in mice resulted in elevated lipid levels in both serum and liver fragments. However, knockdown of lncARSR in mice fed with high cholesterol diet showed decreased lipid levels in serum and liver fragments compared with control mice. Furthermore, we found that the expression of HMG-CoA reductase (HMGCR), the rate-limiting enzyme of cholesterol synthesis was increased with lncARSR overexpression, which was accompanied with the increase of hepatic de novo cholesterol synthesis rate. Mechanistically, we found that lncARSR increased the expression of mature SREBP-2, which is a primary transcription factor of HMGCR. And lncARSR activated the PI3K/Akt pathway. When PI3K/Akt pathway was blocked by LY294002, the inhibitor of PI3K, the effect of lncARSR on SREBP-2 and HMGCR disappeared. Our data indicated upregulated lncARSR promotes hepatic cholesterol biosynthesis via modulating Akt/SREBP-2/HMGCR pathway, and implied that lncARSR may serve as a therapeutic target for cholesterol disorder.