2. Academic Validation
  3. LncRNA Gm35585 transcriptionally activates the peroxidase EHHADH against diet-induced fatty liver

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

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. lyzhang@cpu.edu.cn.
  • 3 Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, China. lyzhang@cpu.edu.cn.
  • 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. beaglejiang@cpu.edu.cn.
  • 5 Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing, China. beaglejiang@cpu.edu.cn.
  • 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. yuqinwei7213@cpu.edu.cn.
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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