A novel long noncoding RNA Lnc‐HC binds hnRNPA2B1 to regulate expressions of Cyp7a1 and Abca1 in hepatocytic cholesterol metabolism

Abstract

Cholesterol metabolism disorder in hepatocytes predicts a higher risk of metabolic syndrome (MetS). Long noncoding RNAs (lncRNAs) have emerged as critical players in cellular cholesterol metabolism, but their functions are not systematically clarified. Here, we have identified a novel lncRNA named lnc-HC negatively regulating cholesterol metabolism within hepatocytes through physical interaction with hnRNPA2B1. By further binding to the target messenger RNA of Cyp7a1 or Abca1, the lnc-HC-hnRNPA2B1 complex decreases expressions of the two genes that are implicated in cellular cholesterol excretion. lnc-HC knockdown can strongly recover the cholesterol disorder in vivo. In the upstream pathway, lnc-HC is up-regulated by high cholesterol by the transcription activator, CCAAT/enhancer-binding protein beta. Conclusion: These findings suggest a subtle feed-forward regulation of lnc-HC in cholesterol metabolism and define a novel line of evidence by which lncRNAs modulate the metabolic system at the post-transcriptional level. (HEPATOLOGY 2016;64:58-72) SEE EDITORIAL ON PAGE 16M etabolic syndrome (MetS) refers to a set of metabolic disorders. Liver, as "the metabolic center," is involved in the development of obesity and lipid disorders. (1-3) Higher dietary cholesterol anticipates a higher risk of cirrhosis and nonalcoholic fatty liver disease, inkling strong threats to people health. (4)(5)(6) In hepatocytes, cholesterol homeostasis is maintained by a complex network involving cholesterol uptake, synthesis, intracellular transport, and excretion. (7) 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) is essential for cholesterol synthesis. Cholesterol 7a-hydroxylase (CYP7A1) is critical for the conversion of cholesterol into bile acids and is the first identified liver X receptor alpha (LXRa) target gene. (8) LXRs are ligand-activated nuclear receptors which act as cholesterol sensors (9) . ATP-binding cassette transporter (ABCA1) induces high-density

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