HNF4A-AS1 promotes hepatic steatosis in metabolic dysfunction-associated steatotic liver disease by driving HNF4A degradation

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a significant public health concern. Accumulating evidence suggests that long noncoding RNAs are dysregulated in MASLD. However, the roles and underlying mechanism of long noncoding RNAs in MASLD progression have not been fully elucidated. Here, we investigated the liver-specific functions of hepatocyte nuclear factor 4 α antisense 1 (HNF4A-AS1) and its mouse homolog, HNF4A opposite strand (Hnf4aos), in the pathogenesis of MASLD. HNF4A-AS1 and Hnf4aos were significantly upregulated in MASLD and diet-induced obese mice, respectively. Functionally, liver-specific knockdown of Hnf4aos reduced blood glucose levels and improved Insulin sensitivity in the MASLD mouse model. Similarly, HNF4A-AS1 knockdown suppressed lipid droplet formation, intracellular triglyceride accumulation, and total Cholesterol production in free fatty acid-induced HepG2 cells. Conversely, HNF4A-AS1 overexpression produced the opposite effects. Mechanistically, HNF4A-AS1 bound to the HNF4A protein and recruited heterogeneous nuclear ribonucleoprotein C (HNRNPC), thereby promoting HNF4A protein degradation. Taken together, our findings highlight the critical role of HNF4A-AS1 in MASLD progression and indicate that repressing HNF4A-AS1/HNF4A axis might be a potential therapeutic strategy for MASLD. SIGNIFICANCE STATEMENT: Long noncoding RNA HNF4A-AS1 and its mouse homolog, Hnf4aos, are upregulated in metabolic dysfunction-associated steatotic liver disease (MASLD) progression. Knockdown of HNF4A-AS1 or Hnf4aos alleviates MASLD progression in vitro or in vivo. HNF4A-AS1 interacts with HNF4A and promotes its protein degradation via HNRNPC, therefore aggravating MASLD progression.

HNF4A; HNF4A-AS1; HNRNPC; Hnf4aos; Long noncoding RNA; Metabolic dysfunction–associated steatotic liver disease.