Mechanistic Studies Of A Long Non-coding RNA APOA4-AS In The Regulation Of Hepatic Lipid Metabolism

Dysregulated lipid homeostasis in the liver is closely associated with obesity.It is important to study the molecular mechanisms of dysregulated lipid metabolism in obesity.Long noncoding RNAs(lncRNAs)are a novel group of universally present,non-coding RNAs(>200 nt)that are increasingly recognized as key regulators of many physiological and pathological process atboth transcriptional and post-transcritional levels.Whether lncRNA is invovled in obesity induced dysregulation of lipid homeostasis in the liver is largely unknown.In this study,we identified 15 lncRNAs which were abnormally expressed in the liver of db/db obesity mice model.Gene enrichment(GO)analysis shows that these lncRNAs neighboring genes are associated with lipid metabolism.One of these lncRNAs GM10680 was named as APOA4-AS because it is transcribed from the opposite strand of APOA4 gene locus.Both APOA4-AS and APOA4 expression are abnormally elevated in obesity.APOA4-AS specifically regulates APOA4 expression,and further regulates plasma TG levels.APOA4-AS transcript directly binds to mRNA stabilizing protein HuR,and deletion of HuR reduces both APOA4-AS and APOA4 transcript levels.In summary,we first found and named a new lncRNA,APOA4-AS that preserves the specific and potential biological function in regulating APOA4 expression and plasma TG levels,providing novel molecular mechanisms that can be applied to biomedical and therapeutic application for metabolic diseases including type 2 diabetes.