Unraveling the Regulatory Impact of LncRNA HNF1AOS1 on Hepatic Homeostasis in Mice
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ABSTRACT:
PROVIDER: PRJNA1199990 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31768824.fastq.gz | Fastqsanger.gz | |||
| SRR31768825.fastq.gz | Fastqsanger.gz | |||
| SRR31768826.fastq.gz | Fastqsanger.gz | |||
| SRR31768827.fastq.gz | Fastqsanger.gz | |||
| SRR31768828.fastq.gz | Fastqsanger.gz |
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Project description:Abstract: Long noncoding RNAs (lncRNAs) play significant roles in tissue development and disease progression and have emerged as crucial regulators of gene expression. The hepatocyte nuclear factor alpha antisense RNA 1 (HNF1A-AS1) lncRNA is a particularly intriguing regulatory molecule in liver biology that is involved in the regulation of cytochrome P450 enzymes via epigenetic mechanisms. Despite the growing recognition of lncRNAs in liver disease, the comprehensive role of HNF1A-AS1 in liver function remains unclear. This study aimed to investigate the roles of the mouse homolog of the human HNF1A-AS1 lncRNA HNF1A opposite strand 1 (HNF1AOS1) in liver function, gene expression, and cellular pro-cesses using a mouse model to identify potential therapeutic targets for liver disor-ders. Knockdown of HNF1AOS1 was performed in in vitro mouse liver cell line using siRNA and in vivo livers of AAV-shRNA complexes. Changes in the global expression landscapes of mRNA and proteins were revealed using RNA-seq and proteomics, respectively. Changes in the selected genes were further validated by real-time quantitative polymerase chain reaction (RT-qPCR). Phenotypic changes were assessed by histological and absorbance-based assays. After the knockdown of HNF1AOS1, RNA-seq and proteomics analysis revealed differential gene expression of mRNAs and proteins involved in the processes of molecular transport, liver regeneration, and immune signaling pathways. Downregulation of ABCA1 and SREBF1 in-dicates its role in cholesterol transport and fatty acid and triglyceride synthesis. Additionally, significant reductions in hepatic triglyceride levels were observed in the HNF1AOS1-knockdown group, underscoring its impact on lipid regulation. Notably, the knockdown of HNF1AOS1 also led to an almost complete depletion of CYP7A1, the rate-limiting enzyme in bile acid synthesis, highlighting its role in cholesterol homeostasis and hepatotoxicity. Histological assessments confirmed these molecular findings, with increased hepatic inflammation, hepatocyte swelling, and disrupted liver architecture observed in the HNF1AOS1-knockdown mice. This study illustrated that HNF1AOS1 is a critical regulator of liver health, influencing both lipid metabolism and immune pathways. It maintains hepatic lipid homeostasis, modulates lipid-induced inflammatory responses, and contributes to viral immunity, indirectly affecting glucose and lipid metabolic balance.
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Project description:Unraveling the molecular mechanism of hyperlipidemia using integrated lncRNA and mRNA microarray data
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Project description:miR-33 is an intronic microRNA within the gene encoding the SREBP2 transcription factor. Like its host gene, miR-33 has been shown to be an important regulator of lipid metabolism. Inhibition of miR-33 has been shown to promote cholesterol efflux in macrophages by targeting the cholesterol transporter ABCA1, thus reducing atherosclerotic plaque burden. Inhibition of miR-33 has also been shown to improve high-density lipoprotein (HDL) biogenesis in the liver and increase circulating HDL-C levels in both rodents and nonhuman primates. However, evaluating the extent to which these changes in HDL metabolism contribute to atherogenesis has been hindered by the obesity and metabolic dysfunction observed in whole-body miR-33–knockout mice. To determine the impact of hepatic miR-33 deficiency on obesity, metabolic function, and atherosclerosis, we have generated a conditional knockout mouse model that lacks miR-33 only in the liver. Characterization of this model demonstrates that loss of miR-33 in the liver does not lead to increased body weight or adiposity. Hepatic miR-33 deficiency actually improves regulation of glucose homeostasis and impedes the development of fibrosis and inflammation. We further demonstrate that hepatic miR-33 deficiency increases circulating HDL-C levels and reverse cholesterol transport capacity in mice fed a chow diet, but these changes are not sufficient to reduce atherosclerotic plaque size under hyperlipidemic conditions. By elucidating the role of miR-33 in the liver and the impact of hepatic miR-33 deficiency on obesity and atherosclerosis, this work will help inform ongoing efforts to develop novel targeted therapies against cardiometabolic diseases.
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