The long non-coding RNA CidecAS regulates hepatocyte lipid metabolism via the alpha-1 subunit of Na⁺/K⁺-ATPase

The rising prevalence of metabolic-associated fatty liver disease (MAFLD) poses a serious public health threat, while long non-coding RNAs, key regulators of hepatic lipid metabolism, are closely linked to its development and progression. This study identified a novel MAFLD-associated antisense lncRNA, lnc-CidecAS, aiming to characterize its molecular structure and elucidate its regulatory role in hepatic lipid metabolism.

The sequence characteristics and coding potential of lnc-CidecAS were determined using RACE technology and flag-tagged expression vectors. Overexpression in AML12 hepatocytes was conducted to assess its effects on lipid metabolism-related genes and extracellular triglyceride (TG) levels. Both aged mice and HFD-induced obesity models were utilized for in vivo validation. Physiological parameters from blood, liver, and muscle tissues were measured after adeno-associated virus-mediated delivery of lnc-CidecAS to evaluate systemic lipid metabolism. Mechanistically, ChIRP-MS was employed to identify lnc-CidecAS interacting proteins, and the functional interaction with ATP1a1 was confirmed through siRNA knockdown and enzymatic activity assays.

Inc-CidecAS was primarily localized in the cytoplasm. Its overexpression in AML12 cells significantly reduced extracellular TG levels while upregulated key lipid metabolism genes (AMPK, ATGL, HSL, CPT1 and ACOX1). In vivo, lnc-CidecAS expression decreased under fasting conditions, declined with age, and showed a negative correlation with blood lipid levels. Overexpression of lnc-CidecAS reduced body fat and serum lipid concentrations in mice. In this HFD-induced obesity model, hepatic-specific overexpression of lnc-CidecAS markedly alleviated fat deposition in the liver and muscle, concurrently lowering serum TG and total cholesterol. Mechanistic studies revealed that lnc-CidecAS binds to ATP1a1, enhancing its gene expression and enzymatic activity, thereby promoting lipid metabolism.

Our study reveals the regulatory role of lnc-CidecAS in hepatocyte lipid metabolism, and reveals its molecular mechanism via interaction with ATP1a1, identifying a novel lnc-CidecAS-ATP1a1 regulatory axis. This discovery expands our understanding of how lncRNAs cooperate with proteins to regulate cellular metabolism. Consequently, targeting this pathway provides a theoretical foundation for developing precise therapies against MAFLD and related metabolic disorders.