Cardiovascular disease (CVD) is the most important chronic noncommunicable disease threatening human life and health worldwide [1]. Atherosclerotic cardiovascular diseases (ASCVDs), such as ischemic heart disease and ischemic stroke, are an important component of CVD [2]. In China, ASCVD is the top cause of death among urban and rural residents and accounts for more than 40 % of total deaths [3]. In recent years, the ASCVD burden in China has continued to increase, and the prevention and control of ASCVD remain important problems [3].

The underlying pathogenesis of atherosclerosis (AS), the pathologic basis of ASCVD, includes disturbances in lipid metabolism and an adverse immune response to chronic inflammation of the arterial wall. Sites of disturbed laminar flow are prone to endothelial damage, which leads to the subendothelial accumulation of low-density lipoproteins (LDLs). Oxidatively modified lipids and LDLs contribute to endothelial immune cell infiltration, and lipid-laden macrophage-like foam cells form early atherosclerotic lesions [4]. Evidence from epidemiologic, genetic, and clinical intervention studies amply confirms that LDL cholesterol (LDL-C) is a pathogenic risk factor for ASCVD and that the extent and duration of exposure to LDL determine the risk of atherosclerotic vascular disease and its complications [5]. The 20th-century U.S. age-standardized coronary heart disease mortality rate has shown a declining inflection point since 1968, with a 1980–2000 decrease of more than 40 %, with control of risk factors contributing 44 %, and the largest contribution from a reduction in total cholesterol (TCHO) levels, with a weight of 24 % [6]. However, even with adequate lipid-lowering therapy (e.g., lifestyle improvement, statin therapy, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors), patients are still at risk of developing ASCVD [[7], [8], [9], [10], [11]]. Thus, identifying new gene targets that can influence cholesterol metabolism is an effective way to continue to lower LDL-C levels, inhibit the development of AS, and reduce the residual risk of CVD.

In the human genome, fewer than 2 % of transcripts can encode proteins, and there are many noncoding RNAs (ncRNAs). Long noncoding RNAs (lncRNAs), a class of ncRNAs consisting of more than 200 nucleotides, are highly tissue-specific and usually less conserved than other types of ncRNAs [12]. Emerging evidence suggests that lncRNAs can regulate gene expression through multiple mechanisms and contribute to the development of a variety of diseases. Several lncRNAs, including lncRNAs involved in cholesterol metabolism, inflammatory cascades and apoptosis, have been shown to regulate key steps in the progression of AS [13]. However, there is an urgent need to study lncRNAs. Our previous study confirmed that ApoE−/− mice overexpressing PSRC1 in the liver had lower lipid levels and a lower atherosclerotic burden than control mice [14]. We hypothesized that a PSRC1-induced lncRNA may be an effective target for the prevention and treatment of AS. Therefore, through high-throughput sequencing, a series of experiments and bioinformatics analysis, ENSMUST00000125548 was found to be the most significantly downregulated transcript in liver tissues of PSRC1-overexpressing ApoE−/− mice and to have no protein-coding ability; moreover, this lncRNA may be associated with dyslipidaemia and AS [15]. ENSMUST00000125548 was named Liver Expression by PSRC1 Induced Specifically (LEPIS). However, the pathobiological role of LEPIS remains unclear and should be investigated. The aim of this study was to investigate the mechanism by which LEPIS regulates cholesterol metabolism and the progression of ankylosing spondylitis and to provide new evidence for further reducing plasma lipid levels or obtaining effective strategies for the prevention and treatment of AS.

In our study, the role of LEPIS and its pathways were thoroughly investigated. We found that 1) overexpression of LEPIS or tropomodulin 4 (TMOD4) in the liver promotes the occurrence of AS and reduces plaque stability; 2) LEPIS interacts with the RNA-binding protein (RBP) human antigen R (HuR) to regulate the expression of TMOD4; 3) LEPIS promotes the shuttling of HuR from the nucleus to the cytoplasm, and HuR binds TMOD4 mRNA and regulates its stability, which is a classic mechanism by which HuR exerts its biological effects [[10], [11], [12]]; and 4) TMOD4 binds to the promoter of PCSK9 to upregulate PCSK9 expression, and the region of HuR that binds to LEPIS and the region of TMOD4 that binds to PCSK9 promoter were identified.