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

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. Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a growing global health issue affecting millions and leads to severe liver conditions. Researchers explored new ways to treat MASLD by studying a molecule called Gm35585. In their study, they used mice fed a high-fat diet to mimic human liver disease. They found that Gm35585 helps to break down harmful fats in the liver by activating a protein called EHHADH, which is involved in fat metabolism. This process reduces fat accumulation in the liver, potentially slowing disease progression. They concluded that Gm35585 could be a promising target for developing new MASLD treatments. Their findings suggest that enhancing the activity of EHHADH through Gm35585 might offer a new therapeutic strategy. Future research could focus on how this approach can be applied to human treatments for fatty liver disease. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.