LncRNA Gm35585 transcriptionally activates the peroxidase EHHADH against diet-induced fatty liver

  • Exp Mol Med. 2025 Mar;57(3):652-666. doi: 10.1038/s12276-025-01420-5.
Ming Jin  1 ,  Qian Lu  1 ,  Ninglin Xia  1 ,  Xue Fan  1 ,  Ziling Zhang  1 ,  Xiaofei Huang  1 ,  Li Sun  1 ,  Luyong Zhang  2  3 ,  Zhenzhou Jiang  4  5 ,  Qinwei Yu  6
Affiliations
  • 1. New Drug Screening and Pharmacodynamics Evaluation Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
  • 2. New Drug Screening and Pharmacodynamics Evaluation Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China. [email protected].
  • 3. Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, China. [email protected].
  • 4. New Drug Screening and Pharmacodynamics Evaluation Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China. [email protected].
  • 5. Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing, China. [email protected].
  • 6. New Drug Screening and Pharmacodynamics Evaluation Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China. [email protected].
PMID: 40082671 DOI: 10.1038/s12276-025-01420-5
Abstract

Metabolic-dysfunction-associated steatotic liver disease is one of the most common chronic liver diseases worldwide and has no approved treatment thus far. Here we report that the hepatic overexpression of Gm35585, a novel lncRNA downregulated in the livers of mice fed a high-fat diet, is functionally important in alleviating hepatic lipid accumulation pathologies. Gm35585 activates the Peroxisome Proliferator-activated Receptor α (PPARα) signaling pathway and promotes the expression of downstream PPARα-target gene, enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase (EHHADH), which is one of the four Enzymes of the peroxisomal β-oxidation pathway. Activation of EHHADH promotes the oxidation of long-chain fatty acids (LCFAs), and the increased levels of hepatic LCFAs contribute to metabolic-dysfunction-associated steatotic liver disease. Mechanistically, Gm35585 binds to retinoid X receptor α (RXRα) and then forms a PPARα/RXRα heterodimer with PPARα and guides the heterodimer to recognize the promoter of EHHADH, which is called Peroxisome Proliferator-activated Receptor response element, causing transcriptional activation of EHHADH. Taken together, Gm35585 is a hepatic lipid metabolism regulator that activates EHHADH transcription, promoting peroxisomal β-oxidation of LCFAs and ultimately ameliorating diet-induced fatty liver.

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